Multicenter clinical evaluation of a multi-dose formulation of propofol in the dog

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RESEARCHARTICLEOpenAccessMulticenterclinicalevaluationofamulti-dose formulationofpropofolinthedogKhursheedRMama1*,JamesSGaynor2,RalphCHarvey3,SheilahARobertson4,RobbinLKoenig5andElizabethMCozzi6AbstractBackground: Propofolisawidelyusedinjectableanestheticagentforinductionandshort-termmaintenancein dogs.Amulti-doseformulationofpropofol(MDP)hasbeendevelopedwhichincludes2%benzylalcoholasa preservative.Inordertodocumenttheuseoftheproductunderclinicalconditions,MDPwastestedinaprospective clinicaltrialconductedatsixsiteswithintheUnitedStates.Onehundredthirty-eighthealthy,client-owneddogswere assignedtooneofsixtreatmentgroupsbasedonpremedicants(none,acepromazine/buprenorphine,midazolam/ buprenorphine,medetomidine/buprenorphine)andmaintenanceagents(MDP,inhaledanesthetic).Anesthesiawas inducedbytheintravenousadministrationofMDPgiventoeffect.Physiologicalindicesincludingheartrate,respiratory rateandbloodpressureweremonitoredpriortoandduringanesthesiainduction,maintenanceandrecovery.Adverse events,definedforseveritybypre-establishedlimitsofthesephysiologicalvalues,aswellassideeffects,definedasany observationoutsidethenormalrange,werenoted. Results: Themeanintubationdosewas7.62.1mg/kgforMDPaloneand4.71.3,4.01.0mg/kgand 3.21.4mg/kgwhenbuprenorphinewasusedincombinationwithmidazolam,acepromazineandmedetomidine, respectively.Ofthe32adverseevents,apnea(12incidents),bradycardia(9incidents)andhypotension(7incidents) weremostfrequentlyrecorded.Emesis,cyanosisandseconddegreeheartblockwereeachnotedonceand successfullyresolved.Thecauseofasingledeath2dayspost-anesthesiawasassessedasasurgicalcomplication. Conclusions: MDPwasfoundtobeacceptableforuseinhealthydogsforinductionandshorttermmaintenance ofanesthesiawhenusedaloneandincombinationwithpremedicantsandinhaledanesthetics. Keywords: Dog,Anesthesia,Clinicaltrial,PropofolBackgroundAformulationofpropofolintendedforone-timeusein dogshasbeenapprovedintheUnitedStatessince1996 [1].Sinceitsintroduction,propofolhasgainedwidespreadacceptanceasananesthesiainductionandshorttermmaintenanceagentindogs.Thedrughasarapid onsetofactionandwhenusedforshort-termmaintenance,recoverytimesandqualityareconsideredfavorable relativetoinhaledanestheticagents[2]. Thesesingle-useinjectablepreparationsofpropofol availableforveterinaryuseareoil-in-wateremulsions containingnopreservative[1,3].Hencethelabelrecommendationisthatanydrugthathasnotbeenusedwithin sixhoursafterthebottleorvialhasbeenpenetrated shouldbediscardedtominimizetheriskofcontamination andpossibleadverseconsequencestothepatient.This canresultinbothdrugwasteandfinanciallossinmany veterinarypracticesituations.Aformulationallowing penetratedbottlestobestoredandre-usedforaperiod oftimewithoutsignificantriskofcontaminationwould minimizetheseconcerns. Onesuchalternativeformulationofpropofolhasbecome availableforintravenoususeindogs.Thepreservative inthisformulationis2%benzylalcohol,acompound thathasbeenusedasapreservativeinotherinjectable solutions(e.g.,atropine)availableforintravenoususe.Ithas beenshowntobehighlyeffectiveagainstgrampositive bacteria,moldsandfungi,andmoderatelyeffectiveagainst gramnegativeorganisms[4].Theadditionofbenzylalcoholasapreservativetotheoriginalpropofolformulation *Correspondence: kmama@colostate.edu1DepartmentofClinicalSciences,CollegeofVeterinaryMedicineand BiomedicalSciences,ColoradoStateUniversity,FortCollins,CO80523,USA Fulllistofauthorinformationisavailableattheendofthearticle 2013Mamaetal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Mama etal.BMCVeterinaryResearch 2013, 9 :261 http://www.biomedcentral.com/1746-6148/9/261

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hasresultedinaproductthatislabeledfora28-dayinuseshelflife[5].Toxicitystudiesconductedunderlaboratoryconditionsonthisformulationshowednosignificant adverseeventswhenadministeredtodogsatupto3times thelabeledinductiondose[5]. Thepresentstudywasdesignedtodocumenttheuse ofMDPcontaining2%benzylalcoholindogsunder clinicalconditions.MethodsAnimalsOnehundredandthirtyeightclient-owneddogswere enrolledinthisstudywhichwasconductedatsixsites, includingthreeuniversityveterinaryhospitalsandthree privatelyownedveterinaryclinics.Priortoinclusiona physicalexaminationwasperformedonalldogsandresults ofacompletebloodcountandserumchemistrywere evaluated.Animalsthathadlaboratoryvaluesoutside thenormalrangeforagivenfacility,werepregnant,had receivedaninvestigationaldrugorhadbeenenrolledin aninvestigationaldrugstudywithin30days,orwerecategorizedasASACategoryIVorVwereexcluded.Owner consentforparticipationwas obtainedpriortoenrolling eachanimalinthestudy.Institutionalanimalcareand useorhospitalmanagementcommitteeapprovalwas alsoobtainedatColoradoStateUniversity,theUniversity ofTennessee,theUniversityofFloridaandtheprivateveterinarypracticesparticipatinginthestudy.Onceenrolled, demographicdataincludingage,breed,genderandbody weightwererecorded.StudydesignThisstudywasdesignedtoincludeatleast100casesin whichMDPwasutilizedastheinductionagentpriorto maintenancewithMDPoraninhalantanesthetic.This numberisconsideredadequatebyregulatoryagenciesto determinesafetyforveterinaryproductsunderconditions ofuse.Dogswereassignedtooneofsixtreatmentgroups basedonpremedicantcombinationsandmaintenance agentstheyweretoreceive(Table1).Groupassignments werenotrandomizedbutratherwerelefttothediscretion oftheinvestigatorwhoevaluatedthepatient ’ sphysical statusandlaboratoryfinding sandconsideredthenature anddurationoftheproceduretobeperformed.The useofanticholinergicsduringanyphaseofanesthetic managementwasalsopermittedatthediscretionofthe on-siteinvestigatorandinjectablecarprofenwasallowed post-operatively. Duetothenecessityofdetermininganappropriate anesthesiaprotocolforeachdog,thestudywasnot blinded.Inadditiontochoiceofthetreatmentgroupto whichapatientwasassigned,theon-siteinvestigator wasfreetochoosethedoseandrouteofdrugsusedfor premedicationineachdogwithinbroadlyestablished guidelinesdesignedtobeinkeepingwiththewiderange ofdosagesusedinclinicalpractice.Thisinformation wasrecordedforallanimals. Inanimalsreceivingpremedi cants,anesthesiainduction withMDPwasinitiatedafterthefulleffectofpremedicants waspresent;MDPwasdeliveredoveraperiodof60 – 90secondsviaanintravenous(IV)catheteruntilendotrachealintubationcouldbe achieved.Thestarttimeand doseofpropofolrequiredforanesthesiainductionanddurationoverwhichthedosewasadministeredwererecorded. TopermitevaluationofthesafetyandefficacyofMDPin thefaceofrepeatedwithdrawals,eachvialwasnumerically identifiedandthedurationofindividualvialusageandthe numberofwithdrawalspervialwerenoted. Anesthesiawasmaintainedwithsuccessiveintravenous injectionsofMDP(groups1 – 3)orwitheitherisoflurane orsevoflurane(groups4 – 6)inoxygenadministered usingasemi-closedrebr eathingornon-rebreathing (Bain)circuitandoutofcirclevaporizerbasedonanimalsizeandindividualpracticestandards.Animals wereallowedtobreathespontaneously.Maintenance agents(MDPorinhaledanesthetic)wereadministered tomaintainanadequateplaneofanesthesiaforthe procedurebeingperformed;thedoseandtimeofadditionalMDPadministrationwasnotedandthevaporizer setting(fortheinhaledagent)wasrecordedatfixedintervals.Theuseofpropofoltosupplementinhalation anesthesiaintheeventofasuddenlighteningofthe anestheticplanewaspermittedandrecorded.Inaneffort toallowforthevariabilityinclinicalpractice,oxygen supplementationwasoptionalfordogsinthepropofol maintenancegroups.BehavioralandphysiologicvariablesThequalityofinductionandtimetointubationfrom startofMDPadministrationwererecorded.Timesto extubation,sternalrecumbencyandstandingfollowing thelastdoseofMDPorfromdiscontinuationofinhalationagentadministrationwerealsonotedforallanimals.Investigatorsassignedsubjectivescoresreflecting thequalityofinduction,maintenanceandrecovery (Excellent,Good,Fair,Poor)basedonpreviouslypublishedscales[6].Forexample,anexcellentinduction wouldincludeasmoothrapidtransitiontorecumbency withoutvocalizationandmusclemovement,whereasa poorinductionwouldincludemusclefasciculation, urinationordefecationandinap propriatevocalization.The durationandtypeofinterventionorsurgicalprocedure werealsonoted. Totalanesthesiadurationwasconsideredfromthe timeofintubationtotheconclusionofdrugadministration(lastdoseofMDPforgroups1 – 3andvaporizer offforinhaledanesthesiagroups4 – 6).Thedurationof druginducedrecumbencyfollowingtheinductiondoseMama etal.BMCVeterinaryResearch 2013, 9 :261 Page2of12 http://www.biomedcentral.com/1746-6148/9/261

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ofMDPwascalculatedforthoseanimalsmaintainedon propofol(groups1 – 3)usingthetimefromintubation tothetimethatthefirstadditional(maintenance)dose wasadministered. Rectaltemperature(T),heartrate(HR),respiratory rate(RR),mucusmembranecolor,indirectsystolic(S), diastolic(D)andmean(M)arterialbloodpressure(BP) wererecordedpriortopremedicationandagainpriorto anesthesiainduction.Heartratewaseitherobtainedby palpationofthepulseorrecordedfromanoscillometric non-invasiveBPmonitorusedtoobtainS,DandMarterial pressurespriortoandduringa nesthesia;cuffsizeapproximated40%ofthecircumferenceofthelimbandwasplaced proximaltothecarpusorhock.Electrocardiographic (ECG)monitoringwasnotrequiredforthestudy,but wasperformedinsomeanimalsatthediscretionof theinvestigator.Hemoglobinsaturationwithoxygen (asmeasuredbyapulseoximeter,SpO2)andend-tidal carbondioxide(asmeasuredbyacapnograph,ETCO2) weremonitoredcontinuouslyandrecordedimmediately followingintubationandagainat5,10,20,30minutes afterintubationandthenat30minuteintervalsduring anesthesiamaintenance.Re spiratoryratewasmeasured byobservationofthechestwallorrecordedfromthe capnograph.Athermistororthermometerwasplaced intheesophagusorrectum,respectively,torecordbody temperatureattheaforementionedtimepointsduring anesthesiamaintenance. Observationswhichincludedpredeterminedparameters ofcentralnervoussystemactivity(e.g.,excitation,excessivedepression/death),a ndlimitsforcardiovascular (e.g.,hypotension,arrhythm ias)andrespiratory(e.g., tachypnea,apnea,hemoglobinoxygensaturation)system parameters,wererecordedifobservedpriortoandat anytimeduringanesthesiaandrecoveryuntilthepatient reachedsternalrecumbency.Observationsofphysiological valuesoutsidethenormalrangewereconsideredside effects.Adverseeventsweredefinedasextremesinvalues orprolongeddurationfortheseobservations:apneafor greaterthan120seconds,aheartratelessthan50beats perminute,meanarterialpressurelessthan50mmHg, anyabnormalECGrhythmwhichuponevaluationwas consideredbythesiteinvestigatortobeharmfultothe patient,hemoglobinsaturationwithoxygenoflessthan 80%(foranyduration)orbetween80and90%formore than3minutes.Additionalsideeffectssuchasexcessive salivationandemesiswerealsonoted.StatisticalanalysisDifferencesamongthesixtreatmentgroupsinpatient characteristicswerestatisticallyevaluatedviaeither chi-squareanalysis(genderandASAstatus)orone-factor analysisofvariancefollowedbyTukey ’ sprocedurefor pair-wisemeancomparisons(ageandweight). Dataoneachquantitativeresponsevariable(e.g.,time tosternalrecumbencyandHRattimesbothpriorto andfollowinginduction)werestatisticallysummarized (meanandstandarddeviation)andwereanalyzedvia analysisofvariance(ANOVA)withtreatmentgroupasa fixedeffectandalsostudysiteasarandomeffect.Because boththevariationamongsite sandtheinteractionbetween sitesandtreatmentgroupswerefoundtobeuniformly non-significant(p>0.10),thefinalANOVAmodelincluded onlytreatmentgroupasafixedeffect.Thetimedrecovery variables(e.g.,timetosternalrecumbency)requiredalogarithmictransformationtosatisfytheANOVAassumption ofNormality,whichwasevaluatedviatheShapiro-Wilk test.Pair-wisecomparisonso ftreatmentgroupmeanswere Table1GroupclassificationsanddurationofproceduresGroupPreanestheticmedications1Maintenance agent Numberofdogs pergroup Durationofprocedure(min) MeanSDandrange21 NoneMultidosepropofol2314.615.8 0.3-62 2 Midazolam/buprenorphineMultidosepropofol2519.714.6 2-64 3 Acepromazine/buprenorphineMultidosepropofol2518.014.3 5-56 4 Midazolam/buprenorphineInhalant2241.118.4 10-75 5 Acepromazine/buprenorphineInhalant2273.653.1 20-203 6 Medetomidine/buprenorphineInhalant2138.320.4 7-981Anticholinergicswereconsideredoptionalforalltreatmentgroups.Anesthesiainalldogswasinducedwithmulti-dosepropofol.Seetextforaddit ionaldetail.2Statisticallysignificant(p<0.05)differencesbetweentreatmentgroupmeansfordurationofprocedure:4>1and5>1,2,3,4,6.Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page3of12 http://www.biomedcentral.com/1746-6148/9/261

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basedontheTukey-Kramerad justmentofprobabilityvaluesformultipletesting.Apvalueof 0.05wasconsideredsignificant.ResultsBecauseboththevariationamo ngsitesandtheinteraction betweensitesandtreatmentgroupsintheANOVAofeach quantitativevariablethatin cludedstudysiteasarandom effectwerefoundtobeuniformlynon-significant(p>0.10) theresultspresentedherearethosefromtheANOVA whichincludedonlytreatmentgroup. Patientdemographics(age,weight,gender)andASA statusarepresentedinTable2.Briefly,patientsranged inagefrom0.25to17yearsandrepresentedmultiple breeds.Bothgenderswerewellrepresented.Themajority ofpatientswereclassifiedasASAIandtheremainderas ASAII.Amongthebreedsincludedinthestudy,there were34mixedbreed,13LabradorRetrievers,7Yorkshire Terriers,5eachofKingCharlesSpaniel,GoldenRetriever, JackRussellTerrierandMiniatureorToyPoodle,and34 otherbreedswhichwererepresentedby4orlessindividuals.Nosignificantdifferencesinpatientnumbers,ASA statusorweightwereidentifiedacrossgroups.Themean ageofgroup2,inwhichmassremovalswerecommon, wasgreaterthanthoseofgroups4and5,inwhichspays andneuterswerecommon.Also,differencesingender uponenrollmentwereobservedbetweengroups;there werestatisticallysignificantdifferencesinnumberof intactversusspayed/neuteredanimals,butnotmales versusfemales.Nostatisticallysignificantdifferencesin baselineT,HR,BPorRRwereidentifiedacrossgroups exceptforadifferenceinbaselineRRbetweenanimals ingroup5(acepromazine/buprenorphine)andgroup6 (medetomidine/buprenorphine)(Table3). Proceduresthatdogsunderwentduringthisstudy includedcastration(35),dentalprophylaxisand/ortooth extraction(33),massremoval(19),radiographs(13),surgicalovariohysterectomy(laparotomy)(10),arthrocentesis, earflush,grooming/nailtrim(3),gastroscopy,auricular hematomarepair,cutaneousbiopsy,jointinjections,mass/ skintagremoval(2)andadiposecollection,arthroscopy/ TPLOplateremoval,endoscopy,enterotomy,entropion repair,epiduralstemcellinjection,gastrotomy,laparoscopic ovariohysterectomy,andallergytesting,shockwave therapy,skintestingandsplintremoval(1).Theduration ofprocedures(averagetimespergrouplistedinTable1) rangedfromlessthanoneminuteto203minutes. Therangeofpremedicationdosesadministeredto individualanimalsacrossallgroupsandstudysiteswere: acepromazine(0.01-0.63mg/k g[0.005-0.29mg/lb]SC, IVorIM);atropinesulfate(0.02-0.075mg/kg[0.0090.03mg/lb]SCorIM);buprenorphine(0.01-0.033mg/kg [0.0045-0.015mg/lb]SCorIM);medetomidine(0.0040.028mg/kg[0.002-0.013mg/lb]IVorIM)andmidazolam hydrochloride(0.02-0.48mg/kg[0.009-0.22mg/lb]SC,IV orIM).Basedonpair-wisemeancomparisonsfollowing ANOVA,thedoseofacepromazinereceivedindogsinthe MDPmaintenancegroupwasfoundtobesignificantly Table2PatientdemographicsbytreatmentgroupGroup123456Total N232525222221138 Age(Years)1Mean4.657.704.843.952.875.675.00 SD3.973.424.163.882.675.244.17 Range(0.8-14.0)(0.8-13.5)(0.3-12.0)(0.3-12.5)(0.3-10.0)(0.3-17.0)(0.3-17.0) Weight(kg)1Mean15.521.615.714.020.714.817.1 SD10.614.513.49.610.59.911.8 Range(2 – 31)(3 – 52)(2 – 46)(3 – 32)(5 – 41)(2 – 33)(2 – 52) Gender(N[%Total])2Male02(8)8(32)8(36)13(59)7(33)38(28) Malecastrated9(39)10(40)10(40)2(9)2(9)7(33)40(29) Female3(13)01(4)4(18)5(23)2(10)15(11) Femalespayed11(48)13(52)6(24)8(36)2(9)5(24)45(33) ASAstatus(N[%Total])2I18(78)16(64)19(76)16(73)19(86)13(62)101(73) II5(22)9(36)6(24)6(27)3(14)8(38)37(27)1Mean,standarddeviation(SD)andrangeforageandweight;significantdifferencesamonggroupsinmeanagewithgroup2>groups4and5(p<0.05).2NreferstothenumberofanimalsineachcategoryofgenderandASAstatus;significantdifferencesamonggroupsingender(p<0.01).Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page4of12 http://www.biomedcentral.com/1746-6148/9/261

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Table3MeanSDofphysiologicalvariablemeasurementsbytreatmentgroupVariableGroupImmediately priorto premedication Immediately priorto induction Immediately postinduction Minutespost-induction 5min10min20min30min Heartrate (beatspermin) (N)11NA(0)117.232.6(22)118.027.1(21)123.726.2(20) 119.728.7(18)112.921.4(10)114.818.5(5) 2113.031.0(25)112.832.2(25)116.336.2(23)110.028.7(21) 112.125.4(19)101.826.7(17)94.218.5(14) 3107.628.9(25) 96.925.8(25)99.534.1(25) 101.030.7(23) 100.326.3(24)103.422.3(16)99.419.1(7) 4127.831.3(22)135.935.0(22)146.828.2(20)146.830.9(19) 141.727.4(18)126.726.0(18)123.120.1(19) 5116.818.9(22)145.144.0(22)142.937.3(21)158.132.0(20) 134.225.2(21)124.223.6(21)114.523.4(20) 6115.633.5(21) 88.436.9(21)94.927.4(20) 104.126.3(19) 102.622.3(19)103.120.4(19)95.118.8(18) Statistical results2None4>(3,6); 5>(2,3,6) 4>(2,3,6); 5>(3,6) 4>(2,3,6); 5>(1 – 3,6) 4>(2,3,6); 5>(3,6) 4>(2,3,6); 5>(3,6) 4>(2,3,6); 5>(3,6) Respiratoryrate (breathspermin) 1NA41.613.828.624.031.216.732.326.622.611.523.59.8 241.113.736.414.926.115.527.118.730.719.932.118.427.015.2 330.613.730.313.323.015.224.611.629.311.627.810.826.415.3 434.812.034.411.823.918.825.713.324.919.923.321.726.516.9 528.66.229.917.512.69.817.415.317.011.614.06.312.68.6 642.417.530.723.612.24.513.86.413.87.114.76.712.95.9 Statistical results26>5None1>(5,6)(1,2)>6(1,2,3)>6(2,3)>5;2>6(2,3,4)>5; (2,4)>6 Systolicblood pressure(mmHg) 1NA148.028.8128.119.9128.232.8127.221.5115.718.2112.814.8 2141.821.3135.030.6119.624.7113.224.0115.328.0111.120.8115.924.4 3136.623.4126.233.6112.321.0108.818.5112.218.7106.917.3106.115.5 4129.623.1137.424.9122.721.3108.815.3106.417.3105.626.7108.631.8 5137.222.3134.516.5124.415.2112.117.1100.911.199.814.7101.313.7 6137.126.6128.934.5125.940.1116.239.4127.952.1124.536.2116.626.3 Statistical results2NoneNoneNoneNone(1,6)>56>5None Diastolicblood pressure(mmHg) 1NA91.533.681.121.179.732.282.822.669.414.974.023.8 289.018.486.822.877.127.571.216.273.319.071.822.975.121.8 392.426.176.927.470.424.063.518.563.815.457.721.358.715.5 487.125.890.628.676.217.262.911.657.915.457.619.860.621.6 598.818.389.017.874.319.061.316.655.14.653.99.153.28.6 698.425.091.431.390.033.676.835.288.244.479.229.271.820.5 Statistical results2NoneNoneNoneNone1>5;6>(3,4,5)6>(3,4,5)(2,6)>5 Meanblood pressure(mmHg) 1NA114.727.1100.217.7101.931.799.920.888.114.890.021.4 2108.917.3102.321.095.324.285.816.490.426.087.521.290.424.1 3107.824.896.227.986.321.383.716.485.513.978.420.781.116.3 4103.723.8109.825.294.418.778.013.677.815.476.619.177.822.0 5113.120.1105.614.392.018.079.717.472.48.969.59.570.310.4 6115.124.8107.131.5105.136.292.633.4105.644.999.530.590.919.3 Statistical results2NoneNoneNone1>(4,5)1>5;6>(4,5)6>(3,4,5)(2,6)>5 HbOxSat(%) 1NANA90.09.994.33.094.52.795.92.297.31.7 2NANA90.16.791.86.793.43.594.82.797.72.4 3NANA93.94.394.03.994.62.794.83.297.52.4 4NANA95.72.495.82.196.72.096.81.795.41.8 5NANA96.51.997.61.297.21.597.21.897.01.7 Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page5of12 http://www.biomedcentral.com/1746-6148/9/261

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higherthanfordogsmaintaine dwithinhaledanesthetics. Themeandosesofmidazolamandbuprenorphinedid notdiffersignificantlybetweengroupsassignedtoreceive thesedrugs. Propofoladministrationforanesthesiainductionbegan anaverageof27.6minutesafterpremedication.The meandoseofMDPgroupedbysedativeortranquilizer usedisshowninTable4.Dogsreceivingnopremedicationreceivedasignificantlyhighermeanpropofoldose (7.62.1mg/kg[3.41.0mg/lb])thanallothergroups. Dogsreceivingmedetomidineforpremedicationreceivedthelowestmeanpropofoldose(3.21.4mg/kg [1.40.6mg/lb])foranesthesiainductionwhichwasalso significantlylessthanthatfordogsreceivingmidazolam (4.71.3mg/kg[2.10.6mg/lb]),butnotacepromazine (4.01.0mg/kg[1.80.5mg/lb]).Actualadministration timeuntiltheanestheticendpointforintubationranged from30to145secondsresultinginratesofinjection between0.9to8.0mg/kg/min(0.4to3.6mg/lb/min). Investigatorsratedthequalityofinductionasexcellent in82(59%),goodin47(34%),fairin8(6%)andpoorin1 (<1%)ofthe138animalsincludedinthisstudy.Fourof thenineinductionsjudgedfairorpoorinvolveddogsthat werepremedicatedwithmidazolam/buprenorphineandin whomadditionalpropofolwasrequiredforanesthesia induction.Ingroupsmaintainedwithpropofol,themean durationofanesthesiaaftertheinitialorinductiondose (untilsubsequentdosing)was5.8,5.5and6.5minutes ingroups1,2and3,respectively. Thedurationofanesthesiaaftertheadministrationof eachindividualmaintenancedoseofMDPrangedfrom 1.7to20minutesinunpremedicatedanimals(group1) and1to12.5minutesinbothgroupsofpremedicated animals(groups2and3).Thetotalmaintenancetime (intubationtolastadministereddose)forgroups1 – 3 rangedfrom1.7to37minutes.Theaverageadditional propofoladministeredformaintenanceofanesthesiain group1dogswas3.21.7mg/kg(1.50.8mg/lb).Group Table3MeanSDofphysiologicalvariablemeasurementsbytreatmentgroup (Continued)6NANA95.63.696.02.495.72.696.52.696.52.6 Statistical results2--(4,5,6)>(1,2)(4,5,6)>(1,2)(4,5,6)>2; 5>3 5>(2,3)None End-tidal CO2(%) 1NANA28.97.931.78.332.57.936.35.540.39.2 2NANA34.812.734.18.038.29.238.09.440.412.2 3NANA31.69.935.99.836.07.237.79.647.09.6 4NANA34.612.237.29.436.89.936.68.738.75.7 5NANA30.57.933.76.336.55.937.44.638.44.4 6NANA37.09.241.47.340.89.342.08.043.88.2 Statistical results1--None6>16>1NoneNone Rectaltemp. (deg.F) 1NA101.70.7101.20.8100.90.9100.40.9100.11.299.81.0 2101.40.7101.30.7100.80.8100.40.7100.10.799.80.899.50.8 3101.30.8100.90.7100.30.8100.01.099.81.399.51.399.11.6 4101.50.8101.20.7100.31.3100.30.8100.20.899.60.999.01.0 5101.71.0101.30.8100.60.9100.40.9100.30.799.90.999.21.1 6101.90.6101.50.9100.71.3100.51.2100.51.3100.11.6100.01.5 Statistical results1None1>31>31>3NoneNoneNone1Numberofanimalsforphysiologicalvariablesmeasuredatagiventimepoint.2Includesallstatisticallysignificant(p<0.05)differencesbetweenmeansfortreatmentgroupsatagivenmeasurementtimepoint. Table4Meantotalmulti-dosepropofol(MDP)requiredforinductionofanesthesia,groupedbypremedicant1PremedicantNoneMidazolamAcepromazineMedetomidine Numberofanimals 23474520 TotalMDPdose(mg/kg)27.554.704.003.15 Standarddeviation 2.141.340.951.38 Range 4.6-16.02.2-8.31.8-5.11.7-7.51Sedativeandtranquilizersgivenincombinationwithbuprenorphine;useofanticholinergicswasoptional.Seetextforadditionaldetail.2Statisticallysignificant(p<0.05)differences:None>(Midazolam,AcepromazineandMedetomidine)andMidazolam>Medetomidine.Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page6of12 http://www.biomedcentral.com/1746-6148/9/261

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2and3dogsrequired1.71.1mg/kg(0.80.5mg/lb) and2.01.2mg/kg(0.90.5mg/lb),respectively.Thisaveragedtoameanmaintenancedoserateof0.48mg/kg/min (0.22mg/lb/min)ingroup1(non-premedicatedanimals) and0.31mg/kg/min(0.14mg/lb/min)and0.4mg/kg/min (0.18mg/lb/min)ingroup2(midazolam/buprenorphine) andgroup3(acepromazine/buprenorphine),respectively. Theseresultswerenotsignificantlydifferent.Thetotal maintenancedosesingroups1,2and3rangedfrom0 (noadditionalmaintenancedosesadministered)to 24.7mg/kgMDP.Theaveragetotaldoses(ranges)of MDP(inductionplusmaintenance),administeredto groups1,2and3were10.1(5.1-30.0),9.3(3.9-23.8)and 8.0(2.5-28.7)mg/kg,respectively. Ofthetwoinhaledanestheticsusedduringthecourse ofthestudy,isofluraneuseaccountedfor85.5%ofthe casesmaintainedbyinhalant.Totalmaintenancetime withinhalantanesthetics(groups4 – 6)rangedfrom16.2 to245minutes.Initialmeanvaporizersettingswere2.1% forisofluraneand3.7%forsevoflurane.Mid-maintenance vaporizersettingswere1.8%forisofluraneand3.5%for sevoflurane.Nineanimalsreceivedsupplementalpropofolduringinhaledanestheticmaintenancetoenhance thequalityofanesthesia.Apneaoccurredinoneanimal inconjunctionwiththeadministrationofasupplemental doseofMDP. Qualityofmaintenancewithpropofolalonewasrated asgoodorexcellentin86%ofpatientsoverall;100%of patientsingroup1and68and92%ofpatientsingroups 2and3,respectively.Ingroup2,qualityofmaintenancein 24%oftheanimalswasratedasfairand8%ratedaspoor. Qualityofmaintenancewasratedfairinasinglegroup3 animal(4%)andwasunrecordedinanotherone(4%). Mean(SD)recoverytimesarepresentedinTable5. Nostatisticallysignificantdi fferenceswerenotedintimeto extubation,andonlysporadic differencesbetweentreatmentgroupswerenotedfortimestosternalrecumbency (group2vs.group4)andtostanding(groups2and5vs. group1).Investigatorsevaluatedthequalityofrecoveryas goodtoexcellentin91,76and92%ofanimalsingroups1, 2and3,respectively,withtheremaininganimalsreceivinga ratingoffair.Indogsrecoveringfrominhalationanesthesia, thequalityofrecoverywasratedasgoodtoexcellentin82, 81and81%oftheanimalsingroups4,5and6,respectively. Elevenpercentofanimalsinthesegroupsreceivedarating offair,and5%(threeanimals)wereratedaspoor. Meanvaluesforphysiologicalparameterspriorto premedicationandanesthesiainductionandduringthe first30minutesofanesthesiaarepresentedinTable3. Differencesbetweengroupsobservedateachtimepoint formeasuredparametersarealsoindicatedinthetable. AverageHRwashighestingroups4and5.Significantdifferenceswereobservedbetweengroups4and5andgroups 2,3and/or6atvarioustime-pointsafterpremedication andbetweengroups5and1at5minutespost-induction. AverageRRtendedtobehigheringroups1 – 4compared togroups5and6.Significantdifferenceswereobserved betweengroups1and6immediatelyandupto10minutes post-induction,betweengroups1and5immediatelypostinductionandbetweengroups2,3and4comparedto groups5and/or6atvarioustime-pointsduringinhalant maintenance.AverageBP(S,DorM)tendedtobehighest ingroups1,2and6withsignificantdifferencesbetween groups3,4and/or5observedduringthemaintenance period.Althoughnotstatisticallysignificantoverall,a decreaseinSBPwasobservedin56%oftheanimals immediatelypost-induction. AverageSpO2tendedtobehighestingroupsmaintained oninhalant,withresultsingroups4,5and6significantly greaterthanthoseingroups1and2immediatelyandat 5minutespost-inductionandgreaterthanthoseingroup2 at10minutespost-induction.TheSpO2wasalsosignificantlygreateringroup5thaningroups2and3atvarioustime-pointsduringmaintenanceanesthesia.There were25animalsinwhichSpO2<90%wasreported,generallyimmediatelypost-induction.Mostoftheseanimals (23/25)weremaintainedonMDP(groups1 – 3).Ofthe group1 – 3animals,apparenthemoglobindesaturationwas exclusivelyobservedinanimalsnotreceivingsupplemental oxygen.Infouroftheseanimals,supplementaloxygenwas provided,butintheremaining19dogs,thetransientapparenthemoglobindesaturationr esolvedwithouttreatment. TheETCO2tendedtobehighestingroup6andwassignificantlygreaterthangroup1immediatelyandat5minutespost-induction.Rectalte mperaturewassignificantly greateringroup1comparedtogroup3priortoinduction andimmediatelyandat5minutespost-induction. Table6summarizesclinicalsideeffectsandadverse eventsbygroup.Themostfrequentlyobservedsideeffectwashypotensionwhichgenerallyoccurredduring inhalationanesthesia.In12ofthe16affectedanimals, additionalintravenousfluidsand/orephedrinewas usedtotreatlowbloodpressure.Apnea,thesecond mostcommonclinicalsidee ffectobserved,typically occurredwithinthefirstfiveminutesafterinduction. Apnealasting120secondsoccurredmorecommonly ingroup2,usuallywhenanimalsreceivedamidazolam doseof0.3mg/kgorgreater.Asaresultofprolonged apnea,fiveanimalsinthisgroupreceivedsupplemental oxygen.Bradycardiaoccurredmainlyduringanesthesia maintenanceandwasseenmostfrequentlyinanimals premedicatedwithmedetomidine(n=6),twoofwhich hadalsoreceivedatropinepremedication.Atropineor glycopyrrolatewasusedinfourinstancestotreatlow heartrate.Tachycardiawasobservedintwoanimals, bothinthepresenceofatropine.Inoneofthedogs,aheart rateof177wasobservedimmedi atelyafterpremedication withacepromazineandatropine.NoincreaseinheartrateMama etal.BMCVeterinaryResearch 2013, 9 :261 Page7of12 http://www.biomedcentral.com/1746-6148/9/261

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wasobservedfollowinginjectionofMDP,however,the heartrateincreasedto253bpmatthe0 – 5minute interval,returningto128bpmat5 – 10minutes.Inthesecondanimal,(group4)noincreaseinheartratewasobservedimmediatelyafterinjectionofMDP,butincreasesup to167bpmwereobservedthroughoutthe30minutesof inhaledanestheticmaintenance.Hypertensionwasrecordedinthreegroup6animalsinwhichMAPrangedfrom 142 – 215mmHg;allthreeanimalshadreceivedatropine. PainoninjectionofMDPwasnotobservedinthisstudy. Therewasonedeathassociatedwithananimalincluded inthestudy.Thisoccurred2dayspostovariohysterectomy ina6-year-oldfemaleJackRussellTerrierassignedto group5.Apost-mortemexaminationwasperformed, andthecauseofdeathwasattributedtosepticperitonitis fromanovarianpedicleabscessconsistentwithintroductionofaforeignmaterialatthetimeofsurgery.Three otherdogsweretreatedfromthesamevialofMDPwithoutincident;onewastreatedbeforeandtwoafterthedog experiencingtheadverseevent. Themaximumdurationofuseforanyindividualvial usedduringthecourseofthestudywas17days,andthe maximumnumberofwithdrawals(needlepenetrations) wasnine.Approximately50%ofthevialswereusedover Table5Geometricmeanrecoverytimesfordogsbytreatmentgroup1GroupTimetoextubation2(min)Timetosternalrecumbency2(min)Timetostanding2(min) Geometricmean(GSD)/range 18.0(1.82)2 – 419.7(1.67)3 – 4414.6(1.54)8 – 56 211.1(1.76)5 – 4115.2(1.71)6 – 4524.4(1.58)10 – 48 310.1(1.71)4 – 2513.3(1.69)5 – 2918.7(1.68)7 – 48 47.3(1.86)3-368.8(1.74)4-3815.2(1.97)4-55 59.0(1.94)3-3312.4(1.87)3-4124.0(1.98)5-115 68.0(1.72)4-2210.6(1.68)4-2518.1(1.90)6-105 Statisticalresults2None2>42,5>11Timemeasuredfromlastpropofolinjection(Groups1 – 3)orvaporizeroff(Groups4 – 6).Seetextforadditionaldetails.2Includesallstatisticallysignificant(p<0.05)meandifferencesbetweentreatmentgroupsbasedonlog-transformeddata. Table6Numberofanimalspergroupwithsideeffects*oradverseevents**recordedduringthestudyTreatmentgroupTotal 123456 Numberofpatientsingroup232525222221138 Numberofpatientsreceivingatropine0011021638 Sideeffect(Adverseevent)No.patientsexperiencingsideeffectoradverseevent() Hypotension1(1)1(1)3(2)9(1)2(2)16(7) Apnea1(2)6(6)2(1)3(2)3(1)15(12) Bradycardia1(1)1(1)2(1)116(6)11(9) Excitation12162113 Tachypnea12317 Arrhythmias 1(1)12(1) Paddling2114 Fasciculation2114 Tenseness1113 Hypertension 33 Cyanosis11(1)2(1) Tachycardia 112 Salivation112 Emesis 1(1)1(1) Death (1)1(1)*Quantitativesideeffectsdefinedasphysiologicalmeasurementsoutsidethenormalrange. **Quantitativeadversereactionsdefinedas:heartratelessthan50bpm,apnea>120seconds,meanarterialbloodpressure<50mmHg,anypotentially lethal ECGrhythm,meanO2saturation<80%(anyduration)or90%for>3min.Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page8of12 http://www.biomedcentral.com/1746-6148/9/261

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atleasttwodays.Onaverage,thevialsremainedinuse fortwodaysduringwhichthreewithdrawalsweremade. Investigatorsdidnotobserveachangeindosingorreductioninqualityofmaintenanceforthoseanimalswho weredosedattheendoftheuseintervalforanyvial.DiscussionPriormulticenterclinicalstudieshaveconfirmedpropofol asafast-actinganestheticagent,withafavorablerecovery andsafetyprofile[1,3].Thesingle-useformulationsofthis drug,however,donotallowmultiplewithdrawalsfor morethansixhoursfromfirstpenetrationwhichcanresultinwastageoftheunuseddrug.Thepurposeofthis studywastodemonstratethesafetyandefficacyofMDP underawiderangeofclinicalcircumstances.Resultsof thisstudysuggestthattheadditionofbenzylalcoholto theformulationofthesterileinjectablehasthepotential toreducewastagebyallowingashelf-lifeofupto28days aftertheinitialwithdrawal/needlepenetrationwithout alteringthesafetyorefficacyofthepreparation.While directcomparisonscannotbemadeintheabsenceof controlgroupsinwhichpreservative-freepropofolwas used,resultsofdosingandprevalenceofsideeffects canbecomparedtothosefrompublishedstudieson single-usepropofol. Thepopulationinthisstudyconsistedofhealthyindividualswithanaverageageof5years;theyoungestdog was3monthsold.Theuseofbenzylalcoholasapreservativeinhumanparenteralsolutionshasbeenassociated withararebutfatalneonatalgaspingsyndromeinprematurehumaninfantsandsomeimmatureanimals [7,8].Exposureassociatedwithtoxicitieswasator above99mg/kg/day,alevel wellaboveexposureencounteredwiththeuseofMDPforinductionandshort termmaintenanceofanesthesiainthisstudy.However giventheexclusionofdogslessthan10weeksofage,we cannotmakeanyrecommendationsregardinguseforthis populationofpatients.Similarly,duetotheuseofMDP foronlyashortdurationinthisstudy(upto37minutes) wecannotcommentonthesafetyofMDPforprolonged infusionashasbeenpreviouslydescribedforpreservativefreepropofol[9]. Theinductiondosesinthisstudyforunpremedicated animalswereslightlyhigherthanreportedforsingle-use propofol[1,3].Thereasonsforthisdifferencearelikely multifactorial.Forexample,populationdifferencesand factorsrelatedtothestudy,suchasstimulatinganimals torecordphysiologicalparameterspriortoinduction, mayhaveplayedarole.Inaddition,therateofpropofol administrationmayhaveinfluencedthetotaldose.For thisstudy,therecommendedrateofadministrationwas 60and90secondsoruntilthepatientcouldbeintubated. Thiswassuggestedinanefforttominimizeanycardiopulmonarydepressionasiscommonafterarapidintravenous bolusofafixeddose.Interestingly,priorreportssuggest thatslowadministrationcandecrease[10,11]orincrease [12,13]theamountofpropofolusedtoachieveafixed endpoint.Itisthoughtthat,whileaslowerrateallows formoregradualequilibrationofthebloodandbrain concentrations,anesthesiamaynotbeachievedifthis isexcessivelyprolonged[10,13].Inductiondosesof6.5 and5.5mg/kgarereportedwithadministrationof single-usepropofolover60 – 90versus10 – 30seconds [1,3];theresultsinthisstudyaresimilartothestudy inwhichtheslowerinjectionratewasused. Unlikeresultsinunpremedicatedanimals,therangeof meandosestoachieveinductioninpremedicatedanimals weresimilartothatpreviouslyreportedforsingle-use propofol[1-3,12-17].Inthecurrentstudy,thepresenceof premedicationreducedthepropofolinductiondoseby38, 47and58%formidazolam/buprenorphine,acepromazine/ buprenorphineandmedetomidine/buprenorphinecombinations,respectively.Agreaterdose-sparingpotency ofmedetomidinecomparedtothatofmidazolamoracepromazinehasbeenreportedforsingle-usepropofol[18-21]. ThemeandurationofanesthesiaforMDP(recorded fromendadministrationtoreq uirementforfirstadditional dose)wascomparabletothatpreviouslyreportedfor single-usepropofolforbothunpremedicatedandpremedicatedanimals[1-3,13].S imilartoresultsreported forthesingle-usepropofol[12,15],thedoserequiredto maintainanesthesiaremainedconsistentovertime,suggestingthattheMDPdidnotaccumulateuponrepeated administrationoverashortperiodoftime. Differencesinpremedicantdoses,theuseofatropineand supplementaloxygen,surgical procedures,andmonitoring methodsamongthestudyanimalsandsiteslikelycontributedtovariationsinphysiologicmeasurements,andmay haveinfluencedtheabilitytodetectdifferencesamongthe treatmentgroups.Overall,however,theeffectsofMDP onphysiologicalvariablesmirroredthoseseeninprior reportsincludingmulticenterclinicaltrialswithsingle-use preparations[1,3,18,22-25].Themostcommonfindingsin allofthesestudiesincludeadecreaseinbloodpressure andrespiratoryrateafterpropofoladministrationwith minimaltonoeffectsonheartratebeyondthatobserved withpremedication.Thissugg eststhattheadditionofbenzylalcoholtotheformulationdidnothaveanysignificant additionalcardiovascularorres piratoryeffects.Tachycardia wasreportedinonlytwodogsinthisstudy,bothpremedicatedwithatropine,whichislikelytohaveplayedarole. Thelowincidenceoftachycardiainthisstudydiffersfrom resultsobservedinatolerancestudyofMDPinwhich increasesinheartratewereobservedimmediatelyafter inductionwithMDP.Thephenomenonappearedtobe dose-related,withamaximumheartrateof230beats perminuteseenatadoseof19.5mg/kgwithlittleeffect observedat6.5mg/kg[5].ItisunlikelythatadogwouldMama etal.BMCVeterinaryResearch 2013, 9 :261 Page9of12 http://www.biomedcentral.com/1746-6148/9/261

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requireabolusdoseofthismagnitude(19.5mg/kg), undertypicalclinicalconditions.Consistentwithother reports,heartratewaslowestinmedetomidine-treated groups[24]. Inallbutthemedetomidinepremedicateddogs(group6), averageS,DandMbloodpressuretendedtodecrease followingMDPinduction.Thishasbeenattributed previouslytopropofolinducedveno-dilationwhich decreasescardiacpreload[25].Thevasoconstriction inducedbymedetomidinelikelyoffsettheseeffects [26,27].Respiratoryratedecreasednumericallyinall groupsfollowinginductionofanesthesiabutthemean decreasewasnotstatisticallysignificantforanygroup. Interestingly,ETCO2tensionstendedtoremainwithinthe normalrangethroughoutthestudy.Bloodgasmeasurementswouldhavehelpeddeterminethedegreetowhich thedecreaseinRRmayhavecontributedtochangesin ventilationinindividualanimalsbutwerenotperformedin thisstudy.TheaverageSpO2immediatelypost-induction was90.09.9,90.16.7and93.94.3ingroups1,2and 3,respectively,theMDPmaintenancegroups(Table3). Thisapparenthemoglobindesaturationwaslikelydue toacombinationofrespiratorydepressionanddrugor recumbency-inducedventilationperfusionabnormalities.Arterialbloodgasanalysismayhavehelpedfurtherelucidatethecause.Priorreportsonasingle-use preparationsuggestthatprop ofol-inducedrespiratory depressionisexacerbatedwhensedatingdrugsandMu (OP3)agonistopioidsareusedwithpropofol[21,28]. Approximately37%ofanimalsintheMDPmaintenancegroups(1 – 3)receivedsupplementaloxygenprior toinduction.Ofthosenotreceivingsupplementaloxygen,theaverageSpO2immediatelypost-inductionwas 85.311.4,86.26.3and91.05.2ingroups1,2and3, respectively.AlthoughthelowSpO2wastransientindogs maintainedonMDP,thesedatasupporttherecommendationtoprovidesupplementaloxygentoanimalsmaintained onpropofol[2].ThehigherSpO2observedindogsmaintainedoninhalantanestheticswasexpected,asthesedogs werebreathingahighfractionofinspiredoxygen.Thiswas similartodogsintheMDPmaintenancegroupswhich receivedsupplementaloxygen(averageSpO2immediatelypost-induction95.11.4,94.82.8and95.81.9 ingroups1,2and3,respectively). Thesideeffectsobservedwerequalitativelycomparable tothoseseenwiththesingle-useproduct[1,3,5,13-17,19] andwerepredominantlyrelatedtothecardiovascularand respiratorysystems.Apneawasmorecommonlyseenduringmaintenancewithpropofolthaninhaledanesthesia, buttheincidencewaslowerthanorcomparabletothat reportedpreviouslyforthesingle-useproduct.Thedistributionofothercardiovasculareffectsbetweenthoseanimalsadministeredpropofolversusinhaledagentstended tomirrorobservationswithsingle-usepropofol,withthe exceptionofhypotension,whichwasobservedlessfrequentlythanexpectedintheMDPmaintenancegroupsin thisstudy.Otherobservedsideeffectswereinkeepingwith thoseassociatedwithspecifi cpremedicants.Forexample, poorsedation[29,30]andexcitementhasbeenreportedasa sideeffectofmidazolam[31],andhypertensionhasbeenassociatedwithmedetomidine[26,27]andthecombinationof medetomidineandatropine[29].AbnormalECGrhythms wereobservedonlyduringinhaledanestheticmaintenance specificallyingroups4and5(with1animalineachgroup). However,itwasmorecommonfordogsinthesegroups tobemonitoredinthismanner.NoECGabnormalities wereobservedinatolerancestudyofMDPatdosesupto 19.5mg/kg[5]. Thetoxicityofbenzylalcoholhasbeencharacterized inthedog[32]aswellasotherspecies[33-35].Cardiovascular,respiratoryandcentralnervoussystemeffects, suchastremors,havebeendocumented.Significantspecies differenceshavebeennoted,withthecatbeingparticularly sensitivetobenzylalcoholtoxicity,whichisattributedto itsglucuronidedeficiency[36].Parenteraltoxicityofbenzylalcoholisalsoreportedtobedependentonconcentrationinsolutionandrateofadministration[32].Inthe currentstudy,thephysiologicandclinicalsideeffectsof MDPweresimilartothosedocumentedforsingle-use propofol.Also,sideeffectswerenotseenathigherlevels inthegroupsmaintainedonMDP,despitetheirhigherexposure.Thus,nospecificadversefindingscouldbeattributedtotheadditionofbenzylalcoholtotheformulation. Despitethereportedsensitivityofcatstobenzylalcohol, theanesthetic,physiologicandsideeffectprofilesofMDP werealsofoundtobesimilarincatstothoseofsingle-use propofol[37]. Therewasnoevidenceofinfectionorsepsisasaresult ofMDPadministration;thesinglecaseinwhichseptic peritonitiswasobservedwasattributedbythepathologist totheintroductionofforeignmaterialatthetimeof surgery.TheuseofthesamevialofMDPintwodogs afterthedogexperiencingtheadverseeventprecluded additionaltestingonthisvialforcontamination.However,laboratorytestingof theMDPwithrepetitiveneedlepuncturesoverthe28day ssupportthesterilityof theproductovertheshelf-life[38]. Thefactthatapproximately50%ofthevialswereused overthecourseofatleasttwodays,indicatesthatapreservativecontainingformulationcanhelpeliminatewaste fromproductremainingafterthe6-hourrecommended periodforsingle-use(preservative-free)propofol.ConclusionsBasedontheresultsofthisstudy,MDPwasfoundtobe acceptableforuseinASAIandIIdogsforinductionand shorttermmaintenanceofanesthesiaorinductionof anesthesiapriortomaintenancewithinhaledanestheticsMama etal.BMCVeterinaryResearch 2013, 9 :261 Page10of12 http://www.biomedcentral.com/1746-6148/9/261

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whenusedaloneandincombinationwithcommonlyused premedicants.Inductionandmaintenancedose,duration ofanesthesiaafterasingle-useandanesthesiaqualitywere comparabletothosereportedpreviouslyforsingledose propofol.Atclinicallyeffectivedoses,noadverseeffects couldbedirectlylinkedtotheadditionof2%benzylalcoholusedasapreservativeinthisformulation.Theinclusionofbenzylalcoholintheformulationallowedtheuse ofonepropofolvialforupto9needleinsertionsfordrug withdrawaloveraperiodupto17days.AvailabilityofsupportingdataThedatasupportingthismanuscriptwillnotbeincludedonline.Abbreviations ASA: Americansocietyofanesthesiologists;IM:Intramuscular;IV:Intravenous; MDP:Multidosepropofol;SC:Subcutaneous. Competinginterests ElizabethCozziisastockholderandemployeeofAbbottLaboratories. AbbottLaboratoriesprovidedfundingtoColoradoStateUniversity,the UniversityofFlorida,theUniversityofTennessee,andtheAnimalAnesthesia andPainManagementCenterfortheconductofthestudyandto BiotechnicalServices,Inc.forthedatamanagementandanalysis.MDPisa patentedformulationthatwasdevelopedbyAbbottLaboratories.Abbott LaboratoriesprovidedfundingtoKhursheedMamaandBiotechnicalServices forthepreparationofthemanuscript;therearenoothercompetinginterests. Authors ’ contributions EMC,KRM,JSG,SARandRCHconceivedanddesignedtheexperiments.EMC providedthetestarticle(MDP).KRM,JSG,SARandRCHperformedthe experiments.RLKandEMCsummarizedandanalyzedthedata.KRM,RLKand EMCpreparedthemanuscript.Allauthorsreadandapprovedthefinal manuscript. Acknowledgements TheauthorsacknowledgeVetPharm,Inc.forstudymanagement,Drs.E.A. HoweandA.KrauseofOcala,FL,investigatorsinthestudy,andThomasJ. Keefe,PhD.forhisassistancewithstatisticalanalysisofthedata. Authordetails1DepartmentofClinicalSciences,CollegeofVeterinaryMedicineand BiomedicalSciences,ColoradoStateUniversity,FortCollins,CO80523,USA.2PeakPerformanceVeterinaryGroup,ColoradoSprings,Co80918,USA.3DepartmentofSmallAnimalClinicalSciences,CollegeofVeterinary Medicine,UniversityofTennessee,Knoxville,TN37996,USA.4Departmentof LargeAnimalClinicalSciences,CollegeofVeterinaryMedicine,University ofFlorida,Gainesville,FL32608,USA.5BiotechnicalServices,Inc,North LittleRock,AR72116,USA.6AbbottLaboratories,AbbottPark,Illinois 60064,USA. Received:6May2013Accepted:16December2013 Published:23December2013 References1. Freedomofinformationactsummary,newanimaldrugapplicationfor RapinovetTM(propofol)anestheticinjectionfordogsandcats,NADA141 – 070, 1996. www.fda.gov/downloads/AnimalVeterinary/Products/ ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm116781.pdf. 2.ShortCE,BufalariA: Propofolanesthesia. VetClinNorthAmSmallAnim Pract 1999, 29: 747 – 778. 3. Freedomofinformationactsummary,newanimaldrugapplicationfor PropoFloTM,NADA141 – 098,1998. www.fda.gov/downloads/ AnimalVeterinary/Products/ApprovedAnimalDrugProducts/ FOIADrugSummaries/ucm355533.pdf. 4.BrunsonEL: Benzylalcohol. In Handbookofpharmaceuticalexcipients. 5th edition.EditedbyRoweRC,SheskeyPJ,OwenSC.London:Pharmaceutical Press;2005:53 – 55. 5. Freedomofinformationactsummary,supplementalnewanimaldrug applicationforPropofol28,NADA141 – 098,2011. www.fda.gov/downloads/ AnimalVeterinary/Products/ApprovedAnimalDrugProducts/ FOIADrugSummaries/ucm248263.pdf. 6.BransonKR,QuandtJE,MartinezEA,CarrollGL,TrimCM,DodamJR, HartsfieldSM,MatthewsNS,MackenthunA,BeleauMH: Amultisitecase reportontheclinicaluseofsevofluraneindogs. JAmAnimHospAssoc 2001, 37: 420 – 432. 7.GershanikJ,BoederB,EnsleyH,McCloskeyS,GeorgeW: Thegasping syndromeandbenzylalcoholpoisoning. NEnglJMed 1982, 307: 1384 – 1388. 8.SchleiferJH,CarsonTL: Toxicityofbenzylalcoholpreservative. JAmVet MedAssoc 1982, 181: 853. 9.MurrellJC,vanNottenRW,HellebrekersLJ: Clinicalinvestigationof remifentanilandpropofolforthetotalintravenousanaesthesiaofdogs. VetRec 2005, 156: 804 – 808. 10.LudbrookGL,UptonRN,GrantC,MartinezA: Theeffectofrateof administrationonbrainconcentrationsofpropofolinsheep. AnesthAnalg 1998, 86: 1301 – 1306. 11.StokesDN,HuttonP: Rate-dependentinductionphenomenawith propofol:implicationsfortherelativepotencyofintravenous anesthetics. AnesthAnalg 1991, 72: 578 – 583. 12.GeelJK: Theeffectofpremedicationontheinductiondoseofpropofol indogsandcats. JSAfrVetAssoc 1991, 62: 118 – 123. 13.MorganDWT,LeggeK: Clinicalevaluationofpropofolasanintravenous anaestheticagentincatsanddogs. VetRec 1989, 124: 31 – 33. 14.WatkinsSB,HallLW,ClarkeKW: Propofolasanintravenousanaesthetic agentindogs. VetRec 1987, 120: 326 –329. 15.HallLW,ChambersJP: Aclinicaltrialofpropofolinfusionanaesthesiain dogs. JSmallAnimPract 1987, 28: 623 – 637. 16.WeaverBMQ,RaptopoulosD: Inductionofanaesthesiaindogsandcats withpropofol. VetRec 1990, 126: 617 – 620. 17.WatneyGCG,PabloLS: Medianeffectivedosageofpropofolforinduction ofanesthesiaindogs. AmJVetRes 1992, 53: 2320 – 2322. 18.GrintNJ,AldersonB,DugdaleAHA: Acomparisonofacepromazinebuprenorphineandmedetomidine-buprenorphineforpreanesthetic medicationofdogs. JAmVetMedAssoc 2010, 237: 1431 – 1437. 19.SanoT,NishimuraR,MochizukiM,SasakiN: Effectsofmidazolam-butorphanol, acepromazine-butorphanolandmedetomidineonaninductiondoseof propofolandtheircompatibilityindogs. JVetMedSci 2003, 65: 1141 – 1143. 20.KuuselaE,VainioO,ShortCE,LeppaluotoJ,HuttunenP,StromS,HujoV, ValtonenA,RaekallioM: Acomparisonofpropofolinfusionandpropofol/ isofluoraneanaesthesiaindexmedetomidinepremedicateddogs. JVetPharmacolTher 2003, 26: 199 – 204. 21.KuuselaE,RaekallioM,VaisanenM,MykkanenK,RopponenH,VainioO: Comparisonofmedetomidineanddexmedetomidineaspremedicants indogsundergoingpropofol-isofluraneanesthesia. AmJVetRes 2001, 62: 1073 – 1079. 22.SmithJA,GaynorJS,BednarskiRM,MuirWW: Adverseeffectsofadministration ofpropofolwithvariouspreanestheticregimensindogs. JAmVetMedAssoc 1993, 202: 1111 – 1115. 23.MuskGC,PangDSJ,BethsT,FlahertyDA: Target-controlledinfusionof propofolindogs – evaluationoffourtargetsforinductionofanesthesia. VetRec 2005, 157: 766 – 770. 24.HammondRA,EnglandGCW: Theeffectofmedetomidinepremedication uponpropofolinductionandinfusionanaesthesiainthedog. JVetAnaesth 1994, 21: 24 – 28. 25.GoodchildCS,SerraoJM: Cardiovasculareffectsofpropofolinthe anaesthetizeddog. BrJAnaesth 1989, 63: 87 –92. 26.PypendopBH,VerstegenJP: Hemodynamiceffectsofmedetomidinein thedog:adosetitrationstudy. VetSurg 1998, 27: 612 – 622. 27.MurrellJC,HellebrekersLJ: Medetomidineanddexmedetomidine: areviewofcardiovasculareffectsandantinociceptivepropertiesinthe dog. VetAnaesthAnalg 2005, 32: 117 – 127. 28.MuirWW,GadowskiJE: Respiratorydepressionandapneainducedby propofolindogs. AmJVetRes 1998, 59: 157 – 161. 29.AlibhaiHIK,ClarkeKW,LeeYH,ThompsonJ: Cardiopulmonaryeffectsof combinationsofmedetomidinehydrochlorideandatropinesulphatein dogs. VetRec 1996, 138: 11 – 13.Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page11of12 http://www.biomedcentral.com/1746-6148/9/261

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