SPECIALARTICLE

ASRAPracticeAdvisoryonLocalAnestheticSystemicToxicity
JosephM.Neal,MD,*ChristopherM.Bernards,MD,*JohnF.Butterworth,IV,MD,
GuidoDiGregorio,MD,KennethDrasner,MD,MichaelR.Hejtmanek,MD,*MichaelF.Mulroy,MD,*
RichardW.Rosenquist,MD,||andGuyL.Weinberg,MD
centralnervoussystem(CNS)and/orcardiactoxicity(most
Abstract:TheAmericanSocietyofRegionalAnesthesiaandPain
oftenfromunintentionalintravascularinjection)thatcan
MedicinePracticeAdvisoryonLocalAnestheticSystemicToxicity
resultindisabilityordeath.Avarietyoffactorsinuencethe
assimilatesandsummarizescurrentknowledgeregardingtheprevention,
likelihoodandseverityoflocalanestheticsystemictoxicity
diagnosis,andtreatmentofthispotentiallyfatalcomplication.Itoffers
(LAST),includingindividualpatientriskfactors,concurrent
evidence-basedand/orexpertopinion-basedrecommendationsforall
medications,locationandtechniqueofblock,speciclocal
physiciansandadvancedpractitionerswhoroutinelyadministerlocal
anestheticcompound,totallocalanestheticdose(theproduct
anestheticsinpotentiallytoxicdoses.Theadvisorydoesnotaddress
ofconcentrationvolume),timelinessofdetection,andadeissuesrelatedtolocalanesthetic-relatedneurotoxicity,allergy,ormet-quacyoftreatment.
hemoglobinemia.Recommendationsarebasedprimarilyonanimal
Interestinlocalanesthetictoxicityhashadseveralpeaks,
andhumanexperimentaltrials,caseseries,andcasereports.When
includingonethatcoincidedwiththeinitialawarenessoflocal
objectiveevidenceislackingorincomplete,recommendationsaresupanesthetictoxicitiesaftertheintroductionofcocainein1884,
plementedbyexpertopinionfromthePracticeAdvisoryPanelplusinput
anotherthatfollowedthelinkingoffatalitiestotheuseof
fromotherexperts,medicalspecialtygroups,andopenforum.Speci
c
bupivacaineandetidocaineinthe1970s,andanotherafter
recommendationsareofferedfortheprevention,diagnosis,andtreattheintroductionofropivacaineandlevobupivacaineinthelate
mentoflocalanestheticsystemictoxicity.
1980sthatcontinuesthroughthepresent.1,2Thereissuspicion
(butscantevidence)thatpatientsundergoingregionalanesthe(RegAnesthPainMed2010;35:152Y161)
siaarenowlesslikelytohaveLASTthaninearlierdecades.
Ontheotherhand,improvedunderstandingofLASTpathophysiologyandnewtreatmentmodalitieshaveemergedin
ocalanestheticsarewidelyandcommonlyusedthroughout
the2000s.Consequently,theAmericanSocietyofRegional
medicalanddentalpractice.Althoughitisrareforpatients
AnesthesiaandPainMedicine(ASRA)commissionedapanel
tomanifestseriousadverseeffectsorexperiencecomplications
ofexpertstoupdaterecommendationsthatcamefromthe2001
secondarytolocalanestheticadministration,adverseevents
ASRAConferenceonLocalAnestheticToxicity.Thecurrent
dooccur.Theserangefromthemildsymptomsthatmayfollow
PracticeAdvisoryfocusesonLAST,whichincludescardiac
systemicabsorptionoflocalanestheticfromacorrectlysited
andCNStoxicityconsequenttounintendedintravascularinjecandappropriatelydosedregionalanestheticproceduretomajor
tionordelayedtissueuptake.Theadvisorydoesnotaddress
tissue-relatedlocalanestheticneurotoxicity,allergy,ortheproductionofmethemoglobinemiabylocalanesthetics.
Fromthe*VirginiaMasonMedicalCenter,Seattle,WA;Universityof
A2006surveyofUSacademicanesthesiologydepartments
Indiana,Indianapolis,IN;DepartmentofAnesthesiology,Universityof
foundnouniform,well-designed,rationalapproachformanIllinoisandtheJesseBrownVAMedicalCenter,Chicago,IL;University
agementoflocalanesthetictoxicity.3TheASRAPractice
ofCalifornia,SanFrancisco,CA;and||UniversityofIowa,IowaCity,IA.
AcceptedforpublicationDecember20,2009.
AdvisoryPanelwasalsoformedtocorrectthisdeciencyby
Addresscorrespondenceto:JosephM.Neal,MD,1100NinthAve(B2-AN),
identifyingkeypracticemodicationstargetedspecicallyat
Seattle,WA98111(e-mail:anejmn@vmmc.org).
improvingprevention,diagnosis,andtreatmentofLAST.Our
ThisstudywassupportedbytheAmericanSocietyofRegionalAnesthesia
recommendationsreectourviewoftheprimacyofprevenandPainMedicine(ASRA).
2010Copyright @ AmericanTheauthorsofthisdocumentarepleasedtoannouncethattheircolleagues
Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this
tionofLASTasthemosteffectiveinterventionforenhancing
152RegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010
METHODOLOGY
article
is prohibited. ISSN:1098-7339
treatmentofLASTinadultsandchildren.AllavailableEnglish-,
ofMedicinesPubMed,Ovid,andGoogleSearch.Article
theirfall2007meeting.ThePanelconsistsofrecognizedexperts
includesallauthorsofthisarticle.Thisgroupwasresponsible
German-,andFrench-languagereportsofhumanandanimal
majorliteraturesearchenginessuchastheNationalLibrary
trolledtrials(RCTs),observationalstudies,caseseries,andcase
bibliographieswerecross-checkedforreferencesnotidenti
experimentalstudiesrelatedtotheprevention,diagnosis,and
scienti
reports.Keywordliteraturesearcheswereundertakenusing
onlocalanesthetictoxicityand/orguidelinedevelopmentand
Thispracticeadvisoryisderivedfromhumanandanimal
TheASRABoardofDirectorsappointedthePanelat
cinquirywereconsidered,includingrandomizedconpatientsafety.
bysearchengines.
ed
Dr.WeinbergwasawardedUSpatent7,261,903B1BLipidEmulsioninthe
SpencerS.Liu,MD,servedasActingEditor-in-Chiefforthisarticle.
Dr.ButterworthservedasaconsultanttoAPPPharmaceuticals,US
Copyright*2010byAmericanSocietyofRegionalAnesthesiaandPain
DOI:10.1097/AAP.0b013e3181d22fcd
oftheAssociationofAnaesthetistsofGreatBritainandIreland.
interestinlocalanesthetictoxicitymaywishtoalsoconsultthework
Dr.Weinbergcontributedtothisdocument.Physicianswithparticular
BGuidelinesfortheManagementofSevereLocalAnaestheticToxicity.[
coincidentwiththisASRAPracticeAdvisory,havedeveloped
intheAssociationofAnaesthetistsofGreatBritainandIreland,
relatedtothisWebsite.
emulsionintreatingcardiactoxicity.Hederivesnosalaryorsupport
providinginformationandaforumfordiscussingtheuseoflipid
maintainswww.lipidrescue.org,aneducational,noncommercialWebsite
anypatientrequiringthistreatment.Dr.Weinbergalsocreatedand
Hedoesnotintendtoprohibitorrestrictthepracticeofthismethodon
method.Hehasneverreceivedsalaryorsupportfromanycompany.
agreementswithanycompanyorcommercialentityrelatedtothis
TreatmentofSystemicPoisoning.[Hedoesnothaveequityinterestor
distributorofropivacainein2008.
Medicine

RegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010LocalAnestheticToxicityPracticeAdvisory

fortheinitialliteraturesearch,assimilationofmaterials,expert
TABLE1.DenitionsforClassicationofRecommendations
opinion,developmentofrecommendations,andwritingthe
andLevelsofEvidence
accompanyingsupportingarticles.Individualsneitherreceived
directnancialsupportfortheirparticipationnordidany
ClassificationofRecommendations
participantsotherthanDrs.WeinbergandButterworthdeclare
ClassIConditionsforwhichthereisevidenceand/or
apotentialconictofinterest(seeappendeddeclaration).The
generalagreementthatagivenprocedureor
ASRAreceivednodirectnancialsupportfromindustryor
treatmentisusefulandeffective
othergrantstounderwriteexpenses(travelsupportforthepanel)
ClassIIConditionsforwhichthereisconflictingevidence
relatedtothisinitiative.
and/oradivergenceofopinionaboutthe
Assuggestedbyrecognizedinstrumentsforguidelinedeusefulness/efficacyofaprocedureortreatment
velopmentsuchastheAppraisalofGuidelinesforResearch&
IIa.Weightofevidence/opinionisinfavorof
Evaluation,4everyeffortwasmadetoensuretheintegrityand
usefulness/efficacy
validityoftheprocessleadingtotherecommendationsmade
IIb.Usefulness/efficacyislesswellestablished
herein.Externalinput,appraisal,andvalidityweresoughtusing
byevidence/opinion
thefollowingmechanisms.ThePanelsrecommendationswere
ClassIIIConditionsforwhichthereisevidenceand/or
circulatedtoaseparategroupofexpertsselectedonthebasis
generalagreementthattheprocedure/treatment
oftheirdemonstratedinterestand/orexpertiseinlocalanesisnotuseful/effective,andinsomecasesmaybe
thetictoxicity(Appendix1).Generalinputwasalsosought
harmful
bycontactingtheEditors-in-ChiefofmajorjournalsformediLevelofEvidence
calanddentalspecialtiesthatcommonlyuselocalanesthetics
(Appendix2).Commentsfromthese2groupswereconsidered
LevelADataderivedfromrandomizedclinicaltrials
andincorporatedwhenappropriate,andparticularlyasthey
LevelBDataderivedfromnonrandomizedorlaboratory,eg,
relatedtocontent,interpretation,andclarityoftherecommenanimalstudies;supportedbymultiplecase
dations.Oneweekbeforepresentationinopenforumatthe
reportsorcaseseries
May3,2008,ASRAmeetinginCancun,Mexico,meeting
LevelCConsensusopinionofexperts
registrantsweree-mailedacopyoftherecommendations.Open
TheaboveschemaismodiedfromanAmericanHeartAssociation
commentwassolicitedprimarilywithregardtoclarityand
schemafordevelopingandgradingguidelines.5
soundnessoftherecommendations.Afternalizingrecommendations,thePracticeAdvisorysummarydocumentand
accompanyingreviewarticlesweresubmittedtoRegional
alongwithextrapolationstotheclinicalsetting.Literature
AnesthesiaandPainMedicineforpublication,wherethey
comprisingcasereportsmaybebiasedtowardpositiveoutcomes
weresubjectedtothejournalsstandardpeer-reviewprocess.
becausecliniciansarereluctanttopresenttheircasesthathave
Readersareencouragedtoreadtheaccompanyingreviews,
pooroutcome,andcasereportswithoutaBteachingpoint[will
whichprovidethedetailsthatledtorecommendationscontained
almostneverbeacceptedforpublication.6Therefore,somelocal
withinthissummaryarticle.
anesthetics,forexample,ropivacaineorlevobupivacaine,might
seemsaferthanisthecase,andspecictreatments,forexample,
GradingtheStrengthofRecommendations
lipidemulsion,mightfailmoreoftenthantheliteratureindiTherearenoRCTsevaluatingserioushumanLAST;future
cates.SomeofourrecommendationsarebasedonexpertopinRCTsareunlikelybecauseoftherarityofthesecomplicaionalone.Thenatureofpracticeadvisoriesisthattheyaddress
tionsandtheassociateddif
cultyofobtaininginformedconsent
issuesofcontroversyanduncertainty.Westrivetoacknowlformedicalinterventionsincriticalillness.Commonstrengthedgethesecontroversies,butthentoofferourbestadvicewithin
of-evidenceschemasthatarebasedonRCT-levelevidenceare
thesettingofuncertainty.Particularlywhenaddressingmore
thereforeinappropriateforthetopicofhumanLASTbutare
controversialissues,ourrecommendationstendtoerrtoward
appropriateforanimalstudies.Hence,thePracticeAdvisorys
conservativemanagement.
recommendationsarebasedonamodi
cation
2010Copyright @ American Society
of Regional Anesthesia andcationofaClassi
Pain Medicine.
Unauthorized
reproduction of this
Ourrecommendationsareintendedtopromotequality
ofRecommendationsandLevelsofEvidenceschemathatwas
Limitations
HISTORY
article is prohibited.
recommendationissupportedbycon
orCshouldnotbeconstruedasimplyingthattheassociated
panelwishestoemphasizethatassigningaLevelofEvidenceB
developedbytheAmericanHeartAssociation(Table1).5The
bycon
suchrecommendationsre
thatthespeci
oftheparticularquestionasitrelatestoLAST,andtothereality
ordoesnotlenditselftoexperimentalinquiryinhumans.
onexistingliteratureandexpertopinion.Thescienti
recommendationsshouldbeviewedasguidelinesthatarebased
hypothesisbeingtestedmaylimittheconclusionsonecanmake,
inlaboratorysystems,anddifferingexperimentalmodels.The
beinterpretedwithknowledgeofspeciesdifferences,variations
tionsisimperfectandalwaysevolving.Animalstudiesshould
thatprovidedthebasisfortheseguidelinesandrecommendaAswithpreviousASRA-sponsoredpracticeadvisories,our
ictinginterpretationsoftheavailabledata.Rather,
cquestioniseitheryettobeaddressedbyaRCT
careandtheyshouldneversupersedesoundmedicaljudgment.
Thosewhoapplytheserecommendationswilldeterminetheir
systemictoxiceffectsofcocaineandcocainespropensityto
practiceinthe1880s.Fromtheoutset,systemictoxicitywasasreportedsinceshortlyaftertheintroductionofcocaineintoclinical
tionsmaynotguaranteeaspeci
patientcare;nevertheless,rigidobservanceofourrecommendaommendationsarenotmeanttobeinterpretedasstandardof
value.Aswithallpracticeadvisories,theserecommendations
directcardiactoxicitywasrecognizedasamajorcomponentof
sociatedwithseizuresandrespiratoryfailure.8Itisunclearwhen
procainein1904.Unfortunately,LASTcontinuedtobeamajor
causelocaltissuetoxicityinpartledtoEinhornsdevelopmentof
willbesubjecttotimelyrevisionaswarrantedbytheevolution
systemictoxicity,ratherthananassociatedadverseeffect.The
ectourrecognitionoftheimportance
Localanestheticsystemictoxicityhasbeenrecognizedand
oftechnology,scienti
ictingdataorislimited
cevidence,andclinicalexperience.7
cpatientoutcome.Ourreccliterature
*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine153

NealetalRegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010

patientsafetyconcern,somuchsothattheAmericanMedical
anestheticbindingsite,ionchannel,signalingpathway,orenzyme
Association(AMA)establishedtheCommitteefortheStudyof
ismostimportantinCNSorcardiactoxicityortheirtreatment.
ToxicEffectsofLocalAnestheticsintheearly1920s.9Itbecame
WhenoneinterpretsanimalstudiesofLAST,itisimportant
clearthatlocalanestheticswerenotonlycapableofcausingdeath
toconsiderthemodelchosenbytheinvestigatorstostudytheir
butthatcardiacarrestcouldprecedeseizuresorevenoccurinthe
hypothesisandwhatspecicclinicalcircumstancethemodel
absenceofseizures.TheAMACommitteestoppedshortofsugisintendedtomimic.18Variablesincludeinvivowholeanimal
gestingabanoncocaine,butemphasizedtheprimacyofaclear
modelsversusinvitroisolatedheartversustissueculture;whole
airwaytooptimizeoxygenationandventilation,athemethat
cell,ionchannel,orsubcellularorganellemodels;largeanimal
DanielMooreandDonaldBridenbaugh10wouldcontinueto
versussmallanimal;awakeversusanesthetized;andbolusdosstressthroughoutthemidandlate20thcentury.Thepotentlipidingversusinfusionmodels.Otherimportantfeatureswillinusolublelocalanestheticsbupivacaineandetidocainewereintroencetheinterpretationofthendings,includingthechosen
ducedintoclinicalpracticeinthe1960sand1970s,respectively.
metricsandparametersofinterest,thetimingofsuchmeasures,
By1969,bupivacainehadbeenlinkedtofetaldeathin1:900
orthepresenceofconfounderssuchashypoxia.Althougheach
womenwhoreceivedaparacervicalblock,admittedlywithouta
oftheseapproachesprovidesspecicadvantage,thereisno
clearunderstandingastowhetherbupivacaineitself,theparaconsensusthatanymodeltrulymimicsclinicaltoxicity.For
cervicalblocktechnique,orsomecombinationthereofwasthe
instance,manycasesoftoxicityoccurinpatientswithunderresponsibleetiologicfactor.Notuntilthelate1970swasbupilyingischemicorothercardiacdisease,whichisnotreadilymovacainelinkedtofatalcardiacarrestinotherwisehealthyadult
deledinstandardexperimentalanimalsorpreparations.Giventhat
patients.ThereportofPrentice11andAlbrightsoftsummarizingthemechanismsofLASTassuredlyrepresentsan
citededitorial1
setinmotiontheeventsthatwouldleadtheUSFoodandDrug
oversimplication,ingeneral,itseemsthatcardiactoxicityreAdministrationandthe3manufacturersofbupivacaineissuinga
sultspredominantlyfromthebindingandinhibitionofNachanBDearDoctor[letterwithdrawingobstetricanalgesiaasan
nelsbylocalanesthetics.Notably,inhibitionofcardiacconduction
indicationfor0.75%bupivacaineandwarningagainstitsfurther
followsarankordersimilartolocalanestheticpotencyforgeneuseinparacervicalblockandintravenousregionalanesthesia.
ratingneuralblockade.19Whencomparedwithlidocaine,cardiac
Despitetheclinicalreleaseoftheapparentlylesscardiotoxicsingle
conductionchannelsareboundmorerapidlyandforlongerduraenantiomersropivacaineandlevobupivacaineinthelate1980s,
tionbythemorepotentlocalanestheticsbupivacaine,etidocaine,
seriousmorbidityandmortalityfromcardiactoxicitycontinued.2
andropivacaine,20albeitlessavidlybytheirS(j)isomers.21Such
Inthe1990s,animalresearchgavehopethatlipidemulsionsmight
evidencenotwithstanding,avastarrayofotherinotropicand
provetobeanantidoteforLAST.12The
metabotropiccellsignalingsystemsareaffectedbylocalanesrstcasereportsof
successfulrescueofhumansexperiencingrefractorycardiac
theticsandhavebeenimplicatedinmediatingsymptomsand
toxicitycameinthemid2000s.13Today,researchisongoingto
signsofLAST.Furthermore,virtuallyeverycomponentofoxireneissuesrelatedtolipidemulsiontherapyforsevereLASTand
dativephosphorylationisinhibitedbypotentlocalanesthetics;
itsprodromes.14
thisobservationprovidessupportformitochondrialmetabolism
asanimportant,potentialtargetoflocalanestheticsandcould
helpexplainwhysymptomsofLASTincludepredominantlythe
FREQUENCY,MODELS,ANDMECHANISMS
organsleasttolerantofanaerobicmetabolism(heartandbrain).
WhatisknownregardingLASTisderivedprimarilyfrom3
LocalanestheticsalsodifferwithregardtotheirCNStoxisourcesVepidemiologicstudiesthatattempttode
city.Thecardiovascular(CV)/CNSratiodescribesthedose
neincidence
inspecicpatientpopulations,caseseriesandcasereportsthat
requiredtoproduceCVarrhythmiasversusthatrequiredto
describeclinicalmanifestationsoftoxicityand/ortreatment,2
produceseizures.Thisratiotendstobelowerwithbupivacaine
andanimalstudiesthataimtoestablishrelativetoxicity,elucomparedwithlidocaine,whichimpliesareducedsafetymargin
cidatemechanisms,andidentifycofactorsthatpromoteorattenforthepotentcompoundswhendetectingimpendingcardiac
uatetheiroccurrence.Epidemiologicstudiesreportstatisticsthat
toxicitybasedonpremonitoryCNSsigns.Thesemorepotentlocal
varywidelydependingonhowtoxicityisde
anestheticsindeedgeneratearrhythmiasatlowerconcentrations
ned,theclinical
scenarioinwhichitoccurs,andhowthedatawerecollected.For
comparedwithlidocaineandmepivacaine.Atcomparabledoses
2010Copyright @ American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this
example,deathfromtheapplicationofcocaineortetracaineto
indogs,bupivacaineandetidocainecausedseverearrhythmias
154*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine
PREVENTION
article is prohibited.
ofLAST2butisunabletode
fromcasereportsandseriesoffersinsightsintoclinicalscenarios
restssecondarytoLASTreportedinthisseries.17Information
typeofblockperformed.Interestingly,therewerenocardiacarfrequencyofseizurestobe0to25in10,000,dependingonthe
lancestudyofFrenchanesthesiologistsdeterminedtheoverall
patientsfromasingleinstitutionaldatabase.16Yetalargesurveilarteryfeedingthebrain),havebeenreportedinupto79in10,000
(wherelocalanestheticsmaybeunintentionallyinjectedintoan
ade,particularlytheinterscaleneandsupraclavicularapproaches
(1.8:10,000).15Seizuresassociatedwithbrachialplexusblockwasreportedin1951tooccurin7of39,278patients
mucousmembranestofacilitateotolaryngologicalprocedures
astowhichanimalmodelbestre
animalstudies,yetthereislimitedconsensusamonginvestigations
regardingthemechanismsofLASTanditstreatmentcomesfrom
ethicalandlogisticalconcerns.Thus,mostofwhatisunderstood
localanesthetictoxicitywilllikelyneverbeperformedbecauseof
mechanisticinformationiscontroversialwithregardtowhich
vascularinjectionortissueuptakeoflocalanesthetic,whichis
orcatheterplacement.Ifanintravascularinjectiondoesoccur,
singleinterventionhasbeenidenti
bestaccomplishedbyearlydetectionofintravascularneedle
itshouldideallycontainthelowestpossibledoseoflocalaneslevels,localanestheticsofallpotenciesarecapableofproducmia.22Y24However,onceplasmaconcentrationsreachhigher
site,thatis,depressedmyocardialcontractilitywithoutarrhythwithoutdecreasedcontractility,whilelidocainecausedtheopporisk.CentraltopreventionislimitingtheopportunityforintratestdosebyMooreandBatrain1981.26Literaturereview
tioninreducingthefrequencyandseverityofLAST,yetno
thetic.Totheseends,variousintravascularidenti
odshavebeenproposedsincethedescriptionoftheepinephrine
nemechanisms.HumanRCTsof
ThisPracticeAdvisoryemphasizestheprimacyofprevenectshumantoxicity.Evenbasic
ingseveremyocardialdepression.25
edthatcanreliablyeliminate
cationmeth-

RegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010LocalAnestheticToxicityPracticeAdvisory

suggeststhatthefrequencyofLASTassociatedwithepidural
takingA-blockers,oranesthetizedwithgeneralorneuraxialanesanesthesiamayhavedecreasedsubsequentlyby10-to100-fold.27
thesia.Epinephrineisalsocontroversialwithregardtoitsrolein
Conversely,actualpublishedreportsofLASThaveincreased
nerveinjury.Althoughepinephrinehasbeenshowninanimal
recently,mostlikelybecauseofrenewedinterestandnew
modelstoworsenlocalanesthetic-inducedneurotoxicity,itis
informationrelatedtotheintroductionofthelesscardiotoxic
uncleariftheadditiveinjuryinhumansisclinicallyrelevant
stereoisomersropivacaineandlevobupivacaineandtoclinical
overandabovethatcausedprimarilybythelocalanestheticitexperiencewithsuccessfullipidemulsionrescue.2
self.35ThefrequencyofseizuresduringperformanceofperiLocalanestheticdosecanbelimitedbyseveralmethods.
pheralnerveblockwassimilartothefrequencyofpermanent
Totaldose(theproductofvolumeconcentration)shouldbe
nerveinjuryinonemajorstudy(1.2versus2.4in10,000,restailoredtotheminimummassoflocalanestheticmoleculesnepectively).36Notably,severeLAST,butnotnerveinjury,has
cessarytoachievethedesiredclinicaleffect.Evidencesuggests
thepotentialtocausedeath.
thatmostperipheralnerveblocksareperformedwithsigni
Ultrasoundguidancemayreducethefrequencyofvascucantlylargerdosesthanarenecessarytoachievedesiredclinical
larpuncture,buttherearenoRCTsthatconrmorrefutean
endpoints28;thesedataarefurthersupportedbyultrasoundactualreductionofLAST.37Twolargecaseseriespresentconguidedregionalanesthesia(UGRA)29andcontinuousperineuictingresultsVonefoundastatisticallysignicant(P=0.001)
ralcatheter30studiesthatdocumentadequateblockadeusing
reductioninthenumberofvascularpuncturesoccurringunder
exceedinglysmalldosesofproperlyplacedlocalanesthetic.31
UGRAversusperipheralnervestimulation,butnodifference
Dosereductionmaybeparticularlyimportantforthosepatients
inLAST.38Theotherseriesreportedasignicant(P=0.044)
thoughttobeatgreaterriskofLAST,forexample,thosepatients
reductioninseizureswithultrasound-assistednervelocalization
atextremesofage(G4monthsor970years)orthosewithcarversusperipheralnervestimulation.39Althoughintravascularindiacconductiondefectorahistoryofischemicheartdisease.
jectioncanbeobservedduringUGRA,40casereportsdescribe
Neitherbodyweightnorbodymassindexcorrelateswithlocal
symptomaticintravascularinjectiondespiteitsuse.41Whether
anestheticplasmalevelsafteraspeci
generationofahypoechoicregionconsequenttoinjectedlocal
cdoseinadults;thecorrelationismoreaccurateinchildren.Blocksite,intrinsicvasoactivity
anestheticisasufcientmonitorofintravascularinjectionto
ofthelocalanesthetic,useofepinephrine,andpatient-related
warrantomissionofepinephrineisthesubjectofconsiderable
factorssuchascardiac,renal,orhepaticdysfunctionaremore
debate,particularlywhenoneconsidersthefrequentneedle
importantpredictorsoflocalanestheticplasmalevelsthaneither
movementsinherenttoUGRAtechniquesversusthegenerally
bodyweightorbodymassindex.
xedneedletechniquesassociatedwithnonultrasoundblocks.
Whentheabovenotedfactorsthatmaypredisposeto
Thus,preventionofintravascularinjectionisperhapsbestacLASTarepresent,reductionoflocalanestheticdoseisintuicomplishedwithacombinationofUGRAandepinephrinetest
tivelylogical,yettherearenoestablishedparameterstoguide
dosing.Becausetheliteratureoffersnormguidanceandno
actualdosereduction.32Incrementalinjectionof3to5mLof
methodofdetectionisperfect,meticulousattentiontodetailrelocalanestheticwithaconcomitantpauseforatleastonecirmainsthemostimportantassetforprevention.Recommenculationtimebeforefurtherinjectionisatime-honoredrecomdationsforpreventingLASTaregiveninTable2.
mendationwithintuitiveappeal,butwithnoobjectiveefcacy
data.Practicalconsiderationssuggestthatthepotentialbenet
fromthisapproachcouldbeoutweighedbyprolongingoverall
CLINICALDIAGNOSISOFSYSTEMICTOXICITY
injectiontimewithanattendantriskofneedlemovement.Of
note,circulationtimesareincreasedwithlowerextremityinTheclassicdescriptionofLASTincludessubjectivesympjectioncomparedwithupperextremityinjection.Aspirationof
tomsofCNSexcitementsuchasauditorychanges,circumoral
needlesandcatheters,althoughrecommended,mayfailtoidennumbness,metallictaste,andagitationthatthenprogresstoseitifyintravascularplacementinatleast2%ofpatients.33Subzuresand/orCNSdepression(coma,respiratoryarrest).Inclasstitutingthelesspotentlevoenantiomersropivacaineor
sicdescriptionsofLAST,cardiactoxicitydoesnotoccurwithout
levobupivacainemightreducethepotentialforsystemictoxicity
precedingCNStoxicity.WhenLASToccurssecondarytodirect
Nonetheless,thesedrugsarepotentiallytoxicandthetheoretical
intravascularinjection(particularlywithinjectionintothecarotid
2010Copyright @ American Society
of Regional Anesthesia
and Pain Medicine. Unauthorized reproduction of this
beneHowcanaclinicianreducetheriskofLAST?Although
tofchiralitybecomeslessimportantwithincreasingdoses,
orvertebralarteries),premonitorysymptomscanbebypassed
article is prohibited.
levoenantiomers.
outputstatesfaroutweighsthepotentialriskreductionofusing
tiessuchasischemicheartdisease,conductiondefectsorlow
anesthetictoxicity.Itispossiblethatriskinherenttocomorbidiparticularlyamongpatientsatgreaterthannormalriskforlocal
dosesareunreliableintheelderly,orinpatientswhoaresedated,
higherinsystolicbloodpressure.Nevertheless,epinephrinetest
phrine0.5Kg/kgisassociatedwitha15-mmHgincreaseor
creasesby15mmHgorhigher.Forchildren,intravascularepineby10beatsperminuteorhigherorsystolicbloodpressureindetectingintravascularinjectioninadultsifheartrateincreases
phrinehasapositivepredictivevalueand80%sensitivityin
patients.27Withregardtoepinephrine,10to15Kg/mLepinebeenshowntoreliablyproducedrowsinessorsedationinlaboring
forreliabilityandapplicability.34Intravenousfentanyl100Kghas
scribed,onlyfentanylandepinephrinemeetsuggestedstandards
markerofintravascularinjection.Ofthevariousoptionsdeimperfect,intravasculartestdosingremainsthemostreliable
ulararrhythmias).Withgreatlyincreasedbloodconcentrations,
inrecognizingtheseearlysignsofLAST,appreciatingtheir
progresstocardiacexcitation(hypertension,tachycardia,ventricandthepatientcanrapidlydevelopseizureactivitythatmay
ularlywiththemostpotentlocalanesthetics,cardiactoxicitymay
publishedcasesofLAST.Intheseinstances,symptomswere
cardia,asystole,decreasedcontractility,andhypotension).Particcardiacexcitationmaybefollowedbycardiacdepression(bradyanatypicalpresentationwasreportedinapproximately40%of
toxicity.Thepractitionersvigilanceisofcriticalimportance
delayedby5minsormoreoroccurredwithonlyCVsignsof
oflocalanestheticsandmanifestatypicalorunexpectedsigns
eringLASTinpatientsthathavereceivedpotentiallytoxicdoses
timingofonset,initialmanifestations,andduration.Wefound
phasizetheextremevariabilityofitspresentation,including
variablepresentation,andhavingalowthresholdforconsidoccursimultaneouslywithseizureactivityorevenprecedeit.
Despitethisclassicdescription,casereportsofLASTemandsymptoms.
*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine155

NealetalRegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010

estingtonotethatmorethanone-thirdofreportsofcardiacand
TABLE2.RecommendationsforPreventingLAST
CNStoxicityinvolvedpatientswithunderlyingcardiac,neurologic,ormetabolicdisease,forexample,diabetes,renalfailure,
isovalericacademia.
Inourreviewedsingleinjectioncases,themediantime
frominjectiontorstsymptomwas52.5seconds(interquartile
range,30Y180seconds),whichsuggestsdirectinjectionintoan
arterysupplyingthebrainoralargeintravascularboluscontainingsufcientlocalanestheticdosetocauseCNSsymptoms
usingafixedneedleapproach,eg,landmark,
evenafterrstpassclearancethroughthelungs.Forthissame
paresthesia-seeking,orelectricalstimulation,timebetween
groupofcases,themeantimeto
rstsymptomwas89seconds
injectionsshouldencompassonecirculationtime(30Y45s);
(95%condenceinterval,67Y120seconds).Mostotherreports
however,thisidealmaybebalancedagainsttheriskofneedle
movementbetweeninjections.Circulationtimemaybeincreased
notedrstsymptomsbetween1and5minsofinjection,sugwithlowerextremityblocks.Useoflargerdosingincrements
gestingpartialintravascularinjection,lowerextremityinjection,
woulddictatetheneedforlongerintervalstoreducethe
and/ortissueuptake.Importantly,approximately25%ofcases
cumulativedosefromstackedinjectionsbeforeaneventof
describedsymptomsrstappearingmorethan5minsafterinLAST.Incrementalinjectionmaybelessimportantwith
jection(onereportdescribeda60-mindelay),whichemphasizes
ultrasoundguidance,giventhatfrequentneedlemovementis
theimportanceofprolongedobservationofpatientsreceiving
oftenusedwiththetechnique(I;C).
potentiallytoxicdosesoflocalanesthetic.Localanestheticsystemictoxicitymayoccurasfrequentlyas1:1000peripheral
intervention(I;C).nerveblocks,43butitislikelythatmostofthesecasesinvolve
minorsubjectivesymptomsthatdonotprogresstofrankCNS
orcardiactoxicity.Ofthosecasesseriousenoughtoreportand
publish,45%involvedonlyCNSsignsandsymptoms,whereas
isanimperfectmakeranditsuseisopentophysicianjudgment,
44%involvedbothCNSandcardiacmanifestations.Reported
itsbenefitslikelyoutweighitsrisksinthemajorityofpatients
(IIa;B):
casesrarelypresentedwithonlycardiacsignsandsymptoms.2
Ouroverallanalysisofcasereportssuggeststhatalthough
)Intravascularinjectionofepinephrine10Y15Kg/mLinadults
producesaQ10beatheartrateincreaseoraQ15-mmHg
LASTtendstofollowclassicpresentations,variationsarecomsystolicbloodpressureincreaseintheabsenceofA-blockade,
mon.Althoughseizurewasthemostcommonpresentingsympactivelabor,advancedage,orgeneral/neuraxialanesthesia.
tom,lessthan20%ofcasesinvolvedanyoftheclassicprodromal
)Intravascularinjectionofepinephrine0.5Kg/kginchildren
symptomssuchasauditorychanges,metallictaste,ordisinhibiproducesaQ15-mmHgincreaseinsystolicbloodpressure.
tion.Thus,practitionersareadvisedtobeever-vigilantofpoten)Appropriatesubtoxicdosesoflocalanestheticcanproduce
tialLAST,particularlyinpatientsattheextremesofagewho
subjectivesymptomsofmildsystemictoxicity(auditory
mayhaveunderlyingcardiac,pulmonary,renal,hepatic,metachanges,excitation,metallictaste,etc.)inunpremedicated
bolic,orneurologicdisease.Importantly,LASTdoesnotalways
patients.
manifestitselfasobviousseizureorcardiacarrhythmiasinclose
)Fentanyl100Kgproducessedationifinjectedintravascularly
temporalrelationshiptolocalanestheticinjection.Practitioners
inlaboringpatients.
shouldconsiderthediagnosisofimpendingLASTinpatients
thatdevelopunexplainedagitationorCNSdepression,orunexplainedsignsofCVcompromise,forexample,progressivehypohumans.IndividualreportsdescribeLASTdespitetheuseof
tension,bradycardia,orventriculararrhythmia,evenifmorethan
UGRA.Theoveralleffectivenessofultrasoundguidancein
15minsafterlocalanestheticinjection.2Recommendationsfor
reducingthefrequencyofLASTremainstobedetermined
diagnosingLASTarecontainedinTable3.
(IIa;C).

&Thereisn
osingleme
&Usethelowesteffectiv
asurethat
edoseoflocalanestheti
&Useincrementalinjectionoflocalanes
canpreven
c(dose=productofvolum
theticsVadminister3-to5tLASTincl
econcentration)(I;C)
mLaliquots,pausing15Y30sbetweeneach
inicalpra
injection.When
ctice.

&Aspiratetheneedleorcatheterbefor
eeachinjection,recognizingthatthe
&Wheninjectingpotentiallytoxicdoses
reisan2%falseoflocalanesthetic,useofanintravascu
negativerateforthisdiagnostic
larmarkerisrecommended.Althoughepin
ephrine

&Ultrasoundguidancemayreducethefre
quencyofintravascularinjection,but
actualreductionofLASTremainsunprov
enin
Theclassofrecommendationandlevelofevidenceforeachinter-

2010Copyright @ American Society

of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this
ventionaregiveninparenthesis(Table1).
TREATMENT
156*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine
article is prohibited.
establishesassociationratherthancause-and-effect,itisinterthesewereinchildren.Althoughanalysisofcasereportsonly
1in5casesinvolvedcontinuousinfusiontechniquesandhalfof
thatis,bupivacaine,ropivacaine,andlevobupivacaine.Lessthan
than90%ofcasesinvolvedthemostpotentlocalanesthetics,
youngerthan16yearsand30%wereolderthan60years.More
thecaseswereinpatientsattheextremesofageV16%were
emerge.First,two-thirdsofpatientswerefemaleandnearlyhalf
lishedinthelast10years.Fromthisreview,severalpatterns
Ourreviewspanned30years,yet65%ofthereportswerepubLASTeventscontainedwithin74reports,therewasonly1death.
cessesratherthantheirfailuresVinourreviewof93separate
Conversely,physicianstendtoreportandpublishtheirsucfordeathorbraindamageassociatedwithregionalanesthesia.42
ClaimsdatanotethatLASTaccountedforone-thirdofclaims
tice.RecentAmericanSocietyofAnesthesiologistsClosed
sourceofmorbidityandmortalityinregionalanesthesiapracLocalanestheticsystemictoxicitycontinuestobeamajor
Subsequentlaboratoryinvestigationscon
circulatorysupport,andpromotingthediminutionofthesysago,10,44preventionofhypoxiaandacidosisbyimmediateresment.AsreportedbyMooreandcolleaguesahalfcentury
benzodiazepinesaretheidealdrugstotreatseizuresbecause
injurytothepatientandacidosis.ThePanelrecommendsthat
worseningexistinghypotensionorcardiacdepressionrequires
temiceffectsoflocalanesthetics.Unlikethecasefortreatment
LASTpatientsisrecognizingtheprimacyofairwaymanageressiontoCVcollapseandseizureorfacilitateresuscitation.
seizuresoccur,theyshouldberapidlycontrolledtoprevent
theyhavelimitedpotentialforcardiacdepression.Intheabexperiencewithlipidinfusioncouldleadtoitsuseinpreference
usingthelowesteffectivedose.ThePanelrecognizesthatfurther
ofBconventional[cardiacarrest,thekeytosuccessfulcareof
torationofoxygenationandventilationcaneitherhaltprogtalareacceptablealternatives;however,theirpotentialfor
senceofreadilyavailablebenzodiazepine,propofolorthiopenTreatmentprioritiesforLASTincludeairwaymanagement,
rmthisconcept.45If

RegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010LocalAnestheticToxicityPracticeAdvisory

sideredasabridgingtherapyuntiltissuelevelsoflocalanestheTABLE3.RecommendationsforDiagnosingLAST
tichavecleared.
Lipidemulsiontherapycanbeinstrumentalinfacilitating
resuscitation,mostprobablybyactingasaBlipidsink[thatdraws
downthecontentoflipid-solublelocalanestheticsfromwithin
metallictasteorabruptonsetofpsychiatricsymptoms),followed
cardiactissue,therebyimprovingcardiacconduction,contractility,
byseizuresthenCNSdepression(drowsiness,coma,or
respiratoryarrest).Neartheendofthiscontinuum,initialsigns
andcoronaryperfusion.49Werecommendaninitialbolusof
ofcardiactoxicity(hypertension,tachycardia,orventricular
1.5mL/kg(leanbodymass)20%lipidemulsion,followedby
arrhythmias)aresupplantedbycardiacdepression(bradycardia,
aninfusionof0.25mL/kgperminutecontinuedfor10mins
conductionblock,asystole,decreasedcontractility).However,
afterhemodynamicstabilityisattained.Failuretoachievestabithereissubstantialvariationinthisclassicdescription,includin
lityshouldpromptanadditionalbolusandincreaseofinfusion
g:
)SimultaneouspresentationofCNSandcardiactoxicity
rateto0.5mL/kgperminute.Approximately10mL/kglipid
)Cardiactoxicitywithoutprodromalsignsandsymptomsof
emulsionfor30minsisrecommendedasanupperlimitfor
CNStoxicity
initialadministration.46
)Thus,thepractitionermustbevigilantforatypicalor
Thereareseveralasyetunansweredquestionsregarding
unexpectedpresentationofLAST(I;B).
lipidemulsiontherapy.Initialrecommendationsconservatively
suggestedthatitbeusedonlyafterstandardresuscitative

&ClassicdescriptionsofLASTdepicta
progressionofsubjectivesymptomsof
CNSexcitement(agitation,auditoryc
hanges,

&ThetimingofLASTpresentationisvaria
ble.Immediate(G60s)presentationsugg
withdirectaccesstothebrain,whereaspresentationthatis
delayed1Y5minssuggestsintermittentintravascularinjection,
estsintravascularinjectionoflocalan
TABLE4.RecommendationsforTreatmentofLAST
lowerextremityinjection,ordelayedtissueabsorption.Because
LASTcanpresent915minsafterinjection,patientsthatreceive
esthetic
&IfsignsandsymptomsofLASToccur,promp
potentiallytoxicdosesoflocalanestheticshouldbeclosely
monitoredforatleast30minsafterinjection(I;B).
whichareknowntopotentiateLAST(I;B).

tandeffectiveairwaymanagementiscruci
&CasereportsassociateLASTwithunde
&Ifseizuresoccur,theyshouldberapid
altopreventinghypoxiaandacidosis,
rlyingcardiac,neurologic,pulmonar
vigilancemaybewarrantedinthesepatients,particularlyifthey
lyhaltedwithbenzodiazepines.Ifbenz
smalldosesofpropofolorthiopentalareacceptable.Future
areattheextremesofage(IIa;B).
y,renal,hepatic,ormetabolicdiseas
datamaysupporttheearlyuseoflipidemulsionfortreating
odiazepinesarenotreadilyavailable,
&TheoverallvariabilityofLASTsignsan
seizures(I;B).
e.Heightened
dsymptoms,timingofonset,andassociat
&Althoughpropofolcanstopseizures,l
practitionersshouldmaintainalowthresholdforconsideringthe
diagnosisofLASTinpatientswithatypicalorunexpected
ionwithvariousdiseasestatessuggests
argedosesfurtherdepresscardiacfunc
signsofCVcompromise(III;B).Ifseizurespersistdespite
presentationofCNSorcardiacsignsandsymptomsafter
benzodiazepines,smalldosesofsuccinylcholineorsimilar
receivingmorethanaminimaldoseoflocalanesthetic(IIa;B).
that
tion;propofolshouldbeavoidedwhenth
neuromuscularblockershouldbeconsideredtominimizeacidosis
Theclassofrecommendationandlevelofevidenceforeachinterandhypoxemia(I;C).
ereare
ventionaregiveninparenthesis(Table1).
&Ifcardiacarrestoccurs,werecomm
endstandardAdvancedCardiacLifeS
)Ifepinephrineisused,smallinitialdoses(10Y100Kgbolusesin
tobenzodiazepines.Iftonic-clonicmovementspersistdespite
theadult)arepreferred(IIa;C)
upportwiththefollowingmodificat
thesemeasures,smalldosesofsuccinylcholinemaybeconsidered
)Vasopressinisnotrecommended(III;B)
ions:
torapidlystopmuscularactivity(continuedseizureactivityex)AvoidcalciumchannelblockersandA-adrenergicreceptor
acerbateshypoxiaandsystemicacidosis),beingmindfulthat
blockers(III;C)
&Failuretorespondtolipidemulsiona
seizureactivityandacidosiswillcontinueunlessinterruptedwith
)Ifventriculararrhythmiasdevelop,amiodaroneispreferred
asedativehypnoticagent.46ndvasopressortherapyshouldprompti
(IIa;B);treatmentwithlocalanesthetics(lidocaineor
Localanesthetic-inducedcardiacarrestrequiresrapidresprocainamide)isnotrecommended(III;C)
nstitutionofcardiopulmonarybypass
&Propofolisnotasubstituteforlip
&Lipidemulsiontherap
torationofcoronaryperfusionpressuretoimprovemyocardial
2010Copyright @ American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this
contractilityandtheoreticallytowashoutlocalanestheticsfrom
(CPB)
idemulsion(III;C).
y(IIa;B):LAST.
article is prohibited.
otherstandardtherapies,cardiopulmonarybypassshouldbeconLASTinwhichthereisinadequateresponsetoepinephrineand
shouldbegiventoavoidingvasopressin.Inrecalcitrantcasesof
gested(G1Kg/kg).Onthebasisofanimalstudies,consideration
LAST,lowerthanBstandard[initialdosesofepinephrinearesugrhage.48Therefore,thePaneladvisesthatifusedintreating
pooroutcomesandwasassociatedwithpulmonaryhemorthandidlipidemulsion,47whereasvasopressinalsoshowedvery
sultedinpooreroutcomesfrombupivacaine-inducedasystole
studiesoflocalanesthetic-inducedcardiacarrest,epinephrineresure,itisalsohighlyarrhythmogenic.Furthermore,inanimal
phrinemayrestorecirculationandinitiallyimprovebloodpresLifeSupportGuidelines.Althoughstandarddose(1mg)epinetypicalout-of-hospitalscenariosaddressedbyAdvancedCardiac
sentsasubstantiallydifferentmedicalproblemfromthemore
nizethatcardiacarrestorarrhythmiaassociatedwithLASTreprepreventionandtreatmentofacidosis.Itisimportanttorecogofcardiacoutputandoxygendeliverytotissuesiscriticalfor
cardiactissuesthroughimprovedtissueperfusion.Maintenance
)ConsideradministeringatthefirstsignsofLAST,afterairway
itisreasonabletonotifytheclosestfacilitycapableofproviding
(IIa;B).BecausetherecanbeconsiderablelaginbeginningCPB,
itwhenCVcompromiseisfirstidentifiedduringanepisodeof
hIfcirculatorystabilityisnotattained,considerrebolusand
h0.25mL/kgperminuteofinfusion,continuedforatleast
hApproximately10mL/kglipidemulsionfor30minsis
recommendedastheupperlimitforinitialdosing
increasinginfusionto0.5mL/kgperminute
10minsaftercirculatorystabilityisattained
h1.5mL/kg20%lipidemulsionbolus
)Dosing:
management
*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine157
Theclassofrecommendationandlevelofevidenceforeachinterventionaregiveninparenthesis(Table1).

NealetalRegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010

3.CorcoranW,ButterworthJ,WellerRS,etal.Localanesthetic-induced
attemptshadfailed,butrecentcasereports6,50Y52supportthe
cardiactoxicity:asurveyofcontemporarypracticestrategiesamong
earlyuseoflipidemulsionatthe
rstsignofarrhythmiafrom
academicanesthesiologydepartments.AnesthAnalg.2006;103:
suspectedLAST,prolongedseizureactivity,orrapidprogression
1322Y1326.
ofthetoxicevent.Becausetissuedepotsoflocalanesthetic
canredistributetothecirculationovertimeanddelayedre4.TheAGREECollaboration.AppraisalofGuidelinesforResearch&
currenceofseveretoxicityhasbeenreported,werecommend
Evaluation(AGREE).Availableat:www.agreecollaboration.org.
thatanypatientwithsignicantLASTbeobservedforatleast AccessedFebruary11,2009.
12hrs.Thereisnoevidencethatoneformulationoflipidemul5.AmericanHeartAssociation.ManualforACC/AHAGuidelineWriting
sionissuperiortoanotherforthetreatmentofLAST.HowCommittees.MethodologiesandPoliciesfromtheACC/AHATask
ever,itisimportanttonotethatpropofolisnotasubstitute
ForceonPracticeGuidelines.Availableat:http://circ.ahajournals.org/
forlipidemulsiontherapybecauseofitslowlipidcontent
manual/index.shtml.2009.AccessedFebruary11,2009.
(10%),thelargevolumesrequiredforthebene
toflipidin
6.ButterworthJF.Casereports:unstylishbutusefulsourcesofclinical
resuscitation(hundredsofmilliliters)andthedirectcardiacdeinformation.RegAnesthPainMed.2009;34:187Y188.
pressanteffectsofpropofol.Ourrecommendationsforthetreat7.HeblJR,NealJM.Infectiouscomplications:anewpracticeadvisory
mentofLASTarepresentedinTable4.Thoserecommendations
[editorial].RegAnesthPainMed.2006;31:289Y290.
aresummarizedinAppendix3,whichisavailableonlineintwo
8.MattisonJB.Cocainepoisoning.MedSurgRep.1891;115:645Y650.
sizesandcanbeprintedandlaminatedfordisplayinareas
wherepotentiallytoxicdosesoflocalanestheticsareused.(See
9.MayerE.Thetoxiceffectsfollowingtheuseoflocalanesthetics.
SupplementalDigitalContent1,http://links.lww.com/AAP/A17, JAMA.1924;82:876Y885.
foracondensedversionofAppendix3,andSupplementalDigital
10.MooreDC,BridenbaughLD.Oxygen:theantidoteforsystemictoxic
Content2,http://links.lww.com/AAP/A18,forafull-sizeversion).
reactionsfromlocalanestheticdrugs.JAMA.1960;174:102Y107.
11.PrenticeJE.Cardiacarrestfollowingcaudalanesthesia.Anesthesiology.
1979;50:51Y53.

FUTUREDIRECTIONS

Itisapparentthatcontinuedinvestigationisneededto
12.WeinbergGL,VadeBoncouerTR,RamarajuGA,Garcia-AmaroMF,
guidefuturemethodsforpreventingandtreatingLAST.ImCwikMJ.Pretreatmentorresuscitationwithalipidemulsionshifts
proved,lesstoxic,longer-actinglocalanestheticsaredesired.
thedose-responsetobupivacaine-inducedasystoleinrats.
Noveldeliverymethodsmayreducethedoserequiredtoachieve
Anesthesiology.1998;88:1071Y1075.
clinicalanesthesiaandanalgesia.Examplesincludebothcurrent
13.RosenblattMA,AbelM,FischerGW,ItzkovichCJ,EisenkraftJB.
technology(UGRA)anddeliverymethodsindevelopment,such
Successfuluseofa20%lipidemulsiontoresuscitateapatient
ascapsaicincoinjection53andsustainedreleasemicrospheres
afterapresumedbupivacaine-relatedcardiacarrest.Anesthesiology.
orliposomes.54Wehopethatcontinuedlaboratoryinvestigation
2006;105:217Y218.
willleadtoimprovedresuscitationmethods.Alternativefor14.DrasnerK.Localanestheticsystemictoxicity:ahistoricalperspective.
mulationsoflipidemulsionornewagentsdesignedtoincrease
RegAnesthPainMed.2010;35:160Y164.
partitioning,binding,capture,orotherwiseneutralizinglocal
15.IrelandPE,FergusonJK,StarkEJ.Theclinicalandexperimental
anestheticmoleculesholdthepromiseofarapid,effectiveanticomparisonofcocaineandpontocaineastopicalanestheticsin
dotetoLAST.Furtherrenementisneededwithregardtothe
otolaryngologicalpractice.Laryngoscope.1951;61:767Y777.
idealtimingoflipidemulsiontherapy,alongwithidenti
cationof
potentialtoxicitiesoradverseeffects.
16.BrownDL,RansomDM,HallJA,etal.Regionalanesthesiaand
OurunderstandingofthemechanismsofLAST,although
localanesthetic-inducedsystemictoxicity:seizurefrequencyand
incomplete,hasincreasedsigni
cantlysincelocalanesthesia
accompanyingcardiovascularchanges.AnesthAnalg.1995;81:321Y328.
wasintroducedmorethanacenturyago.Stepwiseimprove17.AuroyY,BenhamouD,BarguesL,etal.Majorcomplicationsof
mentsinourknowledgeregardingprevention,diagnosis,and
regionalanesthesiainFrance.TheSOSRegionalAnesthesiaHotline
treatmenthavelikelyledtoareductioninfatalitiesassociated
Service.Anesthesiology.2002;97:1274Y1280.
withLAST;itislesscertainwhetherthefrequencyofnonfatal
2010Copyright @ American Society
of Regional Anesthesia and18.GrobanL.Centralnervoussystemandcardiaceffectsfrom
Pain Medicine. Unauthorized reproduction of this
seizuresandcardiaceventshasalsodeclined,particularlythose
long-actingamidelocalanesthetictoxicityintheintactanimalmodel.
158*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine
article is prohibited.
successfulresuscitation)suggeststhatLASTremainsasigni
genceofpublishedreportsofLAST,(particularlyinvolving
developmentofUGRAandlipidemulsiontherapy,theresurepiduraltechniques).Althoughprobablylinkedtotherecent
eventsassociatedwithperipheralnerveblock(asopposedto
thetics,(2)thefrequentuseofdosessuf
clinicalproblem.Considering(1)theextensiveuseoflocalanespreparedtorespondimmediatelytotheseeventswhentheyoccur.
understandtheirpotentialforseveresystemictoxicityandtobe
mainstheresponsibilityofallcliniciansusinglocalanestheticsto
abilitytoprevent,detect,andtreatthesecomplications,itrecantmorbidityormortality,and(3)theimperfectnatureofour
REFERENCES
cienttocausesigni

cant
1.AlbrightGA.Cardiacarrestfollowingregionalanesthesiawith
2.DiGregorioG,NealJM,RosenquistRW,WeinbergGL.Clinical
etidocaineorbupivacaine.Anesthesiology.1979;51:285Y287.
cases,1979-2009.RegAnesthPainMed.2010;35:179Y185.
presentationoflocalanestheticsystemictoxicity:areviewofpublished
23.FeldmanHS,ArthurGR,CovinoBG.Comparativesystemictoxicityof
19.BlockA,CovinoBG.Effectoflocalanestheticsoncardiacconduction
24.GrobanL,DealDD,VernonJC,JamesRL,ButterworthJ.Ventricular
21.ValenzuelaC,SnydersDJ,BennettPB,TamargoJ,HondeghemLM.
20.ClarksonC,HondeghemL.Mechanismforbupivacainedepression
anestheticdrugsinanesthetizeddogs.AnesthAnalg.1996;82:648Y656.
electrophysiologicandhemodynamiceffectsofseveralamidelocal
Stereospecificblockofcardiacsodiumchannelsbybupivacainein
guineapigventricularmyocytes.Circulation.1995;92:3014Y3024.
22.BruelleR,LeFrantJY,delaCoussayeJE,etal.Comparative
convulsantandsupraconvulsantdosesofintravenousropivacaine,
ofcardiacconduction:fastblockofsodiumchannelsduringthe
actionpotentialwithslowrecoveryfromblockduringdiastole.
bupivacaine,andlidocaineintheconsciousdog.AnesthAnalg.
andcontractility.RegAnesth.1981;6:55Y61.
RegAnesthPainMed.2003;28:3Y11.
Anesthesiology.1985;62:396Y405.
1989;69:794Y801.

RegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010LocalAnestheticToxicityPracticeAdvisory

arrhythmiaswithorwithoutprogrammedelectricalstimulationafter
44.MooreDC,CrawfordRD,ScurlockJE.Severehypoxiaandacidosis
incrementaloverdosagewithlidocaine,bupivacaine,levobupivacaine,
followinglocalanesthetic-inducedconvulsions.Anesthesiology.
andropivacaine.AnesthAnalg.2000;91:1103Y1111.
1980;53:259Y260.
25.ButterworthJ.Modelsandmechanismsoflocalanestheticcardiac
45.HeavnerJE,DrydenCF,SanghaniV,etal.Severehypoxiaenhances
toxicity:areview.RegAnesthPainMed.2010;35:167Y176.
centralnervoussystemandcardiovasculartoxicityofbupivacaine
inlightlyanesthetizedpigs.Anesthesiology.1992;77:142Y147.
26.MooreDC,BatraMS.Thecomponentsofaneffectivetestdose
46.WeinbergGL.Treatmentoflocalanestheticsystemictoxicity.
priortoepiduralblock.Anesthesiology.1981;55:693Y696.
RegAnesthPainMed.2010;35:186Y191.
27.MulroyMF,HejtmanekMR.Preventionoflocalanesthetictoxicity.
47.WeinbergGL,DiGregorioG,RipperR,etal.Resuscitationwith
RegAnesthPainMed.2010;35:175Y178.
lipidversusepinephrineinaratmodelofbupivacaineoverdose.
28.NealJM,GerancherJC,HeblJR,etal.Upperextremityregional
Anesthesiology.2008;108:907Y913.
anesthesia.Essentialsofourcurrentunderstanding,2008.RegAnesth
48.DiGregorioG,SchwartzD,RipperR,etal.Lipidemulsionissuperior
PainMed.2009;34:134Y170.
tovasopressininarodentmodelofresuscitationfromtoxin-induced
29.DugganE,ElBeheiryH,PerlasA,etal.Minimumeffectivevolume
cardiacarrest.CritCareMed.2009;37:993Y999.
oflocalanestheticforultrasound-guidedsupraclavicularbrachialplexus
block.RegAnesthPainMed.2009;34:215Y218.
49.WeinbergGL,RipperR,MurphyP,etal.Lipidinfusionaccelerates
removalofbupivacaineandrecoveryfrombupivacainetoxicityinthe
30.PaqueronX,NarchiP,MazoitJX,etal.Arandomized,observer-blinded
isolatedratheart.RegAnesthPainMed.2006;31:296Y303.
determinationofthemedianeffectivevolumeoflocalanesthetic
requiredtoanesthetizethesciaticnerveinthepoplitealfossafor
50.MarkowitzS,NealJM.Immediatelipidemulsiontherapyinthe
stimulatingandnonstimulatingperineuralcatheters.RegAnesthPain
successfultreatmentofbupivacainesystemictoxicity.RegAnesth
PainMed.2009;34:276.
Med.2009;34:290Y295.
31.EichenbergerU,StockliS,MarhoferP,etal.Minimallocalanesthetic
51.CharbonneauH,MarcouTAP,MazoitJX,ZetlaourPJ,BenhamouD.
volumeforperipheralnerveblock:anewultrasound-guidednerve
Earlyuseoflipidemulsiontotreatincipientmepivacaineintoxication.
dimension-basedmodel.RegAnesthPainMed.2009;34:247Y250.
RegAnesthPainMed.2009;34:277Y278.
32.RosenbergP,VeeringBT,UrmeyWF.Maximumrecommendeddoses
52.SonsinoDH,FischlerM.Immediateintravenouslipidinfusioninthe
oflocalanesthetics:amultifactorialconcept.RegAnesthPainMed.
successfulresuscitationofropivacaine-inducedcardiacarrestafter
2004;29:564Y575.
infraclavicularbrachialplexusblock.RegAnesthPainMed.2009;34:
276Y277.
33.PanPH,BogardTD,OwenMD.Incidenceandcharacteristicsof
failuresinobstetricneuraxialanalgesiaandanesthesia:aretrospective
53.IlfeldBM,YakshTL.Theendofpostoperativepain:afast-approaching
analysisof19,259deliveries.IntJObstetAnesth.2004;13:1073Y1076.
possibility?And,ifso,willwebeready?RegAnesthPainMed.
2009;34:85Y87.
34.GuayJ.Theepiduraltestdose:areview.AnesthAnalg.2006;102:
921Y929.

54.RoseJS,NealJM,KopaczDJ.Extended-durationanalgesia:update
onmicrospheresandliposomes.RegAnesthPainMed.2005;
35.NealJM.Effectsofepinephrineinlocalanestheticsonthecentraland
30:275Y285.
peripheralnervoussystems:neurotoxicityandneuralbloodflow.
RegAnesthPainMed.2003;28:124Y134.
36.AuroyY,NarchiP,MessiahA,etal.Seriouscomplicationsrelated
toregionalanesthesia.ResultsofaprospectivesurveyinFrance.
Anesthesiology.1997;87:479Y486.
37.NealJM.Ultrasound-guidedregionalanesthesiaandpatient
safety:anevidence-basedanalysis.RegAnesthPainMed.
RudydeJongJohnPicard
2010;35(suppl1):S59YS67.

APPENDIXI

ExternalExpertAppraisers

NickDennyPerRosenberg

38.BarringtonMJ,WattsSA,GledhillSR,etal.Preliminaryresultsof
BrendanFinucaneMegRosenblatt
theAustralasianRegionalAnaesthesiaCollaboration:aprospective
J.C.GerancherJohnRowlingson
2010Copyright @ American Society auditofover7000peripheralnerveandplexusblocksfor
of Regional Anesthesia
and Pain Medicine. Unauthorized reproduction of this
JimHeavnerRudyStienstra
APPENDIX2
article is prohibited.
TimMeekTimVadeBoncouer
ProfessionalSocietiesInvitedtoCommentonDraftGuidelines
MarkNorrisCynthiaWong
GregLiguoriBillUrmey
AmericanAcademyofOrthopedicSurgeons
AmericanCollegeofEmergencyPhysicians
AmericanPodiatricMedicineAssociation
AmericanAcademyofFamilyMedicine
AmericanSocietyofPlasticSurgeons
AnesthesiaPatientSafetyFoundation
AmericanCollegeofSurgeons
AmericanDentalAssociation
*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine159
39.OrebaughSL,WilliamsBA,VallejoM,KentorML.Adverseoutcomes
40.VadeBoncouerTR,WeinbergGL,OswaldS,AngelovF.Early
41.ZetlaouiRJ,LabbeJ-P,BenhamouD.Ultrasoundguidanceforaxillary
42.LeeL,PosnerKL,ChaneyFW,CaplanRA,DominoKB.Complications
43.MulroyMF.Systemictoxicityandcardiotoxicityfromlocalanesthetics:
2009;34:534Y541.
neurologicalandothercomplications.RegAnesthPainMed.
251Y255.
withoutultrasoundvisualization.RegAnesthPainMed.2009;34:
associatedwithstimulator-basedperipheralnerveblockswithversus
2008;33:278Y279.
supraclavicularbrachialplexusblock.RegAnesthPainMed.
detectionofintravascularinjectionduringultrasound-guided
2008;108:761.
plexusblockdoesnotpreventintravascularinjection.Anesthesiology.
closed-claimsanalysis.RegAnesthPainMed.2008;33:416Y422.
associatedwitheyeblocksandperipheralnerveblocks:anASA
556Y561.
incidenceandpreventivemeasures.RegAnesthPainMed.2002;27:

2010Copyright @ American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this
article is prohibited.

NealetalRegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010

2010Copyright @ American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this
160*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine
article is prohibited.

RegionalAnesthesiaandPainMedicine&Volume35,Number2,March-April2010LocalAnestheticToxicityPracticeAdvisory

*2010AmericanSocietyofRegionalAnesthesiaandPainMedicine161