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

MISSING IMAGE

Material Information

Title:
Multicenter clinical evaluation of a multi-dose formulation of propofol in the dog
Series Title:
BMC Veterinary Research
Physical Description:
Mixed Material
Creator:
Khursheed R Mama
James S Gaynor
Ralph C Harvey
Sheilah A Robertson
Robbin L Koenig
Elizabeth M Cozzi
Publisher:
BMC Veterinary Research
Publication Date:

Subjects

Subjects / Keywords:
Dog
Anesthesia
Clinical trial
Propofol

Notes

Abstract:
Background: Propofol is a widely used injectable anesthetic agent for induction and short-term maintenance in dogs. A multi-dose formulation of propofol (MDP) has been developed which includes 2% benzyl alcohol as a preservative. In order to document the use of the product under clinical conditions, MDP was tested in a prospective clinical trial conducted at six sites within the United States. One hundred thirty-eight healthy, client-owned dogs were assigned to one of six treatment groups based on premedicants (none, acepromazine/buprenorphine, midazolam/ buprenorphine, medetomidine/buprenorphine) and maintenance agents (MDP, inhaled anesthetic). Anesthesia was induced by the intravenous administration of MDP given to effect. Physiological indices including heart rate, respiratory rate and blood pressure were monitored prior to and during anesthesia induction, maintenance and recovery. Adverse events, defined for severity by pre-established limits of these physiological values, as well as side effects, defined as any observation outside the normal range, were noted. Results: The mean intubation dose was 7.6 ± 2.1 mg/kg for MDP alone and 4.7 ± 1.3, 4.0 ± 1.0 mg/kg and 3.2 ± 1.4 mg/kg when buprenorphine was used in combination with midazolam, acepromazine and medetomidine, respectively. Of the 32 adverse events, apnea (12 incidents), bradycardia (9 incidents) and hypotension (7 incidents) were most frequently recorded. Emesis, cyanosis and second degree heart block were each noted once and successfully resolved. The cause of a single death 2 days post-anesthesia was assessed as a surgical complication. Conclusions: MDP was found to be acceptable for use in healthy dogs for induction and short term maintenance of anesthesia when used alone and in combination with premedicants and inhaled anesthetics.

Record Information

Source Institution:
University of Florida
Holding Location:
University of Florida
Rights Management:
All rights reserved by the source institution.
System ID:
AA00020081:00001

Full Text

PAGE 1

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

PAGE 2

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

PAGE 3

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

PAGE 4

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

PAGE 5

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

PAGE 6

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

PAGE 7

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

PAGE 8

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

PAGE 9

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

PAGE 10

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

PAGE 11

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

PAGE 12

30.KojimaK,NishimuraR,MutohT,TakaoK,MatsunagaS,MochizukiM,Sasaki N: Comparisonofsedativeeffectsofmedetomidine-midazolam, acepromazine-butorphanolandmidazolam-butorphanolindogs. JAmVetMedAssoc 1999, 46: 141 – 148. 31.PypendopB,VerstegenJ: Acomparisonofthesedativeandanalgesic effectsofbuprenorphineincombinationwithacepromazine,midazolam ormedetomidineindogs. JVetAnaesth 1994, 21: 15 – 20. 32.KimuraET,DarbyTD,KrauseRA,BrondykHD: Parenteraltoxicitystudies withbenzylalcohol. ToxicolApplPharmacol 1971, 18: 60 – 68. 33.CullisonRF,MenardPD,BuckWB: Toxicosisincatsfromuseofbenzyl alcoholinlactatedRinger ’ ssolution. JAmVetMedAssoc 1983, 182: 61. 34.McCloskeySE,GershanikJJ,LetoraJJ,WhiteL,GeorgeWJ: Toxicityof benzylalcoholinadultandneonatalmice. JPharmSci 1986, 75: 702 – 705. 35.EuropeanCommissionHealthandConsumerProtectionDirectorate-General: Opinionofthescientificcommitteeonfoodonbenzylalcohol. Brussels:European Commission;2002.SCF/ADD/FLAV/78Final17Sept. 36.WilckeJR: Idiosyncraciesofdrugmetabolismincats:effectson pharmacotherapeuticsinfelinepractice. VetClinNorthAmSmallAnim Pract 1984, 14: 1345 – 1354. 37.TaylorPM,ChengelisCP,MillerWR,ParkerGA,GleasonTR,CozziE: Evaluationofpropofolcontaining2%benzylalcoholpreservativeincats. JFelineMedSurg 2012, 14: 516 – 526. 38.AbbottLaboratories: Inusestabilitystudyformulti-dosepropofol. Abbott Park,IL:AbbottLaboratories;2010.doi:10.1186/1746-6148-9-261 Citethisarticleas: Mama etal. : Multicenterclinicalevaluationofa multi-doseformulationofpropofolinthedog. BMCVeterinaryResearch 2013 9 :261. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Mama etal.BMCVeterinaryResearch 2013, 9 :261 Page12of12 http://www.biomedcentral.com/1746-6148/9/261