Safety of local anesthetics,

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Anais

Brasileiros

de

Dermatologia

www.anaisdedermatologia.org.br

REVIEW

Safety

of

local

anesthetics

夽,夽夽

Ana

Carolina

Figueiredo

Pereira

Cherobin

∗

,

Glaysson

Tassara

Tavares

DermatologyService,HospitaldasClínicas,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil Received1May2019;accepted23September2019

Availableonline18December2019

KEYWORDS

Anaphylaxis; Anesthetics,local; Drug-relatedside effectsandadverse reactions

Abstract Localanestheticsareessential medicationsforthe conductionofdermatological procedures.Theystopthedepolarizationofnervefibersandaredividedinto twomain cat-egories,theamideandestertypes.Systemictoxicitywithreflexonthecentralnervousand cardiovascularsystemsistheirmostfearedadversereactions,andtheanaphylacticreactionis themostconcerningone.Althoughpotentiallyfatal,theseeventsareextremelyrare,solocal anestheticsareconsideredsafeforuseinin-officeprocedures.

Introduction

In-ofﬁcedermatological proceduresare usual andinclude fromthebiopsyofminorinjuriestocosmiatricprocedures andlongcomplexsurgeries.Localanesthesiaisessentialfor theviability of, and goodtolerance to, their conduction. Thismethodissafeandrecommendedformostprocedures performed outside the out-and inpatient environment.1,2

Theaimofthepresentstudywastomakealiteraturereview aboutthesafetyofapplyinglocalanestheticswithemphasis onadversereactions.

夽 _How_to_cite_this_article:_Cherobin_ACFP,_Tavares_GT._Safety_of

localanesthetics.AnBrasDermatol.2020;95:82---90.

夽夽_Study_conducted_at_the_Dermatology_Service,_Hospital_das

Clíni-cas, Universidade Federal de MinasGerais, Belo Horizonte,MG, Brazil.

∗_{Corresponding}_author.

E-mail:anacherobin@yahoo.com.br(A.C.F.P.Cherobin).

Methods

The methodology used to select the articles was based on the PICO method (Problem/Patient/Population, Inter-vention/Indicator, Comparison and Outcome). Patients subjectedtodermatologicalprocedurescomposedthe pop-ulation of the present study, local anesthetics were the interventionandtheadverse reactionsweretheoutcomes ---thecomparisongroupwasnotdetermined.

Results

and

Discussion

Resultsinthisreviewweredividedintothefollowing subti-tles:Actionmechanismsoflocalanesthetics,Classiﬁcation andpharmacokinetics,Typesof localanesthetics,Adverse reactions,Applicationtechniques,Safetyofanestheticsand Specialsituations.

https://doi.org/10.1016/j.abd.2019.09.025

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Action

mechanism

of

local

anesthetics

Pain sensation depends on the ability of the nervous sys-temtotransmitelectricalimpulses.Thispropagationoccurs due to different electrolyte concentrations between the intracellularregion---whichpresentshighpotassium concen-tration (K+₎ _and_lower _sodium_{concentrations} _(Na+₎ _--- _and

theextracellularregion,whereconcentrationsarereversed. Thisionicgradientiskeptbythesodium-potassium adeno-sine triphosphatase (Na+ _K+ _ATPase) _pump. _The _external

membraneof thenerve(at rest) presentspositiveloadin comparisontotheinternalregionduetothelowmembrane permeabilitytoNa+_and_to_the_action _of_the_pump,_which

excludesthreeNa+_ions_for_each_of_the_two_internalized_K+

ions.3,4

The membrane becomes permeable to the Na+

accu-mulated inside the cell whenever there is stimulus over the nerve, and this process ends up in depolarization. This change in Na+ _permeability _also_changes _the

electri-cal potential through the membrane; the propagation of thiselectricalpotentialiscalledactionpotential.Thenerve returnstotherestingstatebychangingthemembrane per-meabilitytoNa+_again.3---5

Local anesthetics act in the Na+ _K+ _ATPase _pump, _and

this process stops the sodiuminﬂow and the propagation of pain stimulus through nervous ﬁbers; thus, it avoids depolarization.2,5

Pain sensation is spread through unmyelinated ﬁbers (FibersC),whicharemoresensitivetolocalanestheticsthan myelinatedﬁbers(FiberAandB).This processallows sen-sationssuchasvibrationandpressuretoremainevenafter completepaininhibition.2,5

Classiﬁcation

and

pharmacokinetics

Localanestheticsarecomposedofastructuredividedinto threeparts:aromaticgroup(lipophilic),intermediatechain andaminegroup(hydrophilic).

The aromatic ring provides lipid solubility to the sub-stance;thehigherthesolubility,thegreatertheanesthetic diffusioninthenervousmembrane.Thispropertyis corre-latedtothepowerofthemedication.

The terminal amine has the tertiary (liposoluble) and quaternaryforms(watersoluble).Theanestheticis adminis-teredinitsquaternaryform,anditsactionoccursaccording tothe proportionofmolecules that turn intothe tertiary formaftergettingincontactwiththephysiologicalpH(7.4).

Theionizationconstant(pKa)oftheanestheticrepresents thepH, and half of themolecules are found in their ter-tiary form,and the other half is in the quaternary form. Mostanesthetics have pKa similartothe physiological pH (7.4).Theacidiﬁedenvironmentfavorsthequaternaryform wheneverthereisinﬂammation;it reducestheamount of anestheticcapableofpenetratingthenerves.5

The intermediate chain canbe composed of esterand amide,whichareresponsiblefortheanesthetic classiﬁca-tion(Table1).5,6

Amide-typeanestheticsaremetabolizedbytheliverand theymustbeusedcarefullyinpatientswithkidneyissues. Ester-type anesthetics are degraded by plasma pseudo-cholinesteraseandtheirmetabolites areexcreted through urine.The Para-Aminobenzoic Acid (PABA) is one of their metabolites, andit is responsiblefor the risk of develop-ingallergicreactionstothisgroupofmedications.Different fromwhat happens withanesthetics in the amide group, thepotentialforcrossreactionsbetweenanestheticsinthis groupisknown.3,5,6

The affinity of anesthetics with plasma proteins is correlatedtothe affinityof suchproteins withthe trans-membrane sodium channels; the greater the affinity, the longerthe action timeof the anesthetic and itsduration (Table1).5,6

Types

of

local

anesthetics

There are different methods to induce local anesthesia: topical,inﬁltrative,ﬁeldblock,peripheralnerveblockand tumescent anesthesia. All these methods have transient regionalanesthesia.3,5

Substances in topical anesthesia are administered straight into the skin or into the mucosa through mois-turizers,ointments, gelsor sprays. Accordingly,theagent penetratesand reachesthe papillarydermis toact inthe endingsofnervebranches.3,5 _The_composite_easily_crosses

theskin whenthepka ofthe anestheticgetsclosetothe skinpH (5.5)and thecorneallayer isthin (suchasinthe eyelids)orabsent(mucosa).7,8

Inﬁltrative anesthesia is obtained through medication administrationrightonthedermis,orthroughsubcutaneous administration,whichcausesdirectinhibitionofnerve end-ings.Actionstartsrightwhenthesubstanceisinjectedinthe dermis;however,theinjectionisquitepainful.Painismilder whenthesubstanceisinjectedinthesubcutaneoustissue,

Table1 Characteristicsofthemostusedanestheticsindermatology.

Anesthetic Proteinafﬁnity Onsetofaction Durationwithout epinephrine(min) Durationwith epinephrine(min) Amidetype Lidocaine 64 2---3min 30---120 60---400 Mepivacaine 77 3---20min 30---120 60---400 Bupivacaine 95 5---8min 120---240 240---480 Estertype Procaine 5.8 5min 15---30 30---90

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butthedurationtimecanbeshorterduetotheabsorption ofhigheramountsofsubstance.3,5

Field blocking consists in the deposition of anesthetic solutionaroundthe desiredsite (circumference shape)to anesthetizethesuperﬁcialanddeepnervesresponsiblefor the innervationsof the target region. Thus, it is possible anesthetizingwithlessproductwhenthereisnodistortion intheareatobetreated.3,5

In order toblock the peripheral nerve,the anesthetic mustbeinjectedaroundthemainnerve.Thismethodallows expressivereductioninthenecessaryvolumeofanesthetic fortheprocedureandpreventsdistortionsintheoperative site.These methods are broadlyused in face,dactyl and naildermatologicalprocedures,besidesdemandingdetailed knowledgeabout anatomyand acknowledged professional expertise.3,5

The tumescent anesthesia is similar to the inﬁltrative one;however, it demands morediluted dosesof the sub-stancerightintheregiontobesubjectedtotheprocedure. Duetothelowerconcentrationofanesthetic,onecanusea largervolumeofitwithlowtoxicityrisk.Thistechniqueis appliedtoliposuction,dermabrasionandhairimplant.5,9

Injectableanesthetics

Lidocaine

Lidocaineisasystemicantiarrhythmic;nowadays,itisthe mostusedinjectableanestheticindermatologicalpractices. Itsactionstartsfast(<1min)anditsdurationis intermedi-ate(30---120min).Themaximumdose oflidocaineallowed forlocalinﬁltrationinadultsis4.5mg/kg/dose(maximum: 300---350mg)withoutepinephrineand7mg/kg/dose (maxi-mum:300---500mg)withepinephrine.Themaximumdosefor childrenunder12yearsrangesfrom1.5to2.0mg/kg/dose (maximum: 150mg) without epinephrine and from 3 to

4.5mg/kg/dose (maximum: 150mg)withit.Childrenover 12 years aretreated withdoses similarto thoseusedfor adults.ThisisaCategoryBmedicationduringpregnancyand its kidney metabolism happens through cytochrome P450 (Tables1and2).1,3,6,9

Mepivacaine

Mepivacaineisanamide-typeanestheticthathasfastaction start and30---120minduration.Itsallowed maximumdose is 300mg with epinephrine and 500mg without it. The dose for children is 4---6mg/kg/dose (maximum: 270mg) without epinephrine. Similarto lidocaine, mepivacaine is metabolized by the liver. It is a Category C in pregnancy (Tables1and2).3,5,6,10

Bupivacaine

Bupivacaineisalsoanamide-groupanestheticwhoseaction startisslowerthanthatoflidocaine(5---8min)andits dura-tion is longer than lidocaine’s (2---4h). Its safety for the pediatricpopulationremainspoorlyestablished.The maxi-mumdoseinadultsis2mg/kg/dose(175mginasingledose) or 400mg/24h withoutepinephrine---whenepinephrineis used, it is possible using doses up to 225mg. Its use is beneﬁcial for prolonged procedures.Bupivacaine has car-diotoxicpotential;therefore,itisnecessarybeingcautious withpatientsusing␤-blockersordigoxin.ItisaCategoryC inpregnancy(Tables1and2).3,6,10,11

Etidocaine

It is also a member of the amide group; its action starts between 3 and 5min, and its duration lasts 200min. The maximum dose recommended is 4.5mg/kg/dose (300mg) without epinephrine and 6.5mg/kg/dose (400mg) with it (Table1).1

Table2 Addresseddosesandpregnancycategoriesofthemostlyusedlocalanestheticsindermatology. Anesthetic Adultdosing

(without epinephrine)

Adultdosing(with epinephrine) Pediatricdosing (without epinephrine) Pediatricdosing (withepinephrine) Categoryin pregnancy Amidetype Lido-caine 4.5mg/kg (max: 300---350) <7mg/kg (300---500) 4.5mg/kg (300) <12yearsold: 4.5mg/kg (100---150) B >12yearsold: <7mg/kg (300---500) Mepivacaine <300mg <500mg 4---6mg/kg(270) C Bupivacaine 2mg/kgor175mg (singledose)or 400mg/24h(total dose) 225mg Safetyand

efﬁcacyhavenot beenestablished

Safetyand efﬁcacyhavenot beenestablished

C

Ropivacaine 2.9mg/kg (200mg)

Safetyand efﬁcacyhavenot beenestablished

B

Estertype

Procaine 350---500mg 600mg <15mg/kg C

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Prilocaine

Prilocaine belongs to the amide group and its action starts between 5 and 6min. Its duration is intermediary, which varies from 30 to120min. Its maximum allowable dose is5.7---8.5mg/kg/dose(maximum of 400mg)without epinephrineand 600mg withit.Itsmetabolism is hepatic andrenal.Ifdosesarehigherthan8mg/kg theremust be risk of methemoglobinemia due to its metabolite ortho-toluidine.1,3,6

Ropivacaine

Ropivacaineisanamide-typeanestheticthatpresentsslow actionstart(1---5min)andlongduration(2---6h).Theallowed maximumdoseis2.9mg/kg/dosewithoutepinephrine addi-tion (maximum: 200mg). Its safety in children was not conﬁrmedsofar.Similartotheothergroupofanesthetics, ropivacaine is metabolized by the liver. It has vasocon-strictoraction andisclassiﬁedinCategoryBinpregnancy (Table2).6,12

Articaine

Anesthetic belonging to the amide group that presents fastaction start (2---4min) andduration similartothatof lidocaine(30---120min).Itsmaximum doseis7mg/kg/dose (350mg)withoutepinephrineand500mgwithit.The max-imum dose recommended for children over 4 years is 7mg/kg/dose.Itsmetabolismishepatic,anditisclassiﬁed inCategoryCinpregnancy.6

Procaine

Procaine is an ester-type anesthetic whose action starts within5minanditsdurationisshort(30---60min).The maxi-mumdoseforadultsis10mg/kg/dose(350---500mg)without epinephrineand14mg/kg/dose(600mg)withit.Similarto other anesthetics in this category,its metabolism is plas-matic.ItisaCategoryCinpregnancy(Tables1and2).1,6

Topicalanesthetics

Topicalanestheticsareavailableindistinctpreparationsand vehicles.Themixturesallowcompoundstobeinliquidstate andathigher,althoughsafe,concentrations.13

Lidocaine

Lidocaineis themost often used anesthetic, either in its isolatedform or in association withother components. It belongsto the amidegroup, which makes this anesthetic lessallergenic. Itis classiﬁedasCategoryBin pregnancy;

however,itisnecessarypayingcloseattentiontolactating, duetoitsexcretioninbreastmilk.8,13

Lidocaineat4%(Dermomax®₎

Lidocainecreamisthemostusedtopicalanesthetic world-wide,eitheraloneorincombinationwithothersubstances.8

Itis traded in 4%cream in Brazil. Itssystemicabsorption changesbased on the location andextent of the treated area.Serumpeakreaches0.05---0.16␮g/mL,afterthe appli-cationof 60g oflidocainecream in a400cm2 _area._Toxic

levelsofthis substance (>5␮g/mL)leadtocardiovascular andcentralnervoussystemdisorders.Themaximum appli-cation area in children weighing up to 10kg is 100cm2_,

whereasthe maximumapplication areain children weigh-ingfrom10---20kgis200cm2_._This_anesthetic_is_classiﬁed_as

categoryBduringpregnancy.8,13

Lidocaine2.5%+prilocaine2.5%(EMLA®₎

Oneof the most usedtopicalanesthetics is based onthe association between lidocaine 2.5% and prilocaine 2.5%. Systemicabsorption dependson theapplication duration, anatomiclocationandontheextensionofthetreatedarea. Occlusion and prolonged application increase medication penetration.Analgesiareaches3mmdownin60min appli-cation and 5mm down after 120min. The use of 60g of medicationin400cm2_of_occluded_body_surface_means_low

toxicityrisk.Itisallowedtouseupto1gofanestheticfor, atmost,1hinnewborns(Table3).8,13

Lidocaine7%+tetracaine7%(Pliaglis®₎

The lidocaine7% and tetracaine7% formation in moistur-izers forms a membrane on skin surface and it helps its localabsorption. The compound penetrates 6.8mm down theskinandmustbeadministered30minbeforethe proce-dure.Localreactionsincludeerythema,pallorandedema.8

Epinephrine

Epinephrine(adrenaline)isa vasoconstrictoroften associ-atedwithlocalanesthetics(1---2:100.000).Itallowsslower systemic reabsorption of the anesthetic by prolonging its effect,reducingitsplasmaticpeakandpromoting hemosta-sis. This compound must be carefully used in patients treatedwithbetablockersorintheoneswithcardiovascular diseases, peripheral vascular diseases, severe hyperten-sion, pheochromocytoma and hyperthyroidism. However, some studies have shown that its use is safe when it is administeredin smalldoses in patients withstable heart disease.1,6,14

Table3 Recommendedmaximumdoseandapplicationáreaofeuteticmixtureoflocalanestheticscream(EMLA®_).8

Ageandbodyweightrequirement Maximumtotaldose(g) Maximumapplication area(cm2₎

Maximumapplication time(hours)

0---3monthsor<5kg 1 10 1

3---12monthsand>5kg 2 20 4

1---6yearsoldand>10kg 10 100 4

7---12yearsoldand>20kg 20 200 4

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Epinephrineadditiontolocalanestheticsalsoprovedto be safe in terminal vascularization sites such as dactyls, hands,feetandgenitalarea.1,15

EpinephrineisclassiﬁedinCategoryCinpregnancyand itsalpha-adrenergicpropertycancausevasoconstrictionin plexusblood fromtheplacenta. However,itsusein preg-nantwomenissafeat lowdoses,sinceitsvasoconstrictor effect limits its systemic absorption and transference to theplacenta.Itsadministrationonpregnantwomenis rec-ommendedto be postponed to after childbirth whenever possible.1,16

The adopted concentrations range from 1:500.000 to 1:200.000;concentrations1:100.000and1:200.000arethe mostoften administeredones. These concentrations have similareffectonvasoconstriction,besidesprolonging lido-cainedurationbyapproximately200%.1

Adverse

reactions

Local anesthetics are quite safe when they are properly used.However,althoughrare,theycancausesomeadverse reactions, including some events with systemic repercus-sion.

Undesiredreactionscanbedividedintotwocategories: the ones associated with needle penetration in the skin andtheonesassociatedwiththeanestheticsolution.Pain, edema,bruise,infection,hyperalgesiaandmusculartrismus standoutamongfactorsintheﬁrstcategory(needle pene-trationintheskin).5_Reactions_associated_with_the_solution

concernlocalorsystemictoxicity,allergicandidiosyncratic reactions.5

Localtoxicity

Localtoxicityisattributedtothe straighteffects oflocal anestheticsontheapplicationsite,suchaspain.Itis com-monlyassociatedwithincorrecttechniqueseitherregarding thesubstance itselfortissuedistensionin theapplication site,forinstance:bruise,infection,dilacerationsofnervous structuresandischemicnecrosis.5,6

Systemictoxicity

Localanestheticsystemictoxicity(LAST)isthemostsevere adversereactionsinceithasthepotentialtokillthepatient. Itoccurswhentheplasmaticlevelintheanestheticrisesto concentrationsabovetherecommended.Thisreactioncan happensuddenlyaftertheapplicationoftheanestheticin thebloodstream,orslowly,duetoincreasedserumlevelsin theanestheticaftertheadministrationofexcessivedoses, ortoreducedmedicationmetabolism.1,5,17---19

First,patient’s present signsof centralnervoussystem activation, which tend to progress: perioral paresthesia, facialparesthesia,disarthria,metallictaste,diplopia, audi-tory disturbances and seizures. High blood pressure and tachycardia can also be associated with such activation. Symptomprogressionbrings alongsigns ofnervoussystem depression,whichleadstorespiratorydepression(lidocaine serum concentration higher than 15␮g/mL). The cardio-vascular effects come later, and they include myocardial

depression, prolonged conduction interval, bradycardia, hypotensionandheartfailure(lidocaineserum concentra-tionhigherthan20␮g/mL).1,5,17

Although potentially severe, the systemic toxicity is extremely rare. The necessary dose of local anesthetics formostdermatologicalproceduresismuchlowerthanthe doserecommendedforeachanesthetic---systemictoxicity isassociatedwithhighdosesofthemedication.1

Vasquesetal.publishedaliteraturereview,which iden-tiﬁed 67 systemic toxicity cases described in 54 articles between2010---yearwhentheLASTprotocolalgorithmwas published bythe AmericanSociety of RegionalAnesthesia andPain Medicine ---and2014. Eight (8)cases,outof the total,emergedaftercontinuousinfusionofthelocal anes-thetic,andtwoothercaseshappenedaftertheinadvertent administrationofthedruginthevesselthroughvenous can-nula.The administrationtechniquewas adequate for 78% of the 50 patients who received one single dose of local anesthetic.Amongthesepatients,23%presentedsystemic toxicityafterinterscalene block, 16%after epiduralblock and13%afterpenileblock.Patientsyoungerthan one-year-oldwerethemostaffectedones(22%).Seven(7)caseswere associatedwithtopicalanesthetics(non-injectable),5cases were associatedwithchildren --- 4 of thesechildren were youngerthan4years.Systemictoxicitywasonlyobserved in two dermatological patients: two children evolved to methemoglobinemiaafterEMLAadministration.17

The prospective study by Starling et al. showed that in-ofﬁce dermatological procedures recorded very low complication rates.After tenyears studyingthe states of Florida and Alabama (U.S.A.), they did not identify any complicationrelatedtolocalanestheticsindermatological procedures.2

ThelongitudinalstudybyAlametal.includedaresearch with437dermatologicalsurgeonsintheUnitedStatesandit alsohighlightedintoxicationcasescausedbylidocaineuse during surgical proceduresconducted for ten consecutive daysbythedoctors.Themaximumdoseofthemedication was6.54mL inexcisions and 15.85mL in reconstructions. The incidenceof adverse reactions related tolocal anes-thesia was 0.15% --- reactions were moderate in 0.13% of thecases(dizziness,drowsinessandtachycardiacausedby epinephrine).20

Aseriesof 20,021 patients wasassessed by Barrington andKlugerinamulticenterstudyconductedinAustraliaand NewZealandbetweenJanuary2007andMay2012.Patients weresubjectedto25,336blocksofperipheralnerveswith andwithoutultrasonography.Patientsyoungerthan13years old were excluded from the experiment. There were 22 episodes of systemic toxicity, which resulted in the inci-dence 0.87 per 1000 blocks.Only one patient evolvedto heart failure after the intravenous injection of the anes-theticduringaparavertebralblockprocedure.Theinjection site, the used anesthetic type, the dose per weight and patientbodymasswerethepredictorfactorsforthe inci-denceofcomplications.21

Sitesetal. didnot identifyanyheart failurecase in a prospectivestudywith12,668patientssubjectedto periph-eralregionalanesthesiafromJuly2003toFebruary2011in ahospitalintheUnitedStates.Onlyonesystemictoxicity casewasrecorded(incidence0.08per1000).22

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The treatment of systemic toxicity consists in stop-ping anesthetic administration and requesting immediate medicalassistance.Then,basic andadvancedlifesupport proceduresmustbeinitiated:preservationofairwaysandof thecardiovascularsystem.Thespeciﬁctreatmentinheart failurecasescountson20%lipidemulsiontherapy.5,6

Hypersensitivityreactions

Type1hypersensitivityreactions(IgE-mediated reactionsandanaphylaxis)

TheprevalenceoftrueIgE-mediatedallergytolocal anes-thetics is estimated tobe lower than 1%.6 _The _literature

reviewbyBholeandcollaboratorspublishedin2012assessed 23seriesofcasesthatincluded2978patientsbetween1950 and2011.Only23ofthesepatients presentedtruetype1 hypersensitivityreactiontotopicalanesthetics.23

Localreactionsaremorecommonandincludeurticaria andangioedemawithoutrespiratorycompromise.The treat-ment consists in administering antihistaminesand closely observingpatients.24

Immediate systemic hypersensitivity reaction (anaphy-laxis) symptoms are observed in the ﬁrst 30min after the exposuretothe anesthetic. Thesesymptoms must be identiﬁed immediately by the doctors. Overall, two or more systemsare involved or thereare evidences of res-piratory or cardiovascular compromise.Symptoms include dyspnea, cough, wheezing, hypotension and tachycardia. The treatmentmust startwiththeimmediateintravenous administrationofvasoconstrictors(epinephrine).24

Incaseofallergicreaction,onecanuseester-type anes-theticsdue tothelow crossedreactionbetweenthem,as well as anesthetics belonging to the amide group. Other options would be the administration of diphenhydramine orbacteriostaticsalinesolution(0.9%benzylalcoholsaline solution)inbiopsiesorsmallskinexcisions.1

TypeIVhypersensitivityreactions

Thelatehypersensitivityreactionincludesallergiccontact dermatitis.AccordingtotheretrospectivestudybyToetal., who assessed 1819 patients subjected to patch test in Canada,itsincidencereaches2.4%.Benzocaineisthemost commonallergen(45%),whichisfollowedbylidocaine(32%) and dibucaine (23%).25 _It _is _estimated _that _its _incidence

reaches3.4%intheUnitedStates.26

Theclinicalframe24and48haftertheexposuretothe agentisfeaturedbyerythema,edema,peeling,inﬁltration, blisteringandskincrusting.Thesymptomsincludeburning anditching.27

Patients who present patch test positive for lidocaine mustbesubjectedtointradermalinjectionof0.1%lidocaine toconﬁrmallergiccontactdermatitisduetothesubstance. Otherlocalanestheticsmustbealsotested.25

Vasovagalreaction

Thisreactionresultsfromanxietyandfrompatients’sense of painandfearof theneedleor of theprocedure itself. Itstimulatestheparasympatheticsystemanditssymptoms canbesimilartoallergicreaction:dizziness,sweating, nau-sea,bradycardiaandhypotension.Inextreme cases,there can be syncope. The treatment consists in calming the

patient down, putting him/her in Trendelenburg position andinapplyingcoldcompressesontheforehead.24

Topicalanesthetics

Localreactionstotopicalanestheticsincludeerythema, pal-lor and edema. Anesthetic creams should not be directly appliedtotheeyes,oralmucosaandinternalauditorycanal duetotheriskoftriggering localirritation. Inaddition,it isimperativebeingcarefulabouttheamountofmedication usedatthetimetoapplyittothegenitalmucosa.8

Systemicreaction,suchasmethemoglobinemia,central nervous system dysfunctions and cardiotoxicity, although rare,canhappen.

Methemoglobinemiaisaparticularconcernforthe pedi-atricpopulation, because ofthe immature metabolism of methemoglobininchildrenunder3month-old.6_This

condi-tioncan be triggered by EMLA® _use, _since _prilocaine _has

thepotentialtopreventoxygentransportbyhemoglobina.8

Methemoglobinlevels from15% to30% result in cyanosis. Levelsfrom30%and50%resultindyspnea,tachycardiaand headache.Levelshigherthan50%causelethargyandcoma.8

The literature review by Tran and Koo (2014) includes 12studiesaboutthesafetyofthetopicalanestheticEMLA. Twelve(12)LASTcaseswereidentiﬁedand9ofthemwere observedinchildren.28

The 7%lidocaine 7%tetracaine-based cream cancause moderateandtransienterythemaandpalloratthe applica-tionsite.8

It is important observing that some techniques can increasethedermalabsorptionoftopicalanestheticsbythe corneallayeroftheskin,suchastheablativelaser.29

Prod-uctapplication oninﬂamed surfaces, or onlargeareas of bodysurface,canalsoincreasethe riskofabsorptionand toxicity.8

Themedicationmustbeimmediatelywashedofftheskin surfaceifanysignoftoxicityisidentiﬁed.Thepatientmust beput in supine position and his/hervital signs must be assessed.The speciﬁc treatment must start based onthe signsandsymptoms.8

Application

techniques

Thecorrectanestheticapplicationtechniqueassures proce-duresafetyandcomfort.Thedoctormustwearglovesand make proper skin antisepsis. The site tobe treated must bemarkedpriortotheadministrationoftheanestheticin ordertoavoidlocaldistortionduetothevolumeofinjected medication.5

Thin and smallneedles must be used whenever possi-ble,becausetheyenablelessdiscomfort.Slowinfusion,skin vibration,use ofwarm solution,skin coolingand minimal injectionsintheskinalsohelpachievingcomfortsensation. Insomecases,topicalanestheticsarerecommendedtobe appliedtotheskinpriortotheinjectableanesthetic,mainly inchildren.1,5

Topical anestheticmust beappliedtointactskin, i.e., onskinfreefromerosionoreczema.Itisimportantavoiding thecontactbetweenthemedicationandtheocularmucosa, aswell as the use of anesthetics belonging tothe amide

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groupinpatients withkidneyissues,and theuseof EMLA anestheticsinnewborns.8

Safety

of

anesthetics

According to the American guidelines published in 2016, localanestheticsaresafemedicationstobeusedinin-ofﬁce dermatologicalprocedures.Systemictoxicityepisodesand episodes of anaphylactic reaction to local anesthetic are rareandmanyauthorsrecommendthemforsurgical proce-duresconductedoutsidethehospitalenvironment.1,2,30---32

TheprospectivestudybyStarlingetal.(2012)collected dataaboutcomplicationsinoutpatientproceduresinFlorida Statefrom2000to2010,andinAlabamaStatefrom2003to 2009,bothintheUnitedStates.InFlorida,theyreported46 deaths and 263 complications during surgical procedures: 45% of these complications happened during procedures conducted by plastic surgeons. Only four complications happenedduringproceduresconductedbydermatologists, without deaths (1.3% of the cases): oneepisode of vaso-vagal reaction after liposuction in patient subjected to generalanesthesia;onecaseofshort-durationatrial ﬁbril-lationinpatient subjectedtoskin excision; oneincorrect surgicalexcisioninMohssurgery;andoneepisodeofsecond degreeburninbedriddenpatientusinghomeoxygen,who wassedatedforthedermatologicalprocedure.InAlabama State,theyreported3deathsand49complicationsduring outpatientprocedures.Plasticsurgerywasthemedical spe-cialtyrecordingthehighestindexofcomplications(42.3%of thecases).Onlyonecomplicationhappenedduring proce-duresconductedbydermatologist,anditdidnotevolveto death;thisnumbercorrespondstoonly1.3%ofthecases: onlyonepatientpresentedinfectioncausedby methicillin-resistantStaphylococcusaureusafteramelanomaexcision. Therewasnocomplicationaftercosmeticproceduresbased onlocalanesthesiaperformedbydermatologists.2

The researchby Hanke,BernsteinandBullockincluded 15,336 patients subjected to liposuction with tumescent anesthesia conducted by dermatological surgeons; their studyshowedcomplicationsinonly0.38%ofthecases.Two patientshadcardiacarrhythmiaandtwopresented persis-tenttachycardia.Nodeathwasreported.33_Klein_and_Jeske

also showed safe lidocaine serum levels when they used high doses of tumescent anesthesia in patients subjected toliposuction.34

TheprospectivecohortstudybyAlametal.recorded sim-ilarresultsfor19patientssubjectedtomicrographic Mohs surgery.Theseauthorsmeasuredsixlidocaineserumlevels administeredinthreedifferenttimesduringasurgical pro-cedure.Therewasnolidocaineserumlevelincreaseattoxic doses,evenduringproceduresthathaveusedhigherdoses oftheanesthetic:thehighestlidocaineserumlevelfound bythemwas0.3␮g/mL.35

In2012,Walshandcollaboratorspublishedastudy show-ing that dermatologists’ knowledge about the doses and toxicity of local anesthetics is satisfactory. However, the treatmentappliedtosystemictoxicitywithlipidemulsion wasproperlyinformedby21.7% oftheparticipants inthe study,andthisindexwasconsideredlowbytheauthors.36

The retrospective study by Kvisselgaard and collabora-torsruledouthypersensitivityreactioninall164patientsin

theirstudy,whowerepreviouslyreferredtoanAllergology andImmunologyclinicwiththesuspicionoftype1reaction tolocalanestheticsbetween2010and2014.Theseauthors believe that this event was rare due to the use of these medications.37

Although adverse reactions toanesthetics arenot fre-quent, doctors must be careful during their use. The selectionoftheadequatemedication,theidentiﬁcationof risk signs and the handing of complications are essential knowledgefordermatologists.6

Special

situations

Pregnancyandlactation

Lidocaine is classiﬁed in Category B in pregnancy and epinephrineinCategoryC.1,16_Doctors_must_be_careful_in_the

useofanestheticsinthiscategoryofpatientsduetotheir increasedlocalsensitivityandtotheirsystemicabsorption of these medicationsin this phase.It is recommendedto avoidintravenousinjectionbecauseoftheriskformaternal andfetalcardiotoxicity.38

Pediatricandelderlypopulations

The applicationoflocalanestheticsinthepediatric popu-lationdemandscaution.Itisimportantdifferentiatingsigns offearfromeffectsonthecentralnervoussystem.6

Muco-cutaneousabsorptioninnewbornsishigherandfasterthan inadults;besides,thelinkbetweenanestheticsandplasma proteinsisfragileinthepediatricpopulation,whichresults inhighintoxication.39

Local anesthetic clearance in elderly is lower due to organicdysfunctionandcompromisedcirculation.Moreover, neuralchangesmakethesepatientsmoresensitivetothese medications.In many cases,lower dosesare necessary in ordertoaccomplishthesameanalgesia.6,40

Comorbidities

Kidney dysfunction can affect the systemic circulation of localanesthetics.Kidneyissuesanduremiacanincreasethe local absorption of these medications and reduce ropiva-caineandbupivacaineclearance.6,38

Alteredbloodcirculationreducesthemetabolismof sub-stances in the liver and kidneys,thus leadingto reduced clearance of anesthetics. Heart failures reduce the local absorptionofthesemedicationsduetolowtissueperfusion. However,increasedanestheticconcentrationscanoccurin thecentralnervoussystem.Epinephrinemustbeusedwith cautionandavoidedinsomecases.6,38

Final

considerations

Local anesthetics can be considered safe medicationsfor usebydermatologists.Althoughsomeadversereactionsare consideredsevere,suchassystemictoxicityand anaphylac-ticreaction,theiroccurrenceis rare.Proper management of these medications, adequate application technique and knowledge about adverse events, and their speciﬁc

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treatment, reduce risks associated with local anesthetics andmaketheirin-ofﬁceapplicationviable.

On September18,2017,newrules foroperationin pri-vate medical ofﬁces, outpatient and hospitals came into forcein Brazil.TheywerepublishedbytheFederal Coun-cilofMedicine(ConselhoFederaldeMedicina---CFM)after somechangesinResolutionCFMn◦2.056/2013.

Offices or services that perform invasive medical pro-ceduresinvolving therisk foranaphylaxis,and respiratory and cardiovascular failure --- including places where only localanestheticswithoutsedationareused---werekeptin Group3DermatologyOffices.Inthiscase,besidesthebasic structureforpropaedeutic,theseofficesandservicesmust have inputandequipmentfor thetherapeuticsand treat-mentofanaphylacticreactions,andforimmediatereliefof complicationscausedbytherapeuticintervention.

Accordingtoevidencesshowninthepresentstudyabout the safety proﬁle of local anesthetics for dermatological procedures, the authors suggest a review about the cur-rent demands of the resolution in force. Dermatological proceduressuchastheexcisionofsmallcutaneouslesions, which demandsafe dosesof local anesthetics (<6.4mLof lidocaine)20_and_are_conducted_by_clinical_{dermatologists}_on

adailybasis,couldbereallocatedforlevel2procedures.

Financial

support

Nonedeclared.

Author’s

contribution

Ana CarolinaFigueiredoPereira Cherobin:Conceptionand planning of the study; elaboration and writing of the manuscript;collection,analysis,andinterpretationofdata; critical review of the literature; critical review of the manuscript.

GlayssonTassaraTavares:Approvaloftheﬁnalversionof themanuscript;conceptionandplanningofthestudy; effec-tiveparticipationinresearchorientation;criticalreviewof themanuscript.

Conﬂicts

of

interest

Nonedeclared.

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