enzyme inhibitor: case report Postoperative angioedema induced byangiotensin-converting DEANESTESIOLOGIA REVISTABRASILEIRA

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REVISTA

BRASILEIRA DE

ANESTESIOLOGIA

^Publicação^Oﬁcial^da^Sociedade^Brasileira^deAnestesiologia www.sba.com.br

CLINICAL INFORMATION

Postoperative angioedema induced by

angiotensin-converting enzyme inhibitor: case report

Flora Margarida Barra Bisinotto

^a^,∗

, Beatrice Cavalcanti Seabra

^a

,

Fernando B. Prata Lóes

^a

, Laura Bisinotto Martins

^a

, Luciano Alves Matias da Silveira

^b

aUniversidadeFederaldoTriânguloMineiro(UFTM),HospitaldeClínicas,Uberaba,MG,Brazil

bUniversidadeFederaldoTriânguloMineiro(UFTM),HospitaldeClínicas,DisciplinadeAnestesiologiadoCET/SBA,Uberaba,MG, Brazil

Received8December2018;accepted14January2019 Availableonline20October2019

KEYWORDS Angioedema;

Bradykinin;

Enalaprilmaleate;

Angiotensin- convertingenzyme;

Angiotensin- convertingenzyme inhibitors

Abstract

Backgroundandobjectives: Angioedemaisapotentiallyfatalconditionthatmayoccuratany timeintheperioperativeperiod.Itmayresultfromhistaminerelease,hypersensitivityreaction to drugs, orbetriggered by bradykinin, innon-allergicreactions of hereditaryor acquired etiology.Theaimofthisreportistoreportacaseofangioedemaintheearlypostoperative period inapatientonantihypertensivemedicationinvolvingangiotensin-convertingenzyme inhibitors.

Casereport: A67-year-oldmale,Afro-descendant,hypertensive,andtakenenalaprilmaleate underwentorthopedicshouldersurgeryundergeneralanesthesiacombinedwithbrachialplexus block.Theprocedurelasted3hoursuneventfully.Afterdischargefromthepost-anesthesiacare unit,thepatientpresentedwithangioedemaandsevereairwayimpairment.Trachealintubation wasattemptedbutitwasimpossibleduetoedemaaffectingthelips,tongue,andoropharyngeal regionEmergencycricothyroidotomywasperformed.Theonsetofangioedemahadnocausal relationshipwiththeadministrationofanymedication;therewerenocutaneousmanifestations andalsonotresponsetotherapyforhypersensitivityreactiontodrugs,suchasantihistamines, corticoid,andadrenaline.Itwasconsideredtobemediatedbybradykinin,asthepatienthad alreadyhadtwosimilarepisodesandwasonregularmedication(enalapril).Theevolutionwas satisfactory.

Conclusion: Angioedemaisapotentiallyfatalconditionwhenitaffectstheairway,andshould berecognizedbyanesthesiologistsandphysiciansworkingintheemergencydepartments.

∗Correspondingauthor.

E-mail:ﬂorabisinotto@gmail.com(F.M.Bisinotto).

https://doi.org/10.1016/j.bjane.2019.09.002

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Angioedema;

Bradicinina;

Maleatodeenalapril;

Enzimaconversorada angiotensina;

Inibidorasdaenzima conversorada angiotensina

angiotensina:relatodecaso

Resumo

Justificativaeobjetivos: Oangioedemaéumacondiçãopotencialmente fatalquepodesur- gir em qualquermomento noperioperatório. Podedecorrer daliberação dehistamina, em umareaçãodehipersensibilidadeadrogasouserdesencadeadopelabradicinina,emreações nãoalérgicas,deetiologiahereditária ouadquirida.Oobjetivodesserelatoédescrever um casodeangioedema,nopós-operatórioimediato,emumpacienteemusodemedicaçãoanti- hipertensivadaclassedosinibidoresdaenzimaconversoradaangiotensina.

Relatodecaso:Pacientede67 anos,masculino, negro,hipertensoe emusodomaleato de enalapril,foisubmetidoacirurgia ortopédicadeombrosobanestesiageralassociadaablo- queiodoplexobraquial.Oprocedimentodurou3horas,semintercorrências.Apósaaltada saladerecuperaçãopós-anestésica,apresentouangioedemacomgravecomprometimentodas viasaéreas.Tentou-sefazerintubaçãotraqueal,masfoiimpossiveldevidoaoedemaqueaco- metiaoslábios,alínguaeregiãoorofaringeana.Fez-seacricotireoidostomiadeemergência.O aparecimentodoangioedemanãoapresentourelaçãocausalcomaadministraçãodequalquer medicação,nãohouvemanifestaçõescutâneasetambémnãorespondeuàterapêuticapara reaçãodehipersensibilidadeadrogas,comoanti-histamínicos,corticoideeadrenalina.Foicon- sideradocomomediadopelabradicinina,poisopacientejáhaviaapresentadodoisepisódios semelhanteseestavaemusoregulardemedicação(enalapril).Aevoluçãofoisatisfatória.

Conclusão:Oangioedemaéumacondic¸ãopotencialmentefatalquandoatingeasviasaéreas edeveserdeconhecimentodoanestesiologistaedosmédicosquetrabalhamnossetoresde emergência.

Introduction

Angioedemaischaracterizedbyabruptepisodesofedema affectingthedeepdermallayeroftheskinandsubcutaneous tissue.Itmayinvolvethelips,face,neck,andextremities.

Itcanalsooccurinthesubmucosaltissueofvariousorgans, particularlysmallintestine.^1,2 Laryngeal involvementmay befatal,while intestinalangioedemamaybeverypainful andmimicanacuteabdomen.Edemaisnotdepressibleand thereisnoerythema,itprefersareaswheretheskinislooser (especiallythefaceandgenitalia)andrarelyitches.Subcu- taneousorsubmucosalcapillariesandpostcapillaryvenules arebelievedtodevelopincreasedpermeabilityasaresult ofthepresenceofvasoactivemediators,suchashistamine, bradykinin,prostaglandins,andproteases.² This increased permeabilityisrapidandcauseslocalplasmaleakageresul- tinginedema.Bradykinin-mediatedangioedemamayoccur inpatients withhereditaryangioedema(HAE)or acquired angioedema(AAE),asinpatientsonangiotensin-converting enzymeinhibitors(ACEinhibitors).^1---6

Angioedemaisofparticularimportancetoanesthesiolo- gistsbecauseitcanappearatanytimeintheperioperative period and quickly become life threatening, as it may involveandcompromisethe upperairwaymucosaleading toasphyxia.¹

Theaimofthepresent studyis toreportthecase ofa patientwhopresentedwithairwayangioedemaduetothe useofACEinhibitors,whichresultedinseriousconsequen- ces.

Consenttopublication:Thepatientgavewritteninfor- medconsentforthiscasepublication.

Case report

A67-year-oldmalepatient,80kg,blackethnicity,schedu- ledforemergencysurgeryontherightshoulder.Hehada historyofcomorbidhypertensionundertreatmentwithena- laprilmaleate(20mg/twicedaily),smoking,andalcoholism;

denied allergyand previous surgical procedure. On physicalexamination,hewasclinicallystable----airwayswithout predictive tests for difﬁcult intubation. Laboratory tests showedanemiawithhemoglobinequalto7.9g.dL⁻¹.Blood transfusion was performed with two units of packed red blood cells, under the medicalclinic discipline guidance.

The electrocardiogram showed nosigniﬁcant changes and chest X-ray wasnormal. His physical status wasclassiﬁed as ASA 2, according to the American Society of Anesthe- siologists (ASA). The patient was treated with enalapril maleate(20mg)atstandardtime;therewasa4hinterval

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Figure1 Pictureofthepatient18hoursafteremergencycricothyrotomy,presentingwithmacroglossiaandlipedema.

beforesurgery. He receivedno pre-anestheticmedication andwasadmittedtothe operatingroom withblood pressure(BP)equalto152/72mmHgandheartrate(HR)equal to77beatsperminute(bpm).Thepatientwasalsomoni- tored by means of a cardioscope, pulse oximetry, and capnography.General anesthesiawith trachealintubation was performed, combined with ultrasound-guided supra- clavicular brachial plexus block. General anesthesia was induced withmidazolam (5mg), fentanyl (200mcg), lido- caine(60mg),propofol(120mg),androcuronium(40mg).

Brachial plexus block wasperformed with 0.375% ropiva- caine(150mg),andcefazolin(2g)wasgivenpriortosurgical incision.Anesthesiawasmaintainedwithsevoﬂuranevia a calibratedvaporizer,withinspiredfractionsrangingfrom2%

to2.5%.Thedurationoftheanesthetic-surgicalprocedure was210minutes.Atthebeginningofanesthesia,hehadepi- sodesofhypotensiontreatedwithlowdosesofmetaraminol.

And20minutesbeforetheendtheprocedure,therewasan increase in blood pressure, which wasnot related to the change ininhalation anestheticconcentrationorpresence ofanyotherstimulusoutsidethesurgicalﬁeld.Bloodpres- sure reached 180/120mmHg.Duringthis period,dipyrone (2g), ondansetrone (8mg), and hydrocortisone (500mg) were administered. After surgery, he received atropine (1mg) and neostigmine (2mg). Hypertension was treated withslowadministrationofintravenousclonidine(75gdilu- ted in 100mL 0.9% saline). Still on this medication, the patientwastakentothePost-AnesthesiaCareUnit(PACU).

Bloodpressure(BP)remainedaround160×100mmHgand heartrate(HR)at60bpmduringthe2-h PACUstay,where hereceivedonlyoxygenviafacemask.WithanAldreteand KroulikScalescoreof9andnocomplaints,thepatientwas dischargedtotheward.About30minutesafteradmission, thenurserequestedthepresenceofthedoctorondutyin the ward because the patient presented with lip edema, macroglossia, difﬁculty breathing, and presence of laryn- gealstridoranddifﬁcultyarticulatingwords.Nomedication hadbeen givenafterthepatientarrivedatthe ward,but the on-duty doctor began treatment for anaphylaxis with oxygenvianasalcatheter,intravenoushydrocortisone,and intramuscularpromethazine.Physicalexamination showed

diffusepulmonary snoring, BP170/100mmHg,HR88bpm, andperipheraloxygensaturation (SpO2) equalto98%.His condition evolved withworsening of snoring and absence ofspeech,but maintainedthehemodynamic stabilityand normal SpO2. He received a sequence of medications thatincludedintravenousdiphenhydramine,ranitidine,and adrenalinewithoutanyimprovementwitheitherdrug.The on-dutydoctorthenoptedfortrachealintubationafterfen- tanyl (100␮g) and etomidate (20mg) administration. But duetoairwayedema,hewasunabletointubateandopted for an emergency bedside cricothyrotomy with insertion of a cannula number 7.0. Without further complications, the patient was taken to the Intensive Care Unit (ICU) andmaintainedonmechanicalcontrolledventilationunder sedation.The anesthesiologistswereinformedof the epi- sode only on the following day, when the patient was taken to the deﬁnitive surgical tracheostomy. The pati- entstillhadsigniﬁcant tongueand lipedema (Fig.1).He remainedhospitalizedforanothersevendaysandwasdis- charged.Incontactwiththepatient’srelatives,hisdaughter reportedthat hehad had a similarcondition twice after starting treatment for hypertension and had been admit- ted to a hospital until the problem was resolved. Since thepatient (father) wasaddicted toalcohol, she didnot knowmoredetails.Uponreturntotheorthopedicsoutpa- tient clinic, the patient wasreferred tothe cardiologist, with a recommendation to change the antihypertensive medicationtoanotherclassof medicationother thanACE inhibitors.

Discussion

The present case illustrates the emergence ofan angioe- demaafter dischargefromPACU, whichresulted ina risk of hypoxia due to severe airway involvement. An emergency surgical approach was required to ensure patient oxygenation,whichresultedinincreasedmorbiditywithICU admission and need for new procedures, such as central venouspunctureandsurgical tracheostomy,in additionto prolongedhospitalstay.

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hadundergonegeneralanesthesiacombinedwithbrachial plexus block, and thus received several medications, the first hypothesis to be considered was that it would be a drughypersensitivityreaction(DHR).However,inthiscase itwasdifficult todetectthepossibledrugsresponsiblefor thereaction,since atthe timeof angioedemamanifesta- tionnodrugwasadministeredandthelastonereceivedby thepatientwasabout3hoursearlier.Thus,elucidatingthe causeofthereactionbecamedifficult.Causaldiagnosis is necessaryforthepatienttobeinformed,notbecomevul- nerableandriskhislifeinanothersituation.Forsuch,some knowledgeisimportant.

Acuteepisodesof angioedemaaremostly mediatedby histamine or bradykinin.^1,4,6 Histaminergics are of allergic origin and usually occur in DHR, called immediate reactions.^6---8 These reactions usually occur within 1hour of taking a triggering drugand involve mast cells and/or basophils. Usually, clinical manifestations are isolated urticaria, angioedema, rhinitis, conjunctivitis, bronchos- pasm,intestinalsymptoms(nausea,vomitinganddiarrhea) or anaphylaxis, with or without cardiovascular collapse (anaphylacticshock).Inretrospectivereviewsofintraope- rative DHR, the most commonly identiﬁed causal agents were antibiotics, neuromuscular blockers, opioids, and latex.⁹ However, in 53% of anaphylaxis cases in a sin- gle large institution, no causative agent was found in the postoperative allergy skin test. Most patients present with onset of symptoms within minutes of antigen exposure, and these symptoms usually subside after taking drugs, such asantihistamines, corticosteroids, and adrenaline.^2,7,8

A secondary response, or late phase, may occur after 1hourof allergenexposureand resultsfromthesynthesis ofleukotrienes,prostaglandins,andplateletactivatingfac- tor.Theselatereactions areassociatedwithvariableskin symptomsandtheirmechanismisheterogeneous,although theyarepredominantlymediatedbyTcells.^7,8Nonsteroidal anti-inﬂammatorydrugs (NSAIDs) are the most commonly relatedtotheselatemanifestations.⁷ Ourpatientdidnot receive NSAIDs and also had no history of allergic reac- tionto these drugs. No drugs were given for a period of 3hours.Thus,theDHRdiagnosis,bothimmediateandlate, wasruledout,duetotheabsenceoftemporalrelationshipof angioedemaonsetanddrugadministrationduringanesthe- sia. Alsodue tothe absenceof skin allergic reactionand lackof responsetotheinstitutedtherapy (corticosteroids andantihistamines),theconditionpersistedformorethan 24hours.

Thus, the patient did not have a histaminergic angioedema, but a bradykinin-mediated angioedema, which is characterized by absence of pruritus and rash and has a gradual onset. High plasma bradykinin levels may be the result of marked production caused by the activation of kinin-kallikrein system or inhibition of its degradation,^2,6 either inherited (HAE) or acquired (AAE). In HAE there is a suggestive clinical history. In the present case, the

and had had two previous episodes after starting treatment for hypertension. Non-steroidal anti-inﬂammatory drugs, especially aspirin,⁷ may also be implicated in the genesis of bradykinin-mediated AAE, but the patient received only dipyrone and brachial plexus block for analgesia.

Manyevents triggered bykininsare relatedtothe use of drugs acting through the angiotensin system, such as ACE inhibitors.^1,3,6 Kinins (bradykinin, calidin, and Met- Lys-bradykinin) are oligopeptides synthesized in plasma and/or interstitial ﬂuidfrom the activation of kininogens by the action of kallikreins. They areinvolved in a number of biological events, includingvasodilation, increased vascular permeability, pain modulation, smooth muscle contraction/relaxation, and effects on cell proliferation.

Bradykinin,apotentvasodilator,isproducedfromthecle- avage of high molecular weight kininogen by the enzyme kallikrein.Angiotensinconvertingenzyme(ACE),alsoknown as kinase II, converts angiotensin I to angiotensin II and inactivatesbradykinin.AngiotensinII hasseveralphysiolo- gical effects contributing to the genesis of hypertension, suchasincreasedvascularresistance,releaseofaldosterone from the adrenal cortex, norepinephrine from sympathe- tic nerve endings, and antidiuretic hormone from the posterior pituitary. ACE inhibitors are commonly used to treat heart failure,hypertension,and otherconditions by reducing angiotensinII concentrations, although theyalso leadtoincreasedbradykininlevels.Ofthethreeenzymes called metalloproteinases,which areprimarily involved in bradykinin degradation, ACE (kinaseII) is the most effec- tive compared to the other two, aminopeptidase P and neutral endopeptidase. Bradykinin is metabolized to N- Arg-bradykinin, the metabolite of active bradykinin, by ACE/kininase II. Approximately half of the patients with ACE-inducedangioedema werefound tohave an enzyma- tic defect in the degradation of this active metabolite, whichinthepresenceofACEinhibitorsmayresultinincre- ased bradykininactivity.¹⁰ The exactmechanism by which ACE inhibitors cause angioedema is not fully understood, but bradykinin has shown to play a role in the pathoge- nesis of this adverse eventdue tostimulation ofvascular receptors called B2. The binding of bradykinin to these receptorsresultsinvasodilationandincreasedvascularper- meability,leadingtoaccumulationof interstitialﬂuidand angioedema.^2,3,6Althoughothervascularmediatorsmayalso beinvolved.

Sincecaptoprilapprovaltotreat highbloodpressurein theearly80s,ACEinhibitors,alongwithangiotensinrecep- torblockers(ARBs),havebeenwidelyprescribedandused in about one third of surgical patients. However, only a smallportionof patientsdevelopangioedema.Arandomi- zedstudy¹¹involving12,557patientstreatedwithenalapril maleateshowedanangioedemaincidenceof0.68%.Makani etal.⁵reporteda0.3%incidenceof ACEinhibitor-induced angioedema in a meta-analysis of 26 randomized studies with74,875patients.Althoughitisan uncommonadverse

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eventofACEinhibitors,whenanalyzingthelargenumberof patientstreatedwithACEinhibitors,itwasfoundthatACE inhibitorsareresponsibleforonethird oftheangioedema casestreated at emergencyservices.^12,13 Patientswithan ACEinhibitor-relatedangioedemawilltypicallyhaveitwith allotherACEinhibitors,becauseangioedemaisanadverse event of these drugs and not a hypersensitivity reaction.

Therefore,anothertypeofantihypertensivedrugshouldbe usedinpatientswithahistoryofACEinhibitor-inducedangi- oedemaduetoitscontraindication.Ourpatientwasadvised aboutthisconduct.Althoughseveralstudieshavereported angioedemainpatientsafterswitchingfromanACEinhibitor toan ARB, thereis noformalcontraindicationtoprescri- bingthesedrugsaftertheinterruptionofanACEinhibitor responsibleforthiscomplication.

ACE inhibitor-inducedangioedemaismore prevalentin African descent patients, secondary to a polymorphism found in the gene encoding aminopeptide P, which plays an essential role in the metabolism of these drugs.⁶ It is alsofound inindividualsover 65yearsof ageandin smo- kers,characteristicsfoundinourpatient.Thetimeinterval betweeninitiationoftreatmentanddevelopmentofangio- edemaisvariable.Somepatientsmaydevelopangioedema within one day, 50% within the first week of treatment, whileinothersitmaytakeeightto10yearstodevelop.^3,6,13 Thereisnothingtosuggestarelationshipwithdosage,type or time of ACE inhibitor administration.⁶ In the clinical case reportedhere, itwasnot possibleto chronologically identify theonset of angioedemaoutbreaks presented by thepatient,inrelationtothebeginningoftreatmentwith enalapril maleate, as the onset was after the beginning of treatment for hypertension. Onestudy¹¹ showed a sig- nificantly higher incidence of angioedema soon after the start of therapy (3.6/1000 patients in the first month of treatment vs. 0.4/1000 patients after 24 weeks of treatment), with an average period of 10.2 months after the start.

When oral cavity and larynx areaffected, edema may progress rapidlytooropharyngeal obstruction withrisk of asphyxiation,aswasthecasereportedhere.Asmentioned inthestudy¹¹involving12,557patientstreatedwithenala- prilmaleate,0.68%hadangioedema,butnonewasaffected severelyenoughtorequiretrachealintubationandnodeaths were reported either. Other studies, however, reported that10%ofpatientswithACEinhibitor-inducedangioedema affectingtheoralcavityrequiredtrachealintubation,with deathreportedinsevenAfro-descendentpatients.

Currently,therearenolaboratorytestsforACEinhibitor- inducedangioedemadiagnosis(incontrasttothelowlevels ofC2,C4,andC1esteraseinhibitorsobservedinHAE).^1,2,4,6 Instead, a clinical diagnosis is made based on previous useofthesedrugsanddisappearanceofangioedemaafter their discontinuation. The triggers for angioedema onset varybetween patients,and alsowithinthesame patient, so that predicting complications is not possible. It may beunprovokedortriggeredbyinnocuousstimulation,such asdevicevibrations, snoringor minortraumafromdental procedures.The frequencyof attacksseemstobeincrea-

sedbystress.¹⁴ Theperioperativescenarioalsorepresents a risk for developing angioedema due to airway manipu- lation and potential trauma, in addition to psychological and physiological stress.¹⁴ In the present case, surgical stressandairwaymanipulationbytrachealintubationmay be considered as possible causes of angioedema onset.

Intuitively,traumashouldbe avoidedduring airwaymani- pulation,although there is noclear relationship between thepresence of traumaand developmentof angioedema.

Therefore,evenifairwaymanipulationisatraumatic,physi- ciansshouldbeawareofthepossibilityofdevelopingairway edema. To date, noroutine anesthetic has been considered contraindicated in patients with bradykinin-mediated angioedema.

Weconclude that,although ACE inhibitor-relatedangi- oedemais a rare event, it is a potentially fatal disorder when airway is involved, so this condition should be knowntoanesthesiologistsandphysiciansinvolvedinemer- gencycare. Anin-depth understandingofthe angioedema pathophysiologyandvariousetiologiesisessentialtoreduce thefrequencyandseverityoftheseevents.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

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