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IND1279210003VersionMay15,2017170515ProtocolTAADRCT

Title:TumescentAnesthesiaAntibioticDelivery(TAAD)andSubQKathforPreventionofSurgicalSiteInfection,ThrombosisandSepsis.WIRBProtocol#pendingFDAINDapprovalClient’sIdentifyingNumber:TAADClinicaltrials.govRegistration#pendingFDAINDapprovalSponsor:JeffreyA.Klein,MD,MPHPrincipalClinicalInvestigator:JeffreyA.Klein,MD,MPH

ClinicalProfessor,DepartmentofDermatology,UniversityofCalifornia,IrvinePrincipalStatisticalInvestigator:DanielJeske,PhD

Professor&Chair,DepartmentofStatistics,UniversityofCalifornia,RiversideClinicalTrialCoordinator:TobedeterminedStatisticalDesignandAnalysis:StatisticalCollaboratory,UCRiverside

DepartmentofStatistics,UniversityofCalifornia,RiversideContact:JeffreyAlanKlein,MD,MPH

30280RanchoViejoRoad,SanJuanCapistrano,CA92675OfficeHoursTel:949-248-1632Fax949-248-0507 AfterHoursCellPhone:949-283-1070Jeff@kleinmd.com

FinancialDisclosure:JeffreyKlein,MDhasseveralUSPatentsondevicesfortumescentlocalanesthesia,tumescentanesthesiaantibioticdelivery(TAAD)andtumescentplateletinhibition.Dr.Klein’swife,KathleenHuttonKlein,MD,hasanownershipinterestinHKSurgical,Inc.,whichmarketsdevicesfortumescentlocalanesthesiaandDrugsunderConsideration:cefazolin,metronidazole,ertapenem,lidocaine,epinephrine.Possiblyertapenemandotherappropriateantibiotics.Therewillbemorethanoneormoreresearchsite(s).

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ii. PurposeofStudyandBackgroundA.Objectivesandpurposeofthepresentstudy.

Despitetheuseofmultipleinterventions,surgicalsiteinfection(SSI)continuestobeasignificantproblem.Thereisaneedforaneffective,accessible,inexpensive,simple,safetechniquethatreducestheriskofSSI.Intravenousantibioticdelivery(IVAD)usinganover-the-needleintravenous(IV)catheteristhecurrentstandardmodeofantibioticdeliveryforSSIprevention.

1)Subcutaneousdeliveryofanantibioticssuchascefazolinandmetronidazoleisoff-label.

2)Subcutaneousinfiltrationofdiluteatumescentlidocainesolution(withorwithoutantibiotics)atlidocainedosagesthatexceed7mg/kgisoff-label.3)Subcutaneousinfiltrationofdiluteantibiotic(s)inatumescentlidocainesolutionusinganovelover-the-needlesubcutaneouscatheter(SubQKath)requiresFDA510(k)approval.

Thismulticenterrandomizedclinicaltrial(RCT)protocolisdesignedto1)comparetwomodesofantibioticdelivery,2)validatethesafetyoftumescentlidocaineatdosagesupto28mg/kg,3)validatethesafetyoftheSubQKathfortumescentanestheticantibioticdelivery(TAAD).4)Thisprotocolisnotaclinicaltrialcomparingtheeffectsofdifferentdrugs.5)ThisRCTcomparesIVADaloneversusconcomitantTAADandIVAD(TAAD+IVAD).TAADusinganovelover-the-needlesubcutaneouscatheter(SubQKath)bydirectsubcutaneous

infiltrationofdiluteantibiotic(s)inatumescentlidocainesolutionisanovelmodeofantibioticdelivery.Thisprotocoldescribesanopenlabelrandomizedclinicaltrial(RCT)withprospective

multicentermeta-analyticstatisticaldesignusingsequentialdataanalysiswithonestoppingpoint.Wehypothesizethat,comparedtoIVADalone,TAAD+IVADwillbesuperiorintermsofreducing

theriskofSSI,aswellasvenousthromboembolism(VTE)andsystemicinflammatoryresponsesyndrome(SIRS).

Tumescentinfiltration(TI)drugdeliveryinvolvessubcutaneousinfiltrationrelativelylargevolumes(1to2litersormore)ofarelativelydilutesolutionofepinephrine(≤1mg)inaliterofeither0.9%physiologicsalineorasimilarbalancedsaltsolutionsuchaslactatedRinger’ssolution.Fromapharmacokineticperspective,adilutetumescentinfiltration(TI)Solutionfunctionsasadrugdeliveryvehicle.Tumescentinfiltration(TI)drugdeliveryisamodeofdrugdeliverythathasapharmacokineticprofiledistinctfromintravenous(IV),intramuscular(IM),oral(PO)ortranscutaneousdelivery.

WhenaTISolutionisusedasavehicletodeliverlidocainesubcutaneouslywehaveTIsolution+Lidocaine=tumescentlidocaineanesthesia(TLA).

Further,whenanantibioticisaddedtoaTLAsolution,TISolution+Lidocaine+Antibiotic,theresultisatumescentanestheticantibioticdelivery(TAAD)solution.

TAADdrugdeliveryovercomestwocommontypesofantibiotictoxicities:total(mg)dose-relatedsystemictoxicityandconcentration-related(mg/L)local-tissuetoxicity.

TIdrugdeliveryprovides1)high,prolonged(12to18hoursormore)localizedsubcutaneousdrugconcentrations,2)slowsteadysystemic(serum)drugdeliveryhavingaconcentration-timeprofilesimilartoaslowconstantIVinfusionand

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3)apeakserumdrugconcentrationthatissubstantiallylessthanwouldbeexpectedbyroutinedosesgivenbyIVdelivery.TAADhasthepotentialtopreventorovercomeanantibiotic-resistantinfectionofsubcutaneous

tissueusinglessthantheusualtotalmgIVdoseofanantibioticwhileprovidinghighersubcutaneousantibioticconcentrationsthancanbeachievedbyIVdelivery,andsimultaneouslyavoidsystemicantibiotictoxicitybylimitingtherateofsystemicantibioticabsorptionandthusminimizingthepeakantibioticserumconcentration.

Forexample,TAADdeliveryofanaminoglycosideantibiotichasthepotentialtoprovidesubcutaneousantibioticconcentrationsthataresufficientlydilutetoavoidlocaltissuetoxicitywhilesimultaneouslyprovidingsubcutaneousantibioticconcentrationsthataresignificantlyhigherthancanbeachievedbyIVdelivery,withareducedriskofsystemic(earorkidney)toxicity.

Thepresentresearchprotocol,onlyallowstheuseofantibioticsthathaveFDAapproval.CefazolinandmetronidazolehaveFDAapprovalandareknowntobesafeandeffectivewhendeliveredbysubcutaneousinfiltrationasdocumentedbypublishedreportsinpeer-reviewedliterature.AclinicaltrialusingsubcutaneousdeliveryofaTAADsolutioncontainingcefazolinandmetronidazolerequiresDivisionofAnti-InfectiveProducts(DAIP)approvalofaninvestigationalnewdrug(IND)application.

Tumescentdilutionreducesthepotentialforsubcutaneous,concentrationdependenttissuetoxicitywhilesimultaneouslyprovidingsubcutaneousdrugconcentrationsthataresignificantlyhigherthancanbeachievedbyIVoranyothermodeofsystemicdrugdelivery.Forantibiotics,thetherapeuticbenefitsofIVdeliveryaremutedbythefactthatIVdeliveryoftenresultsinsub-therapeuticsubcutaneousantibioticconcentrationsandtheassociatedincreasedriskofdevelopingdrugresistance.Forsomecutaneousinfectionsandforpreventingsurgicalsiteinfections,tumescentinfiltrationdrugdeliveryovercomestheselimitationsofIVdelivery.ScientificGeneralizability

Thisprotocolisnotaclinicaltrialcomparingtheeffectsofdifferentdrugs.Thisclinicaltrialprotocolisdesignedtocomparetwomodesofantibioticdelivery.

Inordertomaximizethegeneralizabilityoftheresultsofthisresearch,theprotocolisdesignedtoaccommodateawidevarietyofclinicalsituationsencounteredinternationally.Theprotocolprovidesfortheinclusionofawidevarietyofpathology,surgicaltechniques,surgeontraining/experience,qualityofsurgicalfacilities,diverselocalhealth,localnutritionandlocaleconomicconditions.Theprotocolspecificallyallowsfortheuseoflocallyavailableantibioticproducts.Individualresearchsiteswillusetheirusualandcustomarysourcesofcefazolin,metronidazole,lidocaine,epinephrine,sodiumbicarbonateandphysiologicsaltsolutions.

Researchsiteswillbeprovidedwithsufficientsupplyofdevices(SubQKaths,tumescentlidocaineanesthesia(TLA)peristalticpumpandtubing)tofacilitateefficientTAADinfiltration.

Forthepurposesofscientificvalidityandgeneralizability,thisresearchintentionallydoesnotrestrictthechoiceofgenericantibiotictothatofasinglespecifiedmanufacturer.Thisprotocolexplicitlyallowstheuseofanygenericversionoftheantibiotic,irrespectiveofthemanufacturer.ThisprotocolalsoallowsTAADofanantibioticthatisonlyavailableasabranded(non-generic)drug.

Insomecases,theprincipalinvestigator(PI)willsupplyindividualresearchsitesinmedicallyindigentcommunitieswithaTAADDrugKitcontainingantibiotics,lidocainewithepinephrine,sodiumbicarbonateand1literbagsofabalancedsaltsolution.

Forthepurposeofstatisticalanalysisandvalidity,foranygivensubject,thesameantibiotic(s)willbeusedforbothTAADandIVAD.

Withinanyindividualresearchsite,itispreferredthattheantibioticformulation,sourceandbrandwillbestandardizedandinvariant,subjecttocontinuedavailabilityoftheantibiotic.

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“Off-Label”AspectsofTumescentDrugDeliveryTheuseofTAADinvolves:1)subcutaneousantibioticdeliverywhichis“off-label”formostFDA-approvedantibiotics,2)unapproveddrugformulations(moredilutetumescentanaesthesiaantibioticdelivery(TAAD)solution3)newunapproved(28mg/kg)recommendedmaximumdosagesfortumescentlidocaine.PrimaryandSecondaryEndPoints

ThisprotocolisdesignedtoprospectivelycollectdatatoevaluatetheefficacyandsafetyoftheTAADmodeofsubcutaneousantibioticdelivery.

Thisprotocolisdesignedtoprospectivelycollectobservationaldatatoevaluatethesafetyandefficacyofthedevices(HKSubQKath,HKtumescentinfiltrationtubingandHKperistaltictumescentinfiltrationpumps)usedforsubcutaneoustumescentinfiltrationofTAADsolutions.

Theprimaryend-pointistheincidenceofsurgicalsiteinfections(SSI).TheprotocolcomparesTAAD+IVADwithIVADalonewithrespectto:1)theincidenceofSSI,2)theincidenceofpost-operativevenousthromboembolism(VTE)and3)theincidenceofsepsis(pathogen-relatedordamage-related).Theprotocolalsorecordsdevice-relatedincidenceofadverseevents.ThedevicesusedforTAADincludeanewsingleusesubcutaneousinfiltrationcannula(HKSubQKath)forthetumescentdrugdelivery,tumescentperistalticpumpsandtumescentinfiltrationtubing.Definitions:Tumescentanesthesiaantibioticdelivery(TAAD)isdefinedasthesubcutaneousinfiltrationofadilutesolutionofantibiotic(s)inasolutionoftumescentlidocaineanesthesia(TLA).TLAconsistsofadilutesolutionoflidocaine(≤1gm/L),epinephrine(≤1mg/L)andsodiumbicarbonate(10mEq/L)in0.9%physiologicsalineorlactatedRinger’ssolution.OurestimatedmaximalsafedosageofTLAlidocaineis28mg/kgwithoutliposuction.

WehypothesizethatTAADtogetherwithintravenousantibioticdelivery(IVAD)willsignificantlyreducetheincidenceofsurgicalsiteinfections(SSI).ThePrincipalaimofthepresentresearchistocomparetwomethodsofantibioticdelivery:1)concomitantTAADandIVAD(TAAD+IVAD)versus2)IVADalone(IVAD),withrespecttothepreventionofSSI.TheIVdosesofantibioticswillbeequalforIVADaloneandforTAAD+IVAD.

ThefocusofthisresearchprojectisonpreventingSSI.Fromastatisticalperspective,studyingSSIamongsubjectswiththehighestriskofSSIminimizessamplesizesrequirementsforagiveneffectsizeandoptimizesstatisticalpower.

ThetargetpopulationsforthepresentclinicaltrialarepatientswhohaveahighriskofSSI.Theseincludepatientsexposedtohigh-risksurgicalprocedures(openabdominalsurgeries,traumasurgeries,burnsurgeries,sternotomy,repairofrecurrentventralhernia)orpatientswhoareobese,havediabetes,areimmune-compromisedorareotherwiseatincreasedriskofSSI.ThesecondaryaimsofthisstudyaretocompareTAAD+IVADvsIVADwithrespecttothe1)preventionofpost-operativevenousthromboembolism(VTE),and2)preventionofpost-operativesepsis(pathogenrelatedortraumarelated).

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TypeofClinicalTrial:Thisresearchisanopenlabelcontrolledrandomizedclinicaltrial(RCT)comparingtwomodesofantibioticdelivery.Itisnotatrialcomparingantibiotics.

PrimaryOutcomeVariableSurgicalSiteInfection(detectedwithin30daysofsurgery):superficial,deepincisional,organspace.SecondaryOutcomeVariables

1.DiagnosisofVenousThromboembolism(VTE)eitherdeepveinthrombosis(DVT)orPulmonaryembolism(PE)within30daysofsurgery(BinaryData)2.DiagnosisofSepsis,includingsystemicinflammatoryresponsesyndrome(SIRS)3.SafetyofTAADandTLA(incidenceofadverseeventsassociatedwithsubcutaneousantibioticsorlocalanesthesia4.Devicesafetyandefficacy:peristaltictumescentinfiltrationpumpandsubcutaneoustumescentinfiltrationcatheter(SubQKath)

OtherOutcomeVariables1.Post-OpICUadmission(orequivalentunit)andnumberofhoursinICU2.LengthofStay(LOS)inhospitalaftersurgery(hours)3.Timeinpost-operative/post-anesthesiarecoveryunit.4.Timefromarrivalinpost-oprecoverytotimeofambulation).5.Post-OpNarcoticRequirements(totalmgandmg/kg)6.Unexpectedre-admissiontohospital(foranyreason)≤30daysofsurgery(BinaryData)7.GeneralAnesthesiaRequirements(QuantitativeMeasure)8.DiagnosisofC.Difficilecolitis

B.Background:1)RiskofSSIColorectalSurgery.Surgicalsiteinfections(SSIs)areahighprioritytargetofhospitalqualityimprovementefforts1. TheincidenceofSSIdependsonseveralriskfactors.AmongthecommonsurgicalprocedureswiththehighestriskofSSIarecolorectalsurgeries.ThegreatestSSIriskfactorswithrespecttopatients’healthstatusincludeobesity,diabetes,advancedageandcompromisedimmunity.Thedegreeofwoundcontaminationisanotherriskfactor,independentofbaselinehealthstatus.EstimatesofSSIratesinGIsurgeryrangefromlessthan1%to15%forroutineelectiveGIsurgicalprocedurestoapproximately20%to30%forsurgeriesdefinedascontaminatedordirty.2TheincidenceofincisionalSSIincolonperforationwithgeneralizedcontaminationcanbeashighas82%comparedtoa25%incidencewithcolonperforationwithlocalizedcontamination.3TheprevalenceofSSIamongcancerpatientsundergoingelectivecolonandrectalsurgeryremainshigh,23.2and27.6%respectively,despiteevidence-basedpreventiveprocedures.4AmongobesecolectomypatientstheriskofSSIisincreasedby60%.5Lowconcentrationsofantibioticwithinperi-incisionaltissueisasignificantriskfactorforSSIincolorectalsurgery.6

AsignificantpercentageofSSIsbecomesapparentafterhospitaldischarge.7RetrospectivediagnosisofSSIisinaccurate.8Reliableresearchresultsrequiregoodprospectiveclinicalfollow-updatacollectedinatimelymanneratleast30daysaftersurgery.

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2)StandardofCareforSSIAntibioticProphylaxis.TheCentersforDiseaseControl(CDC)1999consensusguidelinesforSSIantibioticprophylaxisistheworldwidestandardofcare9.TheseguidelinesspecifyrapidbolusIVADofasufficientdoseofappropriateantibiotic(s)initiatedandcompletedwithin60to30minutesofincision,re-administrationofantibioticsifthedurationofsurgeryexceeds4hours,anddiscontinuationofantibioticswithin24hoursafterincision. TherearetwopotentialproblemswiththeCDCguidelines.Compliancewithantibioticguidelinesinclinicalpractice,especiallythetimingofIVAD,isoftennotmuchbetterthan60%1011.Secondly,evenwith100%compliance,theincidenceofSSIcolorectalsurgeryisstillunacceptablyhigh.ItisnowrecognizedthatIVADmaynotalwaysachievesufficientantibioticconcentrationinsubcutaneoustissue.InadequateantibiotictherapyincreasesthelengthofstayandcostincomplicatedSSI12.AmongcolectomypatientsanSSIincreasescostbymorethan$17,000. TAADmayprovidesolutionstotheseproblems.TAADcanbeimplementedatanytimebetween0to4hourspriortoincisionwithsuperiorsubcutaneousantibioticconcentrationscomparedtoIVAD.Amongobesepatients,thecumulativeantibioticexposureorareaunderthecurveoftheantibioticconcentration-timeprofile(AUC)insubcutaneousinterstitialfluidfollowingTAADismorethan100timesthatafterIVAD.133)SubcutaneousBacterialContamination

IntraoperativecontaminationofthesurgicalincisionsiteistheobviouscauseofSSI.AmongcolorectalsurgerypatientswhodevelopSSIthereisan85%incidenceofintraoperativebacterialcontaminationoftheoperativefield14.VirtuallyallbacteriaassociatedwithSSIareextracellularpathogens.ItisaxiomaticthatsuccessfulantibioticprophylaxisofSSIrequiresbactericidalconcentrationsofantibioticwithintheinterstitialfluid(ISF)ofincisedsubcutaneoustissueatthetimeoftheincisionandbactericidalconcentrationoftheantibioticthatpersistoverthedurationofthesurgery.4)SurgeryImpairsSubcutaneousBioavailability

AntibioticconcentrationsintissueatasurgicalincisionsitefollowingIVADcanbesignificantlylessthantheconcentrationinbloodandmaybeinsufficienttopreventthegrowthofbacteria.

Surgeryrelatedhypothermiawithperipheralvasoconstriction,tissuetrauma,desiccation,edema,inflammation,hemorrhage,hypovolemia,reducedcardiacoutput,hypotensionandcapillarythrombosisalldecreaseperfusionattheincisionsiteanddiminishantibiotictransferfrombloodontotheincisionalsurface.Cauteryassociatedchar,necrotictissue,foreignbodies(suturematerial),incision-surfacebloodclots,hematomas,andseromasarenidiforinfection.Thepresenceofavascularsurgicaldetritusdecreaseslocalresistancetobacterialinfectionandincreasestheriskofbacterialbiofilmformation.5)ObesityImpairsSubcutaneousBioavailability

ObesityincreasestheriskofSSI15.ObesityimpairssubcutaneousantibioticbioavailabilityfollowingIVAD.Theareaunderthecurve(AUC)ofdrugconcentrationasafunctionoftimeisameasureoftissueexposuretoadrug.FollowingIVAD,theratioAUCtissue/AUCplasmaisameasureofantibioticpenetrationfrombloodintotissue.Inobesepatientsthisratiois22%thatofnormalsubjects.Inobesepatients,thesubcutaneouspenetrationofcefoxitinafterIVADwaslessthan10%in8of10patients16. Ninetyminutesafterthepre-operativeIVdeliveryof500mgmetronidazoleforintra-abdominalsurgerythemetronidazoleconcentrationinsubcutaneousfatwas36%(4.9µg/g)ofthe13.6µg/mlinserumasmeasuredbyHPLC17.

Inastudyofabdominalwallsurgeries26patientsreceivedmetronidazole500mgintravenouslyduringinductionofanesthesia2hoursbeforesurgery.Plasmaandmusclelevelsofmetronidazolerangedfrom5.7to15.7µg/ml,wellabovetheminimuminhibitoryconcentrationfor90percentof

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Bacteroidesfragilis.However,metronidazoleconcentrationinsubcutaneousfat(0.6-1.7µg/ml)didnotachievetherapeuticlevels18. TAADisspecificallyintendedfordrugdeliveryintothesubcutaneoustissueofobesepatients.ThethicknessoftheabdominalmidlinesubcutaneousfatisamoreimportantSSIriskfactorthanisbodymassindex(BMI)19.TAADisasimplevariationoftumescentlocalanesthesia(TLA),whichinturnwasoriginallydevelopedspecificallyforpatientswiththickareasofsubcutaneousfattomakeliposuctionasaferandlesspainfulprocedure.6)AntibioticConcentrationafterTAAD

Basedonourclinicalpharmacokineticresearch,atequalantibioticdosages,TAADprovidesantibioticpenetrationinsubcutaneoustissue,whichexceedsthatofIVADbyatleast10-fold.Infact,TAADguaranteesthatthecefazolinandmetronidazoleconcentrationinsubcutaneousfatwillequaltheconcentrationoftheantibioticwithintheinfiltratedtumescentsolutionandthereforecanbeselectedtobeashighasnecessary.

Becausetheefficacyofamodeofantibioticdeliveryisproportionaltothecumulativeantibioticexposurewithinthetargetedtissue,TAADoughttopreventsuperficialSSIfarmoreeffectivelythanIVAD.Incontrast,incontaminatedcolorectalsurgeriesIVantibioticdeliveryismoreeffectivethanTAADforantibioticdeliveryintodeepparenchymaltissues.TAADcannotbereliedupontoproducessufficientlyhighserumconcentrationstopreventsepticemiaoranintra-peritonealabscess.ThusTAAD+IVADoughttobesuperiortoeitherTAADorIVADaloneforcolorectalsurgery.7)TumescentInfiltration TAADinfiltrationinvolvesthesubcutaneousinfiltrationofantibioticsinarelativelylargevolume(typically≥1liter)ofdiluteantibioticsdissolvedinasolutionoftumescentlocalanesthesia(TLA)consistingoflidocaine(<1gm/L),epinephrine(<1mg/L),sodiumbicarbonate(10mEq/L)inphysiologicsaline.PainlessinfiltrationofaliterormoreofTAADsolutionwithoutsignificantsedationorsystemicanalgesiarequirestraining,skillandmedicaldevicesspecificallydesignedforTAAD.TheefficiencyofinfiltratingalargevolumeofTAADsolutionisimprovedwiththeuseofspecializedtumescentinfiltrationcannulas(HKSubQKath),peristalticinfiltrationpump(HKTLAPump)andinfiltrationtubing(HKinfiltrationtubing).8)SubcutaneousMetronidazole

Dilutemetronidazoleissafeforsubcutaneousinfiltration.2021Metronidazoleisavailableasawater-solublepro-drugmetronidazolephosphateforparenteraldeliveryinaniso-osmoticsolutioncontaining500mgmetronidazolein100ml22.

AlthoughtheFDAapprovedlabelingformetronidazoledoesnotmentionsubcutaneousinfiltration,thismodeofdeliveryhasbeenusedwithsuccess.Instate-runhospitalsinIndia,appendicitisisoftenassociatedwithpre-existingmalnutritionandanemia,latepresentation,septicemiaandgrossperitonealcontamination,whichleadtoaveryhighwoundinfectionrate.Inastudyinvolving60patientsundergoingexploratorylaparotomyforperforationperitonitiswithpyoperitoneum,allpatientsreceivedprophylacticIVantibiotics.TheresultingSSIratewas66.6%(20/30)withsalineirrigationoftheincisionsiteversus26.6%(8/30)withsubcutaneousinfiltrationofmetronidazole(P<0.01).Therewerenoadversedrugreactionsattributabletosubcutaneousinfiltrationofmetronidazole23. TAAD-metronidazoleinfiltrationinvolvesthesubcutaneousinfiltrationofarelativelylargevolumeoftumescentmetronidazole(approximately500mg/bagofTAADsolution,andupto2bagsobesepatients).

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9)SubcutaneousCefazolin Subcutaneousdeliveryofdilutecefazolinisrecognizedasasafeprocedure.24Forsomesurgeonsitiscommonpractice,toinjectcefazolinintoperi-incisionaltissuesortosprinklecefazolinpowderdirectlyontoacutsurfaceofaskinincisionattheendofthesurgicalprocedure.Although”off-label”,thisprocedureisconsideredsafe,butprobablyinefficientgiventhatthebacterialcontaminationhasalreadyoccurredatthetimeofantibioticdelivery. TheFDA–approvedcefazolinpackage-insertstatesthatcefazolinisindicatedforIVorIMdelivery.Thereisnodiscussionregardingtheindicationorcontraindicationforsubcutaneousdelivery.Whenthecefazolinpackageinsertwaswrittenintheearly1970’s,subcutaneousdeliverywasnotdiscussed.Thegoalofantibioticdeliverywastoachieverapidsystemicabsorption.IVandIMdeliveryyieldfasterandmorecompletesystemicabsorption.However,thegoalofTAADinSSIprophylaxisbydirectsubcutaneousinjectionispreciselytoachievetheslowestsystemicabsorptionwiththehighestandmostprolongedlocaltissueconcentrationsofcefazolin. 10)TAADBenefits

TheantibioticsolutionforTAADproducesanintenselocalvasoconstriction,delayedsystemicantibioticabsorption,andprolongedantibioticexposurewithinsubcutaneousinterstitialfluid. WithTAADthelargevolumeofantibioticsolutionbothincreaseslocalinterstitialpressureandactsasasubcutaneousreservoirofantibioticwhichtogetherprovideacontinuousflowofantibioticsolutionfromthesurroundinghyper-hydratedtumescentinterstitialspaceontotheincisionalwoundsurface.

Biofilmscanformdirectlyontraumatizeddesiccatedadiposetissue25.Theeliminationofincisionalsurfacetissuedesiccationphysicallypreventsbacterialadhesiontowoundsurfaceandbiofilmformation.Theoozeoftumescentantibioticfluidfromthecutsurfaceofthewoundiscontinuoushoursafterinfiltration.Thisoozingdrainageisbeneficialinthatitdeliversaconstantflowantibioticinexceptionallyhighclinicalconcentrationontotheincisionsurfacethuspreventingtissuedesiccationandreducingtheriskofinfectionandbiofilmformation262728.

LidocaineisknowntobebactericidalthustheTLAcomponentofTAADmaybebactericidal.ItisremarkablethattheincidenceofSSIassociatedwithsimplemicro-cannulaliposuctiontotallybytumescentlocalanesthesia,whenperformedcautiouslybywell-trainedsurgeons,isessentiallyzero.2930

ThecombinationoflidocaineandepinephrinewithinaTAADsolutionproducesprofoundintra-operativelocalanesthesiaandprolonged(approximately12hoursormore)ofpost-operativeanalgesia.ThusTAADcanbeexpectedtodecreaserequirementsofgeneralanestheticagentsandpost-operativenarcoticanalgesicsandalsofacilitateearlierpost-operativeambulation. 11)TAADMayReduceThromboembolismandBloodViscosity

Theleadingcauseofdeathassociatedwithliposuctionundergeneralanesthesiaispulmonaryembolism31.Incontrast,theincidenceofvenousthromboembolismfollowingtumescentliposuctiontotallybylocalanesthesiaisvirtuallyzero.32Thisremarkabledichotomymightbeexplainedbytheantiplateletactivityoflidocaineintumescentlocalanesthesia(TLA).Itisknownthatlidocaineinhibitsplateletfunction3334.Thereisevidencethatlidocainemayreducetheriskofpost-operativethromboembolism353637.Ourdatafromanon-goingclinicaltrialamongliposuctionpatientssuggeststhatin-vivosystemicplateletfunctionissignificantlyreducedafterinfiltrationofTLAandtheplateletinhibitionpersistsinthepostoperativeperiod38.Withtumescentliposuctiontotallybylocalanesthesia,wehaveobservedthatthereisnodifferencebetweenpreoperativeandpostoperativeplateletcount.

TLAcontainsbothlidocaineandepinephrine.Lidocaineinhibitsplateletactivation.Epinephrinestimulatesplateletactivation.Lidocaineisacapillaryvasodilator.Epinephrineisacapillaryvasoconstrictor.Extensiveworldwideclinicalobservationinvolvingmillionsoftumescentliposuction

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surgeriesaccomplishedtotallybylocalanesthesiasuggeststhatepinephrinevasoconstrictionoutweighslidocainevasodilation,andlidocaineplateletinhibitionoutweighsepinephrineplateletactivation.

Amongcolorectalsurgerypatients,obesity,diabetes,andcancerincreasetheriskofbothSSIandvenousthromboembolism(VTE).OnestudyfoundthatamongcolorectalsurgerypatientswithulcerativecolitistheriskofDVTwas7.4%39.Ingeneral,colorectalsurgerypatientshaveariskofVTEof1.6%to2.4%.404142.TAADmayreducetheriskofVTE.AnotherstudyfoundthatcolorectalsurgeryforcancerhadariskofVTEashighas16%43.

TLAreducescutaneousandsubcutaneousincisionsitebleeding.TheprofoundlocalizedsubcutaneouscapillaryvasoconstrictioninducedbythelargevolumeofverydiluteepinephrineinaTLAsolutionreducesbothsurgicalbleedingandtheincidenceofhematoma.Priortotheuseoftumescentlocalanesthesia,theliposuctionaspirateundergeneralanesthesiacontained15to30percentbloodandroutinelyrequiredautologousbloodtransfusion44.Incontrast,withtumescentliposuctiontotallybylocalanesthesia,thispercentagetotalbloodintheaspirateisapproximately1to2percent.45

Therearenorandomizedclinicaltrialswhichhavetestedthehypothesisthattumescentlidocainemaysignificantlyreducetheeffectofpostoperativethromboembolismamonghigh-riskpatientsaftermajorsurgery.Inthepresentmulticenterrandomizedclinicaltrial,theoccurrenceofpost-operativedeepveinthrombosisorpulmonaryembolismwillbeanimportantsecondaryoutcomevariable.12)TAADInfiltration:Timing&Technique

ThetimingofTAADisnotascriticalasisthetimingofIVantibioticdelivery.CurrentSSIprophylaxisguidelinesmandatea30minutewindowforIVAD(within30to60minutesbeforeincision)inordertooptimizesubcutaneousantibioticconcentrationatthetimeofincision.Ifdeliveredtooearlyperi-incisionalinterstitialfluid(ISF)concentrationsofantibioticwillhavedeclinedconcomitantlywiththeexponentialdecreaseofserumconcentrationsafterbolusIVAD.IfIVADisdonetoolatethentherewillbeinsufficienttimeforantibiotictobetransferredintotheincisionsiteISFbeforeincisionaltraumaandbacterialcontaminationoccur46474849.

Compliancewithrecommendeddosingschedulesforprophylacticantibioticsincolorectalsurgeryislessthanoptimal.Becauseofcompetingworkflowdemandsinabusyoperatingroom,this30minutetargetcanbemissed40%ofthetime50.

TAADhasthepotentialtorelaxthistime-constraintbydeliveringalong-lastinghighconcentrationofantibioticintosubcutaneoustissuehoursbeforethepatiententerstheoperatingroom.Highsubcutaneousinterstitialfluidantibioticconcentrationspersistforatleast12hoursormoreafterinfiltration.WhenTAADisfollowedbyIVAD,theresultingsubcutaneousandsystemicantibioticconcentrationsaremorelikelytobesufficient,evenifIVADisonlydonewithinminutesbeforeincision.

TAADispreferablydonebeforeenteringtheoperatingroom(OR).TAADinfiltrationcanbedoneineitherapatient’shospitalroomorapre-oppreparationareaunderminimalsedation.Aphysician,aregisterednurseoraphysicianassistantcandotheinfiltrationofTAADsolutionusingtumescentinfiltrationcannulas(HKSubQKath),peristalticinfiltrationpump(HKKTP)andinfiltrationtubing(HKKIP-IIinfiltrationtubing). Becausethepatientisawakewithminimalsedation,minimizingpatientdiscomfortduringinfiltrationisapriority.Painlesstumescentinfiltrationisnotdifficulttoachieve,especiallyinobesepatients,butdoesrequiregentlenessandattentiontodetail. Fromapatientperspective,tumescentinfiltrationfeelsoddbutitisusuallynotregardedas“painful”.Alargemajorityofpatientsrequirenoancillarysedationduringtumescentinfiltration.Oralclonidine(0.1mg)isaneffectiveanxiolyticthatminimizesthechronotropiceffectsofepinephrine.Clonidineiswithheldifthebloodpressureislessthan100/60orpulseislessthan60.Orallorazepam(1mg),withorwithoutclonidine,isalsoeffectiveforpatientswhoareanxiousaboutneedles.Rarelyis

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midazolam(2mgIMorIV)required.Atropine(0.4mgIVorIM)canbegivenbeforeinfiltrationtopreventsyncopeforpatientswhohaveanyhistoryofvaso-vagalsyncopeornear-syncope.. WhenTAADiscompletedbeforeenteringtheoperatingroom(OR),theinfiltrationprocessdoesnotinterferewiththeORwork-flownordoesitprolongthetotaltimeintheOR.Alternatively,TAADinfiltrationcanbeperformedundergeneralanesthesia.WhenTAADisdoneintheORtheinfiltrationproceduremayconsumeexpensiveoperating-roomtime,addtothelogisticburdenofabusyoperatingroomstaffanddelaytheincision.Detumescence

Detumescence,animportantaspectofTAAD,istheprocessbywhichthetumescenttissuegraduallybecomeslessswollenoveranhourormorefollowingcompletionoftumescentinfiltration.Afterdetumescence,boththegrossappearanceoftheincisedfatandtheeaseofsurgicalmanipulationbecomemorenormal.Infiltratingasub-optimalvolumeoftumescentsolutioncanreducethetimerequiredfordetumescence.However,anyvolumereductionoreliminationofthelidocaineandepinephrinecomponentsinaTAADsolutionislikelytoadverselyaffectthedurationandefficacyoftheantibacterial,antiplateletandpostoperativeanalgesiceffectsofTAAD5152.iii. CriteriaforSubjectSelectionA.NumberofSubjects

Assuminga14%incidenceofSSI,andconsideringa50%reductionintheriskofSSIwithTAADasaclinicallysignificantimprovement(effectsize=50%)oursamplesizeanalysisestimatesthatapproximately330to660subjectswillberequiredtoachieveastatisticalpowerof0.8(Weusedagroupsequentialstatisticalanalysiswithoneintermediatestoppingpoint.Seestatisticalanalysisforsamplesizeestimatesandpoweranalysis).

B.GenderofSubjectsThisstudywillinvolvebothmalesandfemales.

C.AgeofSubjects:Participatingvolunteerpatientsmustbeatleast18yearsold.PediatricpatientswillonlybeenrolledwithFDAINDapproval.

D.RacialandEthnicOriginThereisnorestrictiononparticipationwithrespecttoracialorethnicorigin.

E.InclusionCriteria(Eligibilitycriteriaforparticipationasaresearchsubjectinclude:1.Subjectsgreaterthan18yearsofagescheduledforsurgicalproceduresconsideredtohaveahighriskforasurgicalsiteinfection(SSI)suchas1)secondaryrepairofaventralhernia,2)openbariatricsurgery,3)openabdominalcolorectalsurgery,4)traumasurgery,5)burnsurgeryor6)sternotomy.2.Patientsoughttohaveoneofthefollowingriskfactorsforsurgicalsiteinfection:emergencysurgery,obesity,diabetesmellitus,cancersurgery,beimmune-compromisedorotherwisebeatanincreasedriskforSSI,orbeinamedicallyindigentenvironmentwheresurgicalaseptictechniqueissuboptimal3.Onlyadultswillparticipateasresearchsubjects,unlessthereisspecificFDAapprovaltoenrollpersonslessthan18yearsofage.4.Thisstudywillinvolvebothmalesandfemales5.PatientsinASA(AmericanSocietyofAnesthesiology)class(IorIIorIIIorIV)willbeincluded.6.Foreachpatient,thewoundclassification,ASAclassification,traumaandburnclassificationwillbecarefullyrecorded.Abdominalwoundclassifications:Clean-Contaminated,Contaminated,orDirtyareeligibletoparticipate.7.Patientsmustbeappropriatelyscreenedfortheproposedsurgery.

11

F.ChoiceofAntibioticsThisisnotaclinicaltrialofantibiotics;ratherthisisaclinicaltrialcomparingtwomodesof

antibioticdelivery.Eachindividualresearchsitemustconsistentlyusethesameantibiotics.Allresearchsitesareencouragedtousecefazolinaloneorbothcefazolinandmetronidazolefor

TAADandIVantibioticdelivery.ForTAAD,individualresearchsiteswillhavetheoptiontousecefazolinaloneorbothcefazolin

andmetronidazole.WithappropriateFDAandIRBclearance,anindividualresearchsitemayuseawater-solubleantibiotic,otherthancefazolinormetronidazole,forTAAD.Suchanantibioticmustnothaveanyknownriskofcausingirritationortissuetoxicitywithsubcutaneousinjection.OtherantibioticsthathavebeenclearedbytheFDAforsubcutaneousinfiltrationmaybeusedinTAAD.

ForIVAD,anindividualresearchsitemustconsistentlyusethesameantibioticcombination.Thepreferredcombinationsarecefazolinaloneorcefazolinwithmetronidazole.IfanantibioticotherthancefazolinandmetronidazoleisusedforIVADalone,thenthecompatibilityoftheantibioticcombinationmustbewellestablishedandpre-approvedbytheFDA.G.PatientStratificationandMatching

ForeverypatienttheASAclassification,woundcontaminationclassification,degreeoftraumaordegreeofburnwillberecorded.Thismulticenterclinicaltrialisspecificallydesignedtobeinclusiveofdifferentsurgicalprocedures.ThisRCTdesignwillaccommodatealargerangeofresearchsitesandsurgicalproceduresandimprovethegeneralizabilityofresults. Thefollowingclassificationofpatientcharacteristicsandsurgicalprocedureswillberecorded 1.Immunocompromisedandcancerpatients

2.Obesepatients,3.Diabetics,4.Emergencyoperations,asdesignatedbythesurgeon,willbeincludedonlywiththeappropriateapprovaloftheinstitutionalIRBatforindividualresearchsites.Emergencycaseswillbeclassifiedtogetherwithotheremergencypatients.

Inordertofacilitatemultivariateanalysisandminimizevariance,thestatusofeachpatientwithrespecttoimmunosuppression,cancer,obesity,diabetesandemergencysurgery,willberecorded.H.ExclusionCriteria:Potentialsubjectswillbeexcludedbecauseofanyofthefollowing: 1.Proceduresinvolvingonlysimpleostomyclosures

2.Knownallergytocefazolinormetronidazoleoranantibioticpreferredandroutinelyusedbythesurgeon3.Personslessthan18yearsold,unlessthereisspecificFDAapprovaltoincludepersons<18years.4.EmergencyoperationasdesignatedbythesurgeonwillbeincludedonlywiththeappropriateapprovalbytheinstitutionalIRBatanindividualresearchsite5.Pregnantorbreast-feedingwomenareexcluded.6.Aknownbleeding/hemorrhagic/thromboticdisorderisexclusionaryunlessthereisawrittenclearancechart-noteorclearanceletterfromaprimarycarephysicianorhematologist7.Significantpsychiatricproblemswhichmightimpairabilitytogivetrulyinformedconsentorwhichmayimpairfollow-upcommunicationwiththesurgeonandstaff8.Clinicallysignificantcardiacarrhythmiasareexclusionaryunlessthereisawrittenclearancechart-noteorclearanceletterfromacardiologist9.Heart/liver/kidneydisease,neuropsychiatricdiseaseclassifyingpatientas≥ASAV10.Majorconcomitantinfectionssuchaspneumoniaorsepsis

12

11.Innon-emergencysurgery,pre-existingactivebacterialskininfectionatthetimeofthesurgicalincision;however,pre-existingbacterialinfectionsarenotexclusionaryinburnortraumapatients.12.Foreignmaterialintheincisionthatcannotberemoved13.Recentsystemicantimicrobialtherapy14.Clinicallysignificantrenalimpairmentoracreatinineclearance<30mL/min.

I.VulnerableSubjectsareexcluded1.Pregnantwomen2.Nursinghomeresidents,orotherinstitutionalizedpersonswhoarenotfullyalert,notcognizantorandnotabletogiveinformedconsentarenoteligibletoparticipateasaresearchsubject3.Children<18yearsofage,unlessthereisexplicitFDAapprovalofparticipationofpediatricpatients.

iv. MethodsandProceduresA.DefinitionsofTechnicalTerms,DegreeofObesity:

1.Obesity:BMI≥30to402.MorbidObesity:BMI≥40to503.SuperMorbidObesity≥50

B.SurgicalWoundClassification:DefinitionofSSIissubdividedintothreesubsets.�SuperficialIncisionalSSIisaninfectionwithin30daysofsurgeryinvolvingskinorsubcutaneoustissue�DeepIncisionalSSIisaninfectionwithin30daysaftersurgerywithoutanimplantor1yearifanimplantisleftinplaceandtheinfectionappearstoberelatedtothesurgeryandtheincisioninvolvesfasciaandmusclelayers�Organ/SpaceSSIisaninfectionoccurringwithin30daysofsurgerywithoutanimplantor1yearifanimplantisleftinplaceandtheinfectionappearstoberelatedtothesurgeryandtheinfectioninvolvesanyorgansorspacesopenedandmanipulatedduringthesurgery

ThefollowingcriteriaforadiagnosisofSSSarelistedinCDCGuidelineforPreventionofSurgicalSiteInfection,1999.GuidelineforPreventionofSurgicalSiteInfection,1999.www.cdc.gov/ncidod/dhqp/pdf/guidelines/SSI.pdfCRITERIAFORDEFININGASURGICALSITEINFECTION(SSI)SuperficialIncisionalSSI:� Infectionoccurswithin30daysaftertheoperation&�infectioninvolvesonlyskinorsubcutaneoustissueoftheincisionandatleastoneofthefollowing:1.Purulentdrainage,withorwithoutlaboratoryconfirmation,fromthesuperficialincision.2.Organismsisolatedfromanasepticallyobtainedcultureoffluidortissuefromthesuperficialincision.3.Atleastoneofthefollowingsignsorsymptomsofinfection:painortenderness,localizedswelling,redness,orheatandsuperficialincisionisdeliberatelyopenedbysurgeon,unlessincisionisculture-negative.4.DiagnosisofsuperficialincisionalSSIbythesurgeonorattendingphysician.DonotreportthefollowingconditionsasSSI:1.Stitchabscess(minimalinflammationanddischargeconfinedtothepointsofsuturepenetration).2.Infectionofanepisiotomyornewborncircumcisionsite.3.Infectedburnwound.4.IncisionalSSIthatextendsintothefascialandmusclelayers(seedeepincisionalSSI).

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DeepIncisionalSSI� Infectionoccurswithin30daysaftertheoperationifnoimplantisleftinplaceor�within1yearifimplantisinplace&theinfectionappearsrelatedtothesurgeryand�infectioninvolvesdeepsofttissues(e.g.,fascialandmuscle)oftheincisionandatleastoneofthefollowing:1.Purulentdrainagefromthedeepincisionbutnotfromtheorgan/spacecomponentofthesurgicalsite.2.Adeepincisionspontaneouslydehiscesorisdeliberatelyopenedbyasurgeonwhenthepatienthasatleastoneofthefollowingsignsorsymptoms:fever(>38ºC),localizedpain,ortenderness,unlesssiteisculture-negative.3.Anabscessorotherevidenceofinfectioninvolvingthedeepincisionisfoundondirectexamination,duringreoperation,orbyhistopathologicorradiologicexamination.4.DiagnosisofadeepincisionalSSIbyasurgeonorattendingphysician.Notes:1.ReportinfectionthatinvolvesbothsuperficialanddeepincisionsitesasdeepincisionalSSI.2.Reportanorgan/spaceSSIthatdrainsthroughtheincisionasadeepincisionalSSI.Organ/SpaceSSI�Infectionoccurswithin30daysaftertheoperationifnoimplantisleftinplaceor�within1yearifimplantisinplace&infectionappearsrelatedtotheoperationand�infectioninvolvesanypartoftheanatomy(e.g.,organsorspaces),otherthantheincision,whichwasopenedormanipulatedduringanoperationandatleastoneofthefollowing:1.Purulentdrainagefromadrainthatisplacedthroughastabwound‡intotheorgan/space.2.Organismsisolatedfromanasepticallyobtainedcultureoffluidortissueintheorgan/space.3.Anabscessorotherevidenceofinfectioninvolvingtheorgan/spacethatisfoundondirectexamination,duringreoperation,orbyhistopathologicorradiologicexamination.4.Diagnosisofanorgan/spaceSSIbyasurgeonorattendingphysician.C.FormulationofTAADSolution:

1.One-literbagofphysiologic0.9%salineassolvent2.Lidocaine1gmandEpinephrine1mgin100ml3.Sodiumbicarbonate10mEqin10ml4.Cefazolin,1gmofpowderedcefazolinperbagofTAADsolution,dissolvedin10mlofsalineobtainedfromthe1Lbagofphysiologicsaline.MaximumdoseofcefazolinbyTAADis2gm.5.Metronidazole,500mgperbagofTAADsolution,wheremetronidazoleisavailableas500mgin100mlandtotalTAADdosenottoexceed1000mg.6.IndividualresearchsitesmayopttoroutinelysubstituteoneormorespecifiedantibioticsforIVantibioticdelivery,insteadofcefazolinandmetronidazole,butonlywithFDAandIRBclearance.

7.MethodofTAADSolutionFormulation(PreparationofthemixtureoftheTAADsolution):

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a.Thepreparationandmixtureofthetumescentantibioticdelivery(TAAD)solutionshouldbedonewithinlessthan4hoursoftheinitiationofthesubcutaneoustumescentinfiltration.TAADsolutioncanbestoredfor4hoursatroomtemperatureandfor24hoursifrefrigerated.b.OnlyalicensedprofessionalwhohasreceivedtrainingandinstructioninthepreparationandmixingoftheTAADshouldmixandpreparetheTAADsolution.c.DuringthepreparationandmixingoftheTAADsolutionnooneshouldengageinconversationorinanywaydistractthepersonwhoispreparingtheTAADsolution.d.AseachcomponentoftheTAADsolutionisaddedtothe1literbagofTAADsolution,thepersonwhoismixingandpreparingtheTAADsolutionshouldaudiblyandclearlycall-outthenameofthecomponentbeingaddedandcheck-offthecomponentfromthelistofcomponentsorderedfortheTAADsolution.e.TheTAADsolutionshouldnotbepreparedwithoutlegiblesignedorderswrittenbyaphysician,physician’sassistantornurse-practitioner.f.ThecomponentsofeachbagofTAADsolution(oradrugco-kitcontainingallthenecessaryingredientsforpreparingaTAADsolution)willincludethefollowingitems:☐1literbagof0.9%physiologicsaline(sodiumchloride) ☐1gramoflidocaineand1milligramofepinephrinein100ml(two50mlbottles)of1%lidocaineand

epinephrine1:100,000,(orone50mlbottleof2%lidocainewithepinephrine1:50,000).☐10milliequivalentsofsodiumbicarbonatein10mlof8.4%sodiumbicarbonate ☐1000mgvialofcefazolinpowder ☐500mgofmetronidazoleina100mlbagofsolution☐Eitherasterilea30mlsyringeandan18gaugeneedle☐Twoadhesivesafetylabelsstating,“SubcutaneousTumescentLidocaine,NOTforIV”☐Onelabelindicatingthenameofthepatient,thenameofthephysicianwhowrotetheorderfortheTAADsolution,thenameofthepersonwhopreparedthebagofTAADsolution,alistofthedrugcontentsofthebag,thedateandtimeofpreparation.g.EachbagofTAADsolutionshouldbepreparedonacleansurfaceasfollows:1.Applyonesafetylabeltoeachsideofthe1literbagofsalineUsingthesyringeandhypodermicneedle:2.ThemaximumcapacityoftheIVbagmayvarydependingonthemanufacturer.Inordertoaccommodatetheadditional210mloffluid(lidocaine100ml,metronidazole100ml&NaBicarb10ml)thatwillbeaddedtothe1000mlbagofsalinewhenpreparingtheTAADsolution,itmaybenecessaryremovesomevolumesalinebeforeinjectingthelidocaineandmetronidazole.3.Transfer100mlof1%lidocainewithepinephrine1:100,000intotheIVbag4.Transfer10mlof8.4%sodiumbicarbonateintotheIVbag5.Aspirate10mlofsolutionfromtheIVbagintothesyringeandinjectitintothevialcontainingthe1000mg=1gmoflyophilizedcefazolinpowder.Shakethevialofcefazolintopromotedissolutionofthecefazolinpowder.Allowthevialtostandforaminuteortwowhilethecefazolinpowderbecomes

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completelydissolved.Aspiratethe10mlofdissolvedcefazolinintothesyringeandinjectitintotheIVbagofsaline.6.Usingthesamesterilesyringeandneedle,transferthecontentsofthe100mlbagofmetronidazolesolution(500mg)intotheofIVbagofsolution.7.ApplythelabellistingthenamesofthedrugsandthenameofthecliniciantothebagofTAADsolution.8.StorethenewlymixedbagofTAADsolutionatroom-temperatureinasecureenvironment(forupto4hours)untilreadyforsubcutaneousinfiltration.Ifthetumescentinfiltrationisdelayedbeyond4hoursaftermixingtheTAADsolution,theTAADbagcanberefrigeratedandstoredforupto24hours.

D.MinimumVolumeofTAADInfiltration:

ThevolumeofTAADsolutiontobeusedinthisTAADclinicaltrialis1bagto2bags.Anaverageadultcaneasilybegivenatleast1literofTAADsolution.Forthisrandomizedclinicaltrial(RCT),the1000mlistheminimalvolumeofTAADsolutionforSSIprevention.ThevolumeofTAADsolutiontobeusedisaclinicaldecisiontobemadebythesurgeonoranesthesiologist.Asmallervolumecanbeinfiltratedatthesurgeon’sdiscretion,especiallyinthincancerpatientswhohavelittlesubcutaneousfat.IfthevolumeofTAADsolutionistoosmall,theremaybenobenefittoTAAD.Obesepatientsoughttobegiven2litersofTAADsolution.ThetotalvolumeofTAADsolutionandtheformulationoftheTAADsolutionmustberecorded.InsufficientvolumeofTAADwillexcludethesubjectfromthisRCT.

E.TumescentLidocaineAnesthesia:Tumescentlidocainelocalanesthesiaisamethodofregionallocalanesthesia.Forthepresentresearchthemaximumdosageoftumescentlidocainewillnotexceed28mg/kg,withorwithoutgeneralanesthesia(GA).Aprevious,WIRB-approvedphaseIclinicaltrialhasestablishedthattheestimatedriskofexceeding6mgoflidocaineperliterofserumatadosageof28mg/kgoflidocaineinatumescentsolutionislessthan1per5,000,000(KleinJA,JeskeDR.EstimatedMaximalSafeDosagesofTumescentLidocaine.AnesthAnalg.2016;122:1350-9).TheFDAhasnoscientificdatarelatingtotherecommendedmaximumsafedosageoflidocaineforinfiltrationlocalanesthesia(basedonaFreedomofInformationActinquiry).TLAhasbeenwidelyusedsince1987fortumescentliposuction.GuidelinespublishedbytheAmericanSocietyofPlasticSurgeryandtheAmericanSocietyforDermatologicSurgeryspecify35mg/kgto55mg/kgfortherecommendedmaximumsafedosageoftumescentlidocaineforliposuction.

F.MethodandDevicesforTAADInfiltration.1.TumescentInfiltrationCannulas:HKSurgicaltumescentinfiltrationcathetersorcannulaswillbeusedforinfiltrationofTAADsolution.Twotypesoftumescentinfiltrationcannulasareavailable:reusablestainlesssteeltumescentinfiltrationcannulas(HKMontyinfiltrationcannulas)orasingle-usedisposablesterileplasticcatheter(HKSubQKath).NodevicewillbeusedwithoutFDA510(k)clearanceorinvestigativedeviceexemption(IDE)approval.2.TumescentInfiltrationPump:EitherananalogHKSurgicalanalogperistalticinfiltrationpump(HKKIPII)oranHKSurgicaldigitalinfiltrationpump(HKKTP).BothpumpshaveFDA510(k)clearance.3.Disposablesingle-usesteriletumescentinfiltration-pumptubingsuppliedbyHKSurgical.

G.ApproximateNumberofSubjectsMulticenterCenterTrial:approximately330to660(Groupsequentialanalysiswithoneintermediatestoppingpointwillbeused)forastatisticalpowerof0.8.

H.PrimaryOutcomeVariable:DiagnosisofSSIwithin30daysofsurgery(BinaryData).SurgicalsiteinfectionisdefinedbytheCDCcriteria(seeivBabove).

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I.SecondaryOutcomeVariables:1.DiagnosisofVenousThromboembolism(VTE)includingdeepveinthrombosis(DVT)orpulmonaryembolism(PE)within30daysofsurgery.ThedefinitionanddiagnosticcriteriaforVTEandroutinemethodsofVTEprophylaxisusedbyeachresearchsitewillberecorded.ThemethodofdiagnosisofVTEmayvaryamongresearchsites.Butwithinanygivensitethediagnosticmethodsshouldbeconsistentlythesame.2.SafetyofTAAD:Incidenceofadverseeventsassociatedwith

a)DilutesubcutaneousTAADsolutionb)InfiltrationofTAADsolution

Thefollowingsafetyassessmentchecklistwillbecompletedbetween24to36hoursafterTAADinfiltration:Indicate(below)ifanyofthefollowingtumescent-infiltrationsitesignsandsymptomsappearwithinthefirst24hoursaftersurgery:TAADADVERSEEVENTSQUESTIONNAIREProblems:Check-OffOneAnswerper

Problem

Grade1None

Grade2

Mild/Moderate

Grade3Severe

Grade4

Life-Threatening

1.DERMATOLOGIC

Bruising None AtTAADsite Excessive,Unusual NA

Petechiae None

AtTAADsite Generalized,Widespread

NA

Pruritus None

AtTAADsite Generalized,Widespread

NA

Induration,Swelling None

AtTAADsite Generalized,Widespread

PainorTenderness None AtTAADsite Excessive,Unusual NA

Rash,Erythema None AtTAADsite Diffuse NA

Rash,Eczematous None AtTAADsite Diffuse NA

Rash,Maculopapular

None AtTAADsite Diffuse

NA

Rash,Bullous None

AtTAADsite Stevens-Johnson ToxicEpidermalNecrolysis

Cellulitis None

OnlyPOAntibiotics IVAntibiotics

Sepsis,TissueNecrosis

NecrotizingFasciitis None

NA LimitedtoTAADSite

Sepsis,WidespreadNecrosis

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2.CARDIOVASCULAR

ThrombosisorPulmonaryEmbolism(PE)

NoSymptoms

Symptoms&Nointerventionindicated

Symptoms & Intervention indicated

Life-threatening PE

Arrhythmia

NoSymptoms&Nointervention

NoSymptoms&Nourgentintervention

Symptoms&Nourgentintervention

Life-ThreateningArrhythmia

Hypertension ≤160/100 160/100to180/110

>180/110 MalignantHypertension

Hypotension NoSymptoms

RequiresPOfluids

IVfluidsneeded Shock

Cardiac Ischemia/MI NA NA

+TestsorSymptoms

UnstableorAcuteMI

Congestive Heart failure (CHF)

NoSymptoms

Symptomsuponexertion

Symptomsatrest,NeedsOxygen

LifeThreatening,UrgentIntervention

Vasovagal Reaction

None Nearsyncope Syncope

Hemorrhage NA Notransfusion Transfusion≤2unitsPRBC

>2unitsPackedRBC(PRBC)

3.ALLERGICREACTIONS

Anaphylaxis None NA GradualOnset ImmediateOnset

Angioedema

None

NoAirwayInvolvement

MildAirwayInvolvementNoInterventionRequired

ThreatenedCompleteAirwayObstruction

4.GI

diarrhea NoneorMinimal

≥3to6overbaseline

≥7stoolsin24hours

Massive,Life-threatening

nausea

Transient

Persistent,Decreasedoralintake24-48hrs

MinimalIntake≥24-48hrs,RequiresIVFluids

Life-Threatening,HypotensiveShock

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Vomiting

NonetoMinimal,AbletoEat

Frequent,MildDehydration

Persistent,RequiresIVFluids

Life-Threatening,HypotensiveShock

Pancreatitis None

Mild Moderate SevereorLife-Threatening

5.MUSCULOSKELETAL

Arthralgia,Arthritis None

Mild,NoInterferencewithActivities

Moderate,InterferswithNormalActivities

Severe,UnabletodoSelf-Care

Myalgia,MusclePains

None

Mild,NoInterferencewithActivities

Moderate,InterferswithNormalActivities

Severe,UnabletodoSelf-Care

6.NEUROLOGIC

AlteredMentalStatus

None

MildLethargy,Somnolence

Confusion,MemoryImpairment

Delirium,Obtundation,Coma

Ataxia None

Detectable,NormalActivities

Moderate,InterferswithNormalActivities

Severe,UnabletodoSelf-Care

Headache None

Mild,Doesn'tInterferwithActivity

Moderate,InterferswithActivity

Severe,UnabletodoSelf-Care

WeaknessNeuromuscular

None

Mild,Doesn'tInterferwithActivity

Moderate,InterferswithActivity

Severe,UnabletodoSelf-Care,orAffectsBreathing

Seizures None NA 1to3Seizures ProlongedSeizures,RefractorytoTreatment

Syncope

None

Mild,Vaso-VagalNearSyncope

LossofConsciousness,NoTreatmentRequired

LossofConsciousness,RequiresTreatment

7.RESPIRATORY

AcuteBronchospam

None

MildSymptoms,NotreamentRequires

Moderate,RequiresTreatment

Severe,PossiblyRequiresIntubation

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Dyspnea None

DyspneaonExertion DyspneaatRest

RespiratoryFailure,RequiresIntubation

9.SENSORY

HearingLoss None

Mild,NoTreatmentRequired

Moderate,InterfereswithActivity

ProfoundBilateralHearingLoss

Tinnitus None

Mild,NoTreatmentRequired

Moderate,InterfereswithActivity

Severe,PreventsNormalActivities

Vertigo None

Mild,NoTreatmentRequired

Moderate,InterfereswithActivity

Severe,PreventsNormalActivities

10.SYSTEMIC

Chills None

Mild,NoTreatmentRequired

Moderate,InterfereswithActivity

Severe,PreventsNormalActivities

FatigueMalaise None

Mild,NoTreatmentRequired

Moderate,InterfereswithActivity

Severe,PreventsNormalActivities

Fever ≤38.6 38.6-39.3 39.4-39.9 ≥40

LABORATORYVALUES:(ComparedtoBaselinePriortoTAAD)

ALTSGPT

WithinNormalLimitsorBorderline NA

SignificantElevation

SevereHepatitis

ASTSGOT

WithinNormalLimitsorBorderline NA

SignificantElevation

SevereHepatitis

Amylase

WithinNormalLimitsorBorderline NA

SignificantElevation

LifeThreateningPancreatitis

HEMATOLOGIC

WBC

WithinNormalLimitsor

NA SevereLeukopenia

LifeThreateningLeukopenia

20

Borderline

AbsoluteNeutrophilCount

WithinNormalLimitsorBorderline NA

SevereLeukopenia

LifeThreateningLeukopenia

PlateletCount

WithinNormalLimitsorBorderline NA

SevereThrombocytopenia

LifeThreateningThrombocytopenia

AENotOtherwiseSpecified

3.SafetyandefficacyofTLAsolution4.Safetyandefficacyofsubcutaneousinfiltrationcatheter5.Safetyandefficacyofperistaltictumescentinfiltrationpumpfor

J.OtherOutcomeVariables1.ICUadmission(orequivalentunit)andnumberofhoursinICU2.LengthofStay(LOS)inhospitalaftersurgery(hours)3.Timeinpost-operative/post-anesthesiarecoveryunit.4.Timefromarrivalinpost-oprecoverytotimeofambulation).5.Post-OpNarcoticRequirements(totalmgandmg/kg)6.Unexpectedre-admissiontohospital(foranyreason)≤30daysofsurgery(BinaryData)7.GeneralAnesthesiaRequirements(QuantitativeMeasure)8.DiagnosisofSepsis9.Diagnosisofsystemicinflammatoryresponsesyndrome(SIRS)10.DiagnosisofC.Difficilecolitis

K.IndependentPredictorVariables:Thefollowingisalistofdataitemstobecollectedpriorto,duringoraftersurgery.

1.PatientRoutineDemographicData:Identification,Age,Sex,Height,Weight,BMI,Race2.Surgeon(s):Name,age,yearsofpost-residencyexperience,boardcertificationorpost-graduateresidencystatus3.Surgeon’schoiceofantibioticstobegivenbyTAADandbyIVAD4.Surgeon’sapproximateannulvolumeofsurgicalproceduressimilartothesurgeriesperformedinthepresentresearch.5.PrimarySurgicalDiagnosis

6.SurgicalProcedure(OpenColonRectalSurgery,OpenBariatricSurgery,etc.)7.TotalDosagesofallGeneralAnestheticAgents8.Useofandtypeofsubcutaneoussutures9.Materialusedforseromuscularsuturing10.AmericanSocietyofAnesthesiologists(ASA)status.11.ListofSignificantMedicalProblemsandCo-Morbidities(Endocrine/Diabetes,Hypertension,Cardiovascular,Pulmonary,Renal,GI,etc)12.ConcurrentDrugs&Dosages13.ImmuneStatus(Diabetesmellitus,Chemotherapy,Radiationtherapy,Corticosteroidorotherimmunosuppressivetherapy,HIVstatus,etc)

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14.Steroid(glucocorticoids)name,dosageanddurationofuse15.Immunosuppressantdruguse(non-steroidal):name,dosagedurationofuse16.Drug(s)knowntosignificantlyaffecthemostasis(plateletfunctioninhibitors,aspirin,ibuprofen,clopidogrel,heparin,etc).17.DrugAllergies18.OccurrenceofConcomitantantibioticIVADprophylaxis(appropriate/adequateorinappropriate/inadequateaccordingtoCDCguidelines)19.Takinganydrug(s)knowntointerferewiththemetabolismoflidocaine,cefazolinormetronidazoleortoadverselyinteractwiththesedrugs(Erythromycin,Clarithromycin,ketoconazole,fluconazole,sertraline(Zoloft),ciprofloxacin.20.Historyofradiationtherapyinvolvingtheareaneartheproposedincisionsite21.Intraoperativehypotensionorhypertension22.Intraoperativehypothermia23.Operativetime:incision-to-close24.AbdominalWoundClass:Clean,Clean-Contaminated,Contaminated,Dirty(SeeAppendix)25.Numberoftimesperdaythatincisionsiteiswashedwithsoapandwater26.Thicknessofmidlineabdominalsubcutaneousfat(estimatedpriortotumescentinfiltration)measuredbyultrasoundifavailable.27.HistoryofSmoking

28.Anyconditionwithsignificantriskofsurgicalsitewoundinfections29.ListofPriorSurgeries30.Pre-existingorConcurrentInfections(cutaneous,urinary,pneumoniaareexclusionary)31.ListofmeasuresforpreventingVTEactuallyemployedforeachindividualsubject

32.PsychologicalDiagnoses,majordepression,psychosis,anxietydisorder.33.Presenceanddurationofprolongedwounddrainage

34.TimeofcompletionoftheIVADwillbeclassifiedintothefollowinggroups: a)IVADcompletedmorethan60minutespriortoincision b)IVADcompletedmorethan30minutesandlessthan60minutespriortoincision c)IVADcompletedbeforeincisionandlessthan30minutespriortoincision d)IVADafterincisionandduringthesurgery e)IVADafterthesurgicalclosure f)NoIVADL.DataMonitoringCommittee:DatawillbemonitoredbytheClinicalTrialsStatisticsCollaboratory,DepartmentofStatistics,UniversityofCalifornia,Riverside,CA

•DanielJeskePhD,Chair,DepartmentofStatistics,UCR•ClinicalTrialCoordinator:TobedeterminedAdditionalmembersoftheDataMonitoringCommitteemayincludeselectedphysiciansaswellasgraduatestudentsandfacultyintheUCRMedicalSchoolortheUCRDepartmentofStatistics,UniversityofCalifornia,Riverside,willcomposethedatamonitoringcommitteetoassurethesafetyofthesubjects.Thestatisticaldesignofthistrialincludesperiodicgroupsequentialanalysis(withonestoppingpoint)toallowearlyterminationofthestudyintheeventofearlystagestatisticalsignificance.

M.ClinicalOversightCommittee:•TherewillbeanIndependentClinicalOversiteCommitteethatwillmonitortheclinicaldata,protocolcomplianceandallreportsofadverseoutcomes.•AgroupofTrialSitePrincipalInvestigatorswillperiodicallyreviewtheclinicaldata,protocolcomplianceandanyreportedadverseoutcomesandconferwiththeDataMonitoringCommitteeandtheClinicalOversiteCommittee.

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•AteachclinicalresearchsitetheSub-PrincipalInvestigatorwillberesponsibleforassuringthesafetyofthesubjectsatthatsite.

N.Thisisacontrolledopenlabelrandomizedclinicaltrial(RCT):•ThistrialisarandomizedclinicaltrialoftheTumescentAntibioticDeliveryplusIntravenousAntibioticDelivery(TAAD+IVAD)versusIVADalone.•Becauseofthenatureoftumescentinfiltration,itisnotpossibletomaskthetreatmentassignment.ThepatientandtheclinicianwhodeliverstheTAADinfiltrationcannotbe“blinded”tothetreatmentassignment.•Itispreferredthattheanother(different)clinicianwilldotheclinicalevaluationslookingforsurgicalsiteinfections(SSA).

O.StatisticalAnalysis,PowerCalculationsandSamplesSizeEstimationDanielJeskePhDandJoyceFu,DepartmentofStatistics,UniversityofCalifornia,Riversidehelpeddesignthestatisticalanalysisforthepresentclinicalinvestigation.Wewillusegroupsequentialanalysiswithonestoppingpoints.Usingbalancedtreatmentallocation,assumingtheincidenceofsurgicalsiteinfectioninthetargetedpopulationis0.14andananticipatedeffectsizeof50percentatalevelofsignificance(alpha)of0.05andapowerof0.8,theestimatedsamplesizefortheTAADRCTiseither330(atfirststoppingpointwith165control=IVADand165treatment=IVAD+TAAD)or660patients.SeeTAADSampleSizeEstimate,attachedasanappendix.

P.TreatmentAssignmentandRandomizationOnlyafterhavingobtainedappropriateinformedconsentfromthepatientwillthepatientberandomlyassignedtoatreatment.AllpatientswillreceiveIVADofcefazolin.Thetiming(30to60minutespriortosurgicalincision)andmg/kgdosageofIVADantibioticwillconformtoacceptedCDCGuidelinesforSSIProphylaxisandthehospitalpolicies.

Inthisstudy,patientswillberandomlyassignedtooneof2treatmentgroups:

•Controlgroup(IVAD)willreceiveIVADonly[50%ofpatients]•Treatmentgroup(TAAD+IVAD)willreceivebothTAADandIVAD[50%ofpatients]

Thefollowingmethodofbalancedrandomassignmentforanopen-labeldesignassuresthattheintendedproportionofpatientswillbeassignedtotherespectivetreatmentgroups.Forexample,atagivenresearchsite,iftherehavebeen4npatientsenrolledwithinasetofmatchedpatients,then2npatientswillbeassignedtoreceivecontroltreatmentIVADand2npatientsassignedtoreceivetreatmentTAAD+IVAD.

Balancedrandomizationwillbephysicallyaccomplishedbyassignmentdeterminedbyflippingafaircoin.Thepersonwhoperformsthefollowingrandomizationtaskshouldnotbeasurgeonoramemberofthesurgicalteam.Specifically,bywayofexample,ifaresearchsiteexpectstoenroll24patients,then1)Sequentiallylabel24envelopsand24cards(5x7inch)from1to24.2)Placeeachcardinsidethecorrespondinglynumberedenvelope.3)Separatetheenvelops-cardsintogroupsoffoureach:{1,2,3,4},{5,6,7,8},…,{21,22,23,24}.4)Selectasetof4envelops,andremoveacardfromoneoftheenvelopes.5)Flipthecoin:

a)IfthecoinshowsheadsthenwriteIVADonthechosencardb)IfthecoinshowstailswriteIVAD+TLDonthecard

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c)After2patientshavebeenassignedtoIVADthentheremainingcard(s)willbeassignedtoIVAD+TAAD.d)Thus,witheachgroupof4cards,exactly2cardswillberandomlyassignedtoIVADand2cardswillberandomlyassignedtoIVAD+TAAD.

6)Foldeachofthecardsonce,withthewrittenassignmentobscuredfromview,thenreplaceeachcardintoitscorrespondingenvelopeandsealallfourenvelops.7)Repeatthissequenceuntilall24cards-envelopshavebeengivenatreatmentassignment.8)Arrangetheenvelopsintonumericalorder9)Onthedayofasubject’ssurgery,afterthepatienthassignedtheinformedconsentandthepatienthasbeenscreenedanddeterminedtoconformtoalloftheinclusioncriteria,butnoneoftheexclusioncriteria,thenextenvelopinthesequence(theenvelophavingthelowestnumber)isassignedtothepatient.(Ingeneral,treatmentassignmentshouldnotbemademorethan12hourspriortosurgeryinordertoavoidpossibleconfusionifthesurgeryweretobecancelled.10)Theassignedenvelopisopenedbyaclinician,thetreatmentindicatedonthecardisassignedtothepatientandtheappropriateordersforIVADaloneorIVAD+TAADwillbeformallywrittenonthehospital’sroutinepre-operativeorderform(s).11)IfthecardindicatesTAAD+IVADthenanassignedresearch-teammemberwillpersonallysuperviseandwitnessthepreparationoftheTAADsolutionorpersonallymixthebag(s)ofTAADsolution.EachbagofTAADsolutionwillbelabeled(frontandback)withHKSafetyLabels,whichstate“NOTforIVUSE”12)Thepatient’snameiswrittenonthecardandthecardisfiledinasecure(locked)locationforfuturereference.13)Thepatient’sname,dateofrandomizationandtreatmentassignmentarerecordedonaconfidentialmasterlistcontainingthenamesofallsubjectsandcorrespondingtreatmentassignments.14)ThemasterlistofpatientsandindividualtreatmentassignmentswillbeemailedtothePIandtheSafetymonitoringcommitteeaftereverysubjecthasbeenenteredintotheclinicaltrial.15)Alternatively,dependingonfuturefunding,wemightinstituteaniPadbasedrandomizationprocesswithfeaturessimilartothosedescribedabove.

Q.FormulationandDosageofTAADSolution:TAADcanconsistofcefazolinandmetronidazoleinasolutionoftumescentlidocaineanesthesia(TLA).EachliterbagofTLAsolutionconsistsoflidocaine,epinephrine,sodiumbicarbonateaddedtoa1literbagof0.9%salineorlactatedRinger’ssolutionorHartman’ssolution.EachbagofTAADsolutionwillcontain:Cefazolin1gmasdesiccatedpowderdissolvedinsalinefromthebag0.9%salineorabalancedsaltsolution.Metronidazole500mg/100mlLidocaine1000mg&Epinephrine1mgin100mloflidocaine(1%)withepinephrine(1;100,000)SodiumBicarbonate10mEqin10mlofsodiumbicarbonate(8.4%)PhysiologicSaline0.9%1000mlTotalvolume=1210ml

R.TAADDosages&Delivery:Withgeneralanesthesia,inpatientswhodonothavesignificantcardiac,hepaticorrenalimpairment,themaximumlidocainemg/kgdosagewillnotexceed28mg/kg,which,ina70kgpatient,isapproximately2gmoflidocainein2bagsofTAADsolution.Patientswhodohavesignificantcardiac,hepaticorrenalimpairmentareexcludedfromparticipatinginthisTAADRCT.

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Withoutoutgeneralanesthesia,themaximumlidocainemg/kgdosagewillnotexceed28mg/kg,which,ina70kgpatient,isapproximately2gmoflidocainein2bagsofTAADsolution.

ThetotalvolumeofTAADsolutionwillprobablyrangefrom1210mlinsmallpatients

andupto2420mlinobesepatients;inotherwords,approximately1to2bagsofTAADsolution.TheminimumvolumeofTAADsolution(inverythinpatients)is500ml.ThedeterminationoftheactualvolumeofTAADsolutiontobeinfiltratedismadebythesurgeonoranesthesiologist.Theinitialstudieswillallowamorepreciseestimateoftherangeofvolumes.ThetargetedareaofsubcutaneoustissuetobeinfiltratedwithTAADsolutionshouldincludetheanticipatedsurgicalincisionlineplusthesurroundingborderareahavingamarginof10to20cmoneachsideoftheincisionsite.Fortheabdomen,thetotalwidthofsubcutaneoustumescence(theambitofTAADinfiltration)willbeabout20to40cm.

TotalTAADantibioticmgdosageswillconformtocommunitystandardsofcare,whichmayexceedantiquatedpackageinsertlabeling.Recentpublicationshaveshownthatincertainclinicalsituations(e.g.obesity)thebioavailability,peakconcentration(Cmax)andTimeAboveMIC(T>MIC)ofantibioticsinsubcutaneoustissuearesub-therapeutic.Thus,recentpeer-reviewedevidencebasedmgdoserecommendationstypicallyexceedcefazolinproductlabeling.

DeliveryofTAADsolutionbysubcutaneousinfiltrationwillbeaccomplishedusingHKSurgicalperistalticinfiltrationpump,peristalticinfiltrationtubing,andSubQKaths(disposable,singleuse,subcutaneousinfiltrationcannulas).AlldeviceswillhaveFDA510(k)clearanceorFDAinvestigativedeviceexemption(IDE).

InstructionsforPreparingTAADSolutionwillbeincludedintheresearchmanual.InstructionsforTumescentInfiltrationwillbeincludedintheresearchmanual.S.ResearchDesign:DrugDeliveryTimingandTechnique

•IVADtiming:ForIVADalone(withoutTAAD)theIVADinfusionshouldbecompletedwithin30to60minutespriortosurgicalskinincision.TheactualtimefromstarttocompletionofIVADwillberecorded.•TAADtimingandtechnique:infiltrationtobecompletedlessthan4hourspriortoskinincision.ForIVAD+TAAD,theIVADwillbeinitiatedandcompletedbeforetheincision.TheactualtimefromstarttocompletionofIVADwillberecorded.•SubcutaneousinfiltrationwillbeaccomplishedbyusingHKtumescentinfiltrationcannulasandHKperistaltictumescentinfiltrationpumpandinfiltrationpumptubing.AlldeviceswillhaveFDAclearance/approval.InfiltrationprocedurewillbecarriedoutwitheitherthepatientawakewithminimalornosedationorwithIVorIMsedationorwhilethepatientisundergeneralanesthesia.Thepatientandsurgeonwilldeterminewhichoftheseinfiltrationoptionswillbeused.

T.CriteriaforDiagnosisofSSI,VTE&SepsisCriteriaforDiagnosisofSSIwillbedefinedaccordingtothecriteriaoftheCentersforDiseaseControlupdatedandpublishedAugust201153.AdmittedlytheCDCdefinitioniscomplexandrequiressometrainingforeffectiveuse.SeesectionivBabove,orequivalentlywww.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf.

“SignificantSSI”isdefinedasaSSIthatrequirestheuseofadditionalhealthcareresources.OnlysignificantSSIwillbeconsideredinthefinalstatisticalanalysis.Thiswillavoid

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confoundingeffectofincluding“false-positive”resultsassociatedwithtrivialornormalincision-siteinflammationortumescentfluiddrainagefromanincisionsite. WerecognizethattheCDCdefinitionofSSIincludeselementsthatcannoteasilybestandardizedsuchasaclinicaldiagnosisofSSIbyaclinician,ortheclinicaldecisiontosubmitwoundswabsforbacterialculture.CriteriaandMethodsforDiagnosisofVTEtobedeterminedandstandardizedbyeachresearchsite.CriteriaandMethodsforDiagnosisofSepsistobedeterminedandstandardizedbyeachresearchsite.

U.MethodstoReducePotentialforBiasinOutcomeDetermination:Therewillbetwoseparatetypesofquestionnaires.SSI,VTE,SepsisQuestionnaires:Post-operativequestionnairesconcernedwithdeterminingtheoccurrenceofSSI,VTE,Sepsiswillnotcontainquestionsthatwouldallowtheinterviewertodetermineinferorguesswhichmodeofantibioticdeliverywasassignedtothesubject.Thepersonwhoconductstheinterviewwillbeinstructednottodiscussthemodeofantibioticdelivery.ModeofDeliverySideEffectsQuestionnaire:Therewillbetwoquestionnairesregardingpossiblesideeffectsoftumescentantibioticdelivery(TAAD).Onequestionnairewillbeconcernedwithpossibleacutelocaltissuetoxicityandacutesystemictoxicity,whichwillbeadministered18to36hoursaftersurgery.Thesecondquestionnairewillbea“dischargequestionnaire”tobecompletedonthedayofdischargefromthehospitalorclinic.Differentpersonswillbeassignedtoadministerthetwodifferentquestionnaires.Thepersonswhoadministerwillbe“SSI,VTE,Sepsis”questionnaireswillbeinstructedtonotdiscusstheirresultswillthepersonswhoadministerthe“SideEffects”questionnaire.V.Methodsofpost-dischargesurveillanceforSSIorVTE

Fundamentaltotheprospectivedesignofthisclinicaltrialisafeasible,valid,reliableandstandardizedmeansofdefininganddetectingSSIand/orVTEduringhospitalizationandafterdischarge.PatientswhohaveanSSIorVTEafterdischargewillbeidentifiedbyoneofthefollowingPost-DischargeSurvey(PDS)techniques:1.Follow-upclinicalinterviewandquestionnaire.Theinterviewandquestionnairewillbeconductedbyadesignatedhealthcareprofessional30to45daysaftersurgery.BecauseoflogisticalandeconomicconstraintsadditionalPDSmethodsmayinclude:2.Post-dischargequestionnaireforpatient(telephone,textmessage,onlinewebsitesurvey,mailoremail)3.CardsgiventopatientstofacilitatenotificationofhealthcarepersonnelofaSSIorVTEbymail,emailortelephonecall4.Medicalrecordchartreviewwiththeintenttoidentify

a.Readmissionsb.Additionalsurgicalproceduresc.Positiveculturesobtainedduringhospitalizationorafterdischarged.Reviewofoperatinglogstosearchforevidenceofasurgicalrevisione.ReviewofRadiology/Ultrasounddiagnostictests

5.DataCollectionGuidelinesanddatacollectionformswillbespecifiedintheresearchers’handbook.6.DataMonitoringGuidelineswillbespecifiedintheresearchers’handbook.7.MonitoringforAdverseEvents:inadditiontosearchforevidenceofSSIandVTE,clinicalobservationwilldocumentanyevidenceofrash,subcutaneoustissueinflammationortoxicity,

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dyspnea,heartpalpations,irregularheartrate,chestpain,headaches,focalweakness,confusion,gastrointestinalirritation,diarrhea,hematemesis,blacktarrystoolsandotheradverseevents.

LocationandDescriptionofSurgicalFacilitiesAllsurgerieswillbeperformedinsurgicalfacilitiesorhospitalsthathavebeenaccreditedbythelocalorstategovernment.Specificresearchsitesandsurgicalfacilitiesremaintobedetermined.

DurationofSubjects’ResearchParticipationPre-Op:Forresearchsubjectsinthisclinicaltrialthereshouldbeminimalextratime-commitmentbeforethedayofsurgery.Pre-operativehistory,physicalexamination,diagnosticevaluationandclearanceprocedurespriortothesurgeryshouldnotrequirethepatienttospendanyextratimepriortothesurgery.Post-Op:Afterthesurgery,theresearchstaffwillcontactthepatientforoneortwobriefpostoperativefollow-upconversationsandquestionnaires.Thirtyto45daysaftersurgery,allsubjectswillberequiredtoparticipateinafollow-upinterviewandquestionnaire,eitherin-personorbytelephone.Ifasubjecthasexperiencedapossiblesurgicalsiteinfectionorapossiblepost-operativebloodclotsinthelegsorlungsorsepsisthenafollow-upexaminationmayberequired.

ListofResearchProcedurestobeusedtoaccomplishthespecificaimsoftheproject:1)Subcutaneoustumescentantibioticdelivery(TAAD)2)Clinicalquestionnaires

DataStorageandConfidentiality:Alldataandclinicalrecordswillbestoredinasecuredareaattherespectiveresearchsite.InadditionthedatafromallresearchsiteswillbecollectedbytheDataMonitoringCommitteeandmaintainedinasecurefashion.ConfidentialitywillconformtoHIPAArequirements.

TransitionfromResearchParticipation:Patientresearchparticipationwillendattheconclusionofthe30to45daypost-operativefollow-upperiod,exceptforpossibleroutineclarificationofquestionnaireanswers.Subsequentroutinenon-experimentalclinicalcareforeachpatientwillcontinuewiththepatient’ssurgeonandprimarycarephysicians.

W.Risk/BenefitAssessment

1.RiskCategory:Theriskcategoryforthisresearchprojectisminimal.2.SafetyofTAAD:ThesafetyofeachdrugcomponentwithintheTumescentAntibioticDelivery(TAAD)solutioniswellestablished(SeeReferences).Thesedrugsincludedilutecefazolin,dilutemetronidazole,dilutelidocaine,diluteepinephrine,dilutesodiumbicarbonate,andphysiologic0.9%saline.ThesedrugshavebeenusedforTAADinthepreviousWIRB-approvedresearch.Seethefollowingpeer-reviewedpublicationsofresultsofthisresearch:KleinJA,JeskeDR.EstimatedMaximalSafeDosagesofTumescentLidocaine.AnesthAnalg.2016;122:1350-9.KleinJA,LangmanLJ.Pharmacokineticsofsubcutaneouscefazolinandmetronidazoleinatumescentlidocainesolutionforpreventionofsurgicalsiteinfectionsandbiofilms.PlastReconstrSurgGlobOpen2017;e1351.Therewerenoadverseeventsrelatedtothedrugsorproceduresinthatclinicaltrial.

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3.Safetyoflidocaineandtumescentlocalanesthesia:ThesafetyofTumescentLidocaineAnesthesia(TLA)iswellestablished.TLAhasbeenusedonmillionsofpatientsandisrecognizedastheworldwidestandardofcareforsafeliposuctiontotallybylocalanesthesia.Eachofthepharmacologicagentsisgenericdrugwithawell-establishedsafetyprofile.TheseincludeLidocaine,Epinephrine,SodiumBicarbonate,andphysiologic0.9%saline.ThesedrugshavebeenusedforTLAinthepreviousWIRB-approvedandnowclosedprotocol(WIRB®Protocol#20050127)entitled:BioavailabilityandAbsorptionKineticsofTumescentLidocaine(clinicaltrials.govNCT00977028).Thatresearchprojectestimatedthat,foraTLAlidocainedosageof28mg/kgwithoutliposuctionandwithoutgeneralanesthesia,theriskofmildlidocainetoxicity(serumlidocaineconcentration≥6μg/ml)is1per5,000,000.Inthepresentclinicaltrialthemaximumdosageoftumescentlidocainewillbe28mg/kgwithoutgeneralanesthesiaand21mg/kgwithgeneralanesthesia.4.SafetyofTumescentInfiltrationTechniqueandDevices:Thetechniquefortumescentinfiltrationiswellestablishedandiscurrentlyusedbythousandsofsurgeonsworldwide.AlldevicestobeusedinthepresentresearchwillhaveFDA510(k)orIDEclearance/approval.5.SafetyofEpinephrine:Thedosagesoftumescentepinephrinethatwillbeusedinthepresentclinicaltrialhavebeenwellestablishedassafeandeffective.Themaximumdosageoftumescentepinephrinetobeusedinthisclinicaltrialisnotexpectedtoproduceanyclinicalproblemsassociatedwithtachycardia.6.SafetyofCefazolinandMetronidazole:Thesafetyofsubcutaneousdeliveryofdilutecefazolinanddilutemetronidazoleiswellestablishedintheliterature,bothforpreventingSSIandforpalliativetreatmentofterminallyillpatients(seereferences).Inthepresentclinicaltrialthemg/kgdosagesofcefazolinandmetronidazolewillconformtocommunitystandardsofcare.

X.PotentialRiskofTAADandTLA:

1)InfiltrationCannula.Therearetwotypesofinfiltrationcannulasthathavebeendesignedforsubcutaneoustumescentinfiltration:1)SubQKathisadisposableover-the-needleplasticcannulaspecificallydesignedforTAADand2)Montyinfiltrationcannulasarestainlesssteelblunttippedcannulas(havingtinyholesdistributeddistallyalong50%to90%ofthecannulalength)thatwereoriginallydesignedforinfiltrationoftumescentlidocaineanesthesiaforlargesurgeriestotallybylocalanesthesia.“Painless”infiltrationofTAADinafullyawakepatientrequiresthebriefuseofasharpneedle(forexample,aspinalneedle)insertedintosubcutaneousfatforinitiatingthetumescentinfiltration.Thereisariskofpunctureofdeepanatomicstructuresassociatedwiththeuseofspinalneedles.Theriskofinjuryfromthisneedleisminimizedbyacarefulinfiltrationtechnique:Theneedleisheldintheclinician’sdominanthandandadvancedparallel(tangential)tothesub-dermalplane,whilethecontralateralhandgentlygraspsandelevatestheskinastheneedleiscarefullyadvancedwiththeneedletipcontinuouslylocatedbetweenthefingerandthumbofthecontralateralhand.Afterthisbriefinitialphaseoftumescentinfiltration,alargergauge(typically18gaugeor16gauge)blunt-tippedMontyinfiltrationcannulaisinsertedintothesubcutaneoustissueandusedforinfiltratingtheremaining90percentormoreoftheTAADsolution.

Y.ProtectionagainstRisk

1)Criteriaforterminatingthestudyinclude:a)Thesurgeondeterminesthatitisunsafe,unethicalorunreasonablethatapatientcontinuetoparticipateintheresearchproject.

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b)Thepatientdoesnottolerateinfiltrationoftumescentlocalanesthesiabecauseofanxietyordiscomfort.(Asanalternative,thepatientcanbegiventheoptionforthetumescentlocalanesthesiatobeinfiltratedbythesurgeonafterinductionofgeneralanesthesiaandbeforetheincision).

2)Monitoringfortoxicoradversedrugevents:PatientswillbeobservedandquestionedwithrespecttoanysignsorsymptomsofadversereactionstothedrugusedforTAADincludingrash,dyspnea,heartpalpations,irregularheartrate,chestpain,headaches,focalweakness,confusion,gastrointestinalirritation,hematemesis,blacktarrystools.TheriskofanallergicadverseeventwithTAADshouldbenodifferentthanthatassociatedwithIVantibioticdelivery.

Z.PotentialBenefittotheSubject:Thereisnoguaranteethatvolunteersubjectswillreceiveanymedicalbenefitsfrombeinginthisstudy.Thepatientmaybenefitbyhavingadecreasedriskforasurgicalsiteinfectionoravenousthromboembolism.Allpatientswhoparticipateinthisresearchprojectwillroutinelyreceivethe“standardofcare”methodsforpreventingasurgicalsiteinfectionandforpreventingapost-operativebloodclotinalegorlung.Approximately50percentofthevolunteersubjectswillreceiveboththe“standardofcare”intravenous(IVAD)preventivetreatmentsforSSIandanadditionaltreatmentintheformofanantibioticsolutioninjecteddirectlyintothesubcutaneousfattytissuesurroundingthesiteoftheincision(TAAD).IfTAADprovestobeoptimalforpreventingSSIamongpatientshavingGIsurgery,traumasurgeryorburnsurgerythenitislikelyTAADwillalsobebeneficialforfutureuseinotherpatientshavingsimilarorothertypesofsurgeries.

ZZ.AlternativestoParticipation:Personsdonothavetoparticipateinthisstudytohaveanappropriatesurgicalprocedure.Anyprospectivevolunteersubjectmaychoosetohavetheroutine“standardofcare”methodsforpreventingasurgicalsiteinfectionandforpreventingapost-operativebloodclotinalegorlungwithoutparticipatinginthisstudy.

vi. SubjectIdentification,RecruitmentandConsent/AssentA.MethodofSubjectIdentificationandRecruitment:Theprimarymethodofrecruitmentwillinvolveadiscussionbetweentheprospectiveresearchsubjectandthesurgeonorthesurgeon’sstaff.Patientswhoarealreadyscheduledtohaveoneofthetargetedsurgicalprocedureswillbeofferedtheopportunitytoparticipateinthisstudy.Therewillbenopublicadvertisingorpublicrecruiting.B.ProcessofConsent:Eachparticipatingsurgeonorthesurgeon’sdesignatedstaffmember,suchasanotherknowledgeableandexperiencedphysician,physician’sassistantorregisterednurse,willdiscussandobtaininformedconsentfromeverypatientorthepatient’sdesignatedguardianincaseofemergencysurgery.C.SubjectCapacitytoGiveInformedConsent:Allprospectiveadultsubjectsmustbefullycapableofcomprehendingandgivingtheirowninformedconsentor,incaseofemergencysurgery,thepatient’sdesignatedguardianmustbefullycapableofcomprehendingandgivinginformedconsent.D.Subject/RepresentativeComprehension:Allprospectiveadultsubjectsoradesignatedguardianmustbefullycapableofcomprehendingandgivingtheirowninformedconsent.E.DebriefingProcedures:Thisisnotapsychologicalstudy.Theonlyformaldebriefingwillconsistofpost-operativefollow-uptelephonecall(s)toorfromthepatientand/orafreereturnfollow-upoffice

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visitbythepatienttomeetwiththesurgeonoroneofthesurgeon’sresearchassistants.Allpatientswillhavetheopportunitytomeetpersonallywiththesurgeonbeforeorafterthesurgeryandasoftenasnecessarytodiscussanyquestionsandaddressanyconcernsthatapatientmighthaveregardingthesurgeryortheresearchproject.F.ConsentForms:Todocumentinformedconsent,allsubjectswillsignatleastthreeconsentforms:IRBResearchConsentForm(individualresearchsiteswillhavetheirownIRB-approvedconsentforms),theHIPAAConsentForminadditiontotheresearchsite’sstandardsurgicalconsentform.G.DocumentationofConsent:Patientconsentformswillbeplacedinthepatient’sresearchchart.Thechartwillbekeptinalockedfilingcabinet.H.CosttotheStudySubject:Studysubjectswillpayforthecostoftransportationtovisitthesurgeonforfollow-upvisits.Ifresearchfundingisobtained,thensubjectsmaybeofferedpaymentfortheirtransportationexpensesforfollow-upvisits.Thereisnoextrachargeorextraexpensetothepatients/subjectsforparticipatinginthisresearchproject.Thereisnochargetothepatientforroutinefollow-upvisitswhicharescheduledaspartofthisresearchproject.I.PaymentforParticipation:Volunteersubjectswillnotbepaidforparticipationinthisresearchproject.ResearchsiteswillnotbepaidbythesponsorofthisresearchforparticipationinthisTAADresearch.IndividualresearcherswillnotbepaidbythebythesponsorofthisresearchforparticipationinthisTAADresearch.Criteriafordiagnosisofsurgicalsiteinfection(SSI)&ProtocolguidelinesinperformingtheprimaryassessmentofSSI:

�Duringhospitalization,dailyvisual&physicalexamofincisionsitewillbedone.

�Betweenpost-opdays30to45,patientistobeevaluatedand/orinterviewedand/orpatient’schartwillbereviewed.

Bibliography1FryDE.Surgicalsiteinfectionsandthesurgicalcareimprovementproject(SCIP):evolutionofnationalqualitymeasures.SurgInfect9:579-584,2008.2WickEC,HiroseK,ShoreAD,ClarkJM,GearhartSL,etal.Surgicalsiteinfiectionsandcostinobesepatientsundergoingcolorectalsurgery.ArchSurg146:1068-1072,2011.3WatanabeM1,SuzukiH,NomuraS,MaejimaK,ChiharaN,KomineO,MizutaniS,YoshinoM,UchidaE.Riskfactorsforsurgicalsiteinfectioninemergencycolorectalsurgery:aretrospectiveanalysis.SurgInfect2014;15:256-61.4Serra-AracilX,Garcia-DomingoMI,ParésD,etal.Surgicalsiteinfectioninelectivesurgeryforcoloncanceraftertheapplicationofpreventivemeasures.ArchSurg146:606-612,2011.

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