Syncope: Classification and risk stratification

ContentslistsavailableatScienceDirect

Journal

of

Cardiology

j ou rn a l h o m ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / j j c c

Review

Syncope:

Classification

and

risk

stratification

Venkata

Krishna

Puppala

(MD),

Oana

Dickinson

(MD),

David

G.

Benditt

(MD)

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received19March2013 Accepted22March2013 Availableonline7January2014

Keywords:

Syncope Riskstratification

Transientlossofconsciousness Syncopeclinic

a

b

s

t

r

a

c

t

Background:Syncopeisoneofthemostcommonreasonsforemergencydepartmentandurgentcare

clinicvisits.Themanagementofsyncopecontinuestobeachallengingproblemforfront-lineproviders inasmuchasthereareamultitudeofpossiblecausesforsyncoperangingfromrelativelybenignconditions topotentiallylife-threateningones.Inanyevent,itisimportanttoidentifythosesyncopepatientswho areatimmediateriskoflife-threateningevents;theseindividualsrequireprompthospitalizationand thoroughevaluation.Conversely,itisequallyimportanttoavoidunnecessaryhospitalizationoflow-risk patientssinceunneededhospitalcareaddstothehealthcarecostburden.

Results:Historically,front-lineprovidershavetakenaconservativeapproachwithadmissionratesashigh

as30–50%amongsyncopepatients.Anumberofstudiesevaluatingboththeshort-andlong-termrisk ofadverseeventsinpatientswithsyncopehavefocusedondevelopmentofrisk-stratificationguidelines toassistprovidersinmakingaconfidentandwell-informedchoicebetweenhospitalizationand out-patientreferral.Inthisregard,amuchneededconsensusonoptimaldecision-makingprocesshasnot beendevelopedtodate.However,knowledgefromvariousavailablerisk-stratificationstudiescanbe helpful.

Conclusion:Thisreviewsummarizesthefindingsofvariousrisk-stratificationstudiesandpointsout

keydifferencesbetweenthem.While,theexistingrisk-stratificationmethodscannotreplacecritical assessmentbyanexperiencedphysician,theydoprovidevaluableguidance.Inaddition,thevarious risk-assessmentschemeshighlighttheneedforcarefulinitialclinicalassessmentofsyncopepatients, selectivetesting,andbeingmindfuloftheshort-andlong-termrisks.

©2014JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.

Contents

Introduction... 172

Classificationofsyncope... 172

Neurally-mediatedsyncope(alsotermedneuralreflexsyncope)... 172

Orthostatichypotension ... 172

Syncopeduetocardiacarrhythmias... 172

Syncopeduetostructuralcardiacdisease... 173

Syncopesecondarytocerebrovascularcauses... 173

Syncopemimics... 173

Riskstratificationofsyncope... 173

Short-termorimmediaterisk... 174

High-riskmarkersofshort-termadverseoutcomes... 175

Long-termrisk... 175

Riskstratificationbasedoncardiacversusnon-cardiaccausesofsyncope... 175

Issyncopeamarkerofincreasedriskofcardiovascularmorbidityandmortality?... 176

Conclusion... 176

Acknowledgment... 176

References... 177

∗Correspondingauthorat:TheCardiacArrhythmiaCenter,UniversityofMinnesotaMedicalSchool,MMC508,420DelawareStreetSE,Minneapolis,MN55455,USA. Tel.:+16126254401;fax:+16126244937.

E-mailaddress:[email protected](D.G.Benditt).

0914-5087/$–seefrontmatter©2014JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.

Introduction

Syncopeisasyndromecharacterizedbyatransientself-limited episodeoflossofconsciousnessoccurringasaresultofabrief inter-ruptionofoxygensupplytothebrain.Thisinterruptionofcerebral nutrientflowinasyncopaleventisalmostalwaysduetotransient cessationofblood flow[1,2].Atransientreversibledropin sys-temicarterialbloodpressuretoalevelbelowthatneededtosustain cerebralperfusionisthemostcommoncauseofsyncope.Other possibilitiesarerare,and includeacutehypoxemia (e.g.aircraft decompression)ormajormetabolicdisturbanceaffectingneuronal pathways.

Sincetransientglobalcerebralhypoperfusionisthesinequanon ofsyncopepathophysiology,othercausesoflossofconsciousness shouldnotbeclassifiedas‘syncope’.Thusseizures,concussions, hypoglycemia,andothernon-perfusionrelateddisturbancesare separatediagnosticissues;thesearenon-syncopecausesof tran-sientlossofconsciousness(TLOC)[1,3].

Intruesyncope,theepisodeischaracterizedbyarapidonset oflossofconsciousnesswithorwithoutanywarningsymptoms. Evenwhenwarningsymptomsarepresentbeforesyncope,lossof consciousnessusuallyoccurswithin10–20softheironset. Recov-eryistypicallypromptandcompletewithoutanyneedformedical interventionandwithoutanynewresidualneurologicfindings. Classificationofsyncope

Theclassificationofsyncopeismainlybasedontheunderlying mechanismsthatleadtothefinaleventoftransientglobal hypo-perfusion.Thediagnosticclassificationofthecausesofsyncope modifiedfromtheEuropeanSocietyofCardiology(ESC)syncope practiceguidelines[1]issummarizedinTable1.

Neurally-mediatedsyncope(alsotermedneuralreflexsyncope)

Thistypeofsyncopeincludesanumberofconditions.Themost importantandalsothemostcommonwithinthiscategoryis vaso-vagalsyncope.Thesecondmostcommoniscarotidsinussyncope (CSS)whichmostlyoccursintheelderlyandprimarilyinmen[3–6]. Carotidsinushypersensitivity(CSH)isaclinicalfindingelicitedby massagingthecarotidsinus.CSHshouldbedistinguishedfromCSS astheformerisaclinicalfindingandthelatterisaclinical mani-festation.CSSisonlydiagnosedifcarotidmassagecausessufficient bradycardia(usually>6s)and/orhypotensiontocause reproduc-tionofthepatients’symptoms.

Situationalsyncopeisathirdcategoryofreflexfaint;itincludes syncopetriggeredbyanyofanumberofactivitiessuchas: mic-turition,defecation,coughing,orswallowing.Theinitialevent(e.g. micturition)triggers [1,3]eithera slowheart rateordepressed vasculartone(orboth)that resultsinsufficient hypotensionto causetransientcerebralhypoperfusionandultimatetransient self-limitedepisodeoflossofconsciousness.Insomecases(e.g.cough syncope,trumpet-blowerssyncope),transientvenousobstruction duetoincreasedintra-thoracicpressuremaycontributetocerebral hypoperfusion.

Orthostatichypotension

Orthostaticsyncopeoccursasresultofthebody’sinabilityto maintainbloodpressureadequateforcerebralperfusionwhenthe individualmovestotheuprightposture,andwhichinturnresults inTLOC[1,7,8].Thechangeinposturefromlyingdowntoanupright positionresultsinshiftofasmuchas500–1000mLofbloodaway fromthechesttovenouscapacitancesystembelowthediaphragm; thisshiftinturnresultsindiminishedvenousreturntoheartand

Table1

ThediagnosticclassificationofthecausesofsyncopemodifiedfromtheEuropean SocietyofCardiologysyncopepracticeguidelines.

Reflex(neurally-mediated)syncope

Vasovagal:

-triggeredbyemotionaldistress -triggeredbyorthostaticstress Situational:

-cough,sneeze

-gastrointestinalstimulation -micturition

-others

Carotidsinussyncope

Orthostatichypotensionsyncope

Volumedepletion:

-inadequatefluidintake(hotweather),diarrhea,vomiting,etc. Drug-inducedorthostatichypotension:

-alcohol,vasodilators,diuretics,beta-adrenergicblockers Primaryautonomicfailure:

-pureautonomicfailure,multiplesystematrophy,Parkinson’sdiseasewith autonomicfailure,Lewybodydementia

Secondaryautonomicfailure:

-diabetes,amyloidosis,spinalcordinjuries

Cardiacsyncope(cardiovascular)

Arrhythmiaasprimarycause: Bradycardia:

-sinusnodedysfunction,atrioventricularconductionsystemdisease -implanteddevicemalfunction

Tachycardia:

-supraventricularincludingatrialfibrillation

-ventricular(idiopathicsecondarytostructuralheartdisease,ordueto channelopathies)

Structuraldisease:

-Cardiac:cardiacvalvulardisease,acutemyocardialinfarction/ischemia, hypertrophiccardiomyopathy,cardiacmasses(atrialmyxoma,tumors,etc.), pericardialdisease/tamponade,congenitalanomaliesofcoronaryarteries, prostheticvalvesdysfunction

-Othercardiovascular:pulmonaryembolus/hypertension,acuteaortic dissection

consequentreductionofcardiacfillingpressureandstrokevolume leadingtohypotensionandcerebralhypoperfusion.

Thehumanbodyhasphysiologicaldefensesagainstorthostatic hypotensive episodes. These include a reflex increase in heart rate,reflexarterialandvenousvasoconstriction(especiallyinthe splanchnicbedandlowerextremities),andneuroendocrine adjust-ments(activationofrenin–angiotensin–aldosterone system)[7]. Allofthesedefensespreventhealthyindividualsfromhavinga syn-copalevent.However,incertainsituationsthesedefensescouldbe undermined.Forexample,superimposedvolumedepletionorloss ofimpairedcardiacresponseduetochronotropicincompetence,or impairedreflexvasoconstrictionduetoautonomicdysfunctionor medications(e.g.beta-blockers,etc.),orlossofskeletalmuscletone whichiscommonintheelderly,maycausereducedvenousreturn. Theindividualasaresultofsyncopewillslumptogravitationally neutral positionwhich usually resultsin promptresumptionof cerebralperfusion.Physicalcounterpressuremaneuverssuchas leg-crossingandmusclestraininghavebeenfoundtobehelpful inincreasingvenousreturnbyenhancingmusclepumpactivity [1].

Syncopeduetocardiacarrhythmias

Cerebralhypoperfusionresultinginsyncopecanoccurdueto eitherbrady-ortachy-arrhythmias.Bradycardiaisthemore com-mon;in thiscategory,symptomatic hypotensioncanoccurasa resultofsinuspauses,high-gradeatrioventricularblockorasystole thatoccursattheterminationofanatrialarrhythmia(particularly attheendofanepisodeofatrialfibrillation).Cardiacpacemaker placementishelpfulinpreventingthesebradycardiacepisodes.

Bothsupraventricularandventriculartachyarrhythmiasmaybe responsiblefortriggeringsyncope.Neurally-mediatedhypotension mayalsocontributeinthesepatients.Patientswithautonomic dys-functionareatgreatestriskforarrhythmia-relatedsyncopesince protectivereflexesthataresupposedtobeineffecttocounterthe tachycardicstressareabsentoraretoosluggish.

The occurrence of syncope due to ventricular tachyarrhyth-mias in patients with poor left ventricular function or due to channelopathy(i.e.longQTsyndrome,catecholaminergic parox-ysmal ventriculartachycardia, Brugadasyndrome) is predictive of increasedrisk of mortality due tosudden cardiac death[9]. Therefore, these patientswhen identified need to bepromptly referredtocardiacelectrophysiologyforfurtherevaluation;most willwarrantplacementofanimplantablecardioverter defibrilla-tor(ICD)andsomemaybecandidatesformappingandablation therapy.

Syncopeduetostructuralcardiacdisease

Althoughinfrequent, syncope can occurasa resultof acute myocardialinfarctionorpulmonaryembolism.Reducedstroke vol-umeistheunderlyingmechanismforcerebralhypoperfusionin thesecases,althoughneural-reflexfactorsmaycontribute, espe-ciallyinthecaseofacutemyocardialischemia.Valvular/structural heartdisease(e.g.severeaorticstenosis, severemitralstenosis, and large left atrial myxoma) can cause syncope. The cerebral hypoperfusion inthesesituations is oftena resultof thedirect hemodynamicimpactofananatomicalanomalyaswellas neurally-mediatedreflexesorlackofthem.Inpatientswithsevereaortic stenosis,inappropriatevasodilatationwithexertionisanaccepted basisforsymptomatichypotensionresultinginsyncope[10].

Syncopesecondarytocerebrovascularcauses

Thebrainiswellprotectedwithmultiplebloodvessels feed-ingtheCircleofWillisandthereforetruesyncopealmostnever occursasadirectresultofcerebrovasculardiseasealone.However, althoughrare,atransientischemicattackinthevertebrobasilar dis-tributionmaycausesyncope.Thepresenceofposteriorcirculation symptomssuchaslossofbalanceandvertigomakestheseevents distinguishablefromothercausesofsyncope.

Stealsyndromeassociatedwithsubclavianstenosisisanother rareconditionthatcanresultinsymptomsofsyncope,dizziness, vertigo,ornystagmusespecially withvigorous useofipsilateral armmuscles.Syncopeasasolitarymanifestationofthiscondition isextremelyrare[11].

Syncopemimics

TLOCcanoccurinavarietyofsituationssuchasseizures, concus-sions,orintoxication.However,asnotedearlier,thesearenottrue syncopaleventsasthebasisisnotcerebralhypoperfusion.They arebeingmentionedhereduetothediagnosticconfusionthatthey maycause.

Psychogenic pseudosyncope (oftentermedpseudoseizureby neurologistsespeciallyifjerkymusclemovementsaccompanythe collapse)isthemostcommonconditioninthesyncopemimics cat-egory.Itmaybedifficulttodistinguishthese‘pseudo’episodesfrom true syncope. However, pseuodosyncope/pseudoseizures most oftenwilloccurseveraltimesadaywhichalmostneverhappens inthecaseoftruesyncope.Tilt-tabletestingmaybehelpfulnot onlyinidentifyingthesepatients,butalsomaypermitdiscussing thediagnosisfranklywiththesepatients[12].

TLOCcanalso occurin casesof cataplexy and certaintypes ofakinetic orminimallykineticseizures[13].In elderlypeople,

accidentalfallsmaycauseTLOCduetoconcussion.Thediagnostic confusion caused by the above-mentioned conditions can be clearedbycarefulattentiontohistorytaking,butanexperienced clinicianisusuallyessential.Whenuncertaintypersists,the place-mentofexternalorimplantablelooprecordersmaybehelpfulto distinguishtheseconditionsfromtruesyncope.

Riskstratificationofsyncope

Syncopeisachallengingsymptomforthefirstcontactprovider [usuallyanemergencydepartment(ED)orurgentcarephysician] todealwith.First,thepatienthasusuallyrecovered,sothereareno clearphysicalfindingstosuggestacause.Second,therearesomany possiblecausestoconsider.Third,thepatientorwitnesses(ifany) mayhavebeensosurprisedbytheunexpectedevent,thatdetailed historical findings are not clearly recollected. Finally, the time availableinanEDtoundertakeadetailedassessmentislimited.

Syncopeisnottypically alife-threateningconditionbyitself (althoughtheunderlyingcausemaybe).However,syncopemay resultinuntowardconsequencessuchasphysicalinjuryand dimin-ishedqualityoflife.Syncopemayalsobeanindicatorofpotentially life-threateningunderlyingconditions;forinstance,severe struc-turalheart diseasewithconsequentmalignant arrhythmiasand heartfailure.

Aconfidentdiagnosisofthecauseofasyncopeeventmayor maynotbemadeinEDorclinic.IncaseswherethecauseofTLOC isestablishedwithcertaintyduringinitialevaluation,the subse-quentcourseofactionisclear.However,moreoftenthediagnosisis unclearandtheresponsibleprovidersarefacedwiththedilemmaof choosingbetweenimmediatehospitalizationversustimely outpa-tientevaluation.Physicianshistoricallyhavefavoredaconservative courseofactionresultinginmanymorepatientsbeingadmittedto hospitalthaniswarranted.

The ESC Syncope Task Force provided guidelines for front-line providers to use for assessing patients presenting with TLOC/collapse/syncopeandtherebyarriveatadecisionbetween inpatientversusoutpatientevaluation.

Fig.1providesanoverviewofanapproachtoassessmentofa patientwhopresentswithTLOC/collapsebasedontheESCSyncope TaskForceGuidelines[1].

Atthepresenttime,despitetutoringthephysiciansinESC guide-lines,highadmissionratesappeartopersist(ashighas30–50%per

Fig.1.Flowchartfordiagnosticevaluationofpatientswhopresenttotheemergency department(ED)orclinicwithtransientlossofconsciousness(TLOC)/syncope. ModifiedafterRef.[1].

variousreports).Bywayofexample,Bartolettietal.[14]examined admissionratesamongpatientsreferredtoEDwithsyncope.The studywasbasedonESCguidelinesformanagementofsyncope[1]. Atotalof1124patientswereevaluatedand400(39.1%)ofthem metatleastonecriterionforadmissionperESCguidelinesand680 (60.9%)didnotmeetanycriteria.Theactualadmissionrateswere 89.3%amongpatientswithindicationand25.3%amongthose with-outanyindication.Thehighadmissionratesamongthelow-risk patientsareindicativeofphysicianconcernforpatientsafetyafter discharge.SimilarfindingswerenotedinEGSYS2study[15]where theadmissionratewasnotedtobeashighas39%despiteproviding expertonlineassistancetothefront-linephysicians.The unneces-saryinpatientadmissionoflow-riskpatientsnotonlyaddstothe costofcarebutalsomaynotimprovepatientsafetyordiagnostic outcomes.

RiskstratificationofTLOC/syncopepatientshasbeenthe sub-jectofseveralrecenttrialswiththeobjectivebeingabletoderive effectivecriteriatohelpchoosebetweeninpatientadmissionand outpatientsyncopeclinicreferral[16].Themostimportant objec-tivesofrisk-stratificationstudiesaretoassesstheimmediateor short-term(1weekto1month)andlonger-term(approximately1 year)riskof:

1)Deathorlife-threateningevents.

2)Recurrenceofsyncopalevents,whichinturnmayleadto phys-icalinjury,disability,ordiminishedqualityoflife.

Althoughaconsensusrisk-stratificationtoolisnotyetavailable, suchatool-setwouldhopefullyhelpEDorclinicphysicians deter-minetheimmediateriskofadverseeventsandifriskisdeemedto behigh,itshouldpromptthephysiciantoadmittothehospitalfor furtherevaluation[16].Incaseswheretheriskisfelttobe inter-mediate,oneshouldconsiderplacementofthepatientinasyncope observationunitifavailable,aswasdoneintheSEEDSstudy[17]. Intheabsenceofimmediateorshort-termriskbasedonsucha tool,thepatientsmaybereferredforoutpatientevaluation prefer-ablyinaclinicdedicatedforevaluationofpatientswithsyncopeor TLOC.Insomesituations,thepresenceofriskfactorsforincreased long-termriskoflife-threateningevents,patientsmayneed hospi-talizationforfurtherassessment.Severalclinicalstudiesfocuson assessmentofshort-termandlong-termriskfactorstoprovidethe neededguidance.

Short-termorimmediaterisk

Theshort-termorimmediateriskofadverseeventsinthe subse-quent30daysafterinitialpresentationhasbeenthefocusofseveral clinicalstudies(Table2).Thefindingsaresummarizedbrieflyhere andinTable2.

1)SanFranciscorule

Theriskfactorsidentifiedtobepredictiveofincreasedriskof adverseeventswithinthe7daysincluded[18]:

1)An abnormal electrocardiogram (ECG) (i.e. new rhythm changesornon-sinusrhythm).

Table2

Short-termrisk(1weekto1month).

Study Clinicalmarkers

SanFrancisco[18] AbnormalECG,lowbloodpressure,CHF,SOB, hematocrit<30%

Roserule[19] AbnormalECG,elevatedBNP,chestpain,fecalblood STePS[21] AbnormalECG,trauma,nowarning,malegender ECG,echocardiography;CHF,congestiveheartfailure;SOB,shortnessofbreath;BNP, brainnatriureticpeptide.

2)Systolicbloodpressure<90mmHg. 3)Hematocrit<30%.

4)Congestiveheartfailure(CHF)(eitherpresentatthetimeof initialpresentationorahistoryofCHF).

Theadverseeventsincludedtheoccurrenceofdeath, myocar-dial infarction, malignant arrhythmia, pulmonary embolism, stroke,subarachnoid hemorrhage,significant hemorrhage or otherseriouseventswhichrequiredreturntoEDand subse-quenthospitalization.

2)TheRoserule

Thiswasan ED-basedsingle center studyfromEdinburgh UKthat wasdesigned toidentify therisk factorspredictive ofanadverseeventwithin1-monthafterinitialpresentation to ED with syncope [19]. The adverse events were defined astheoccurrence ofdeath, acutemyocardial infarction, life-threateningarrhythmia,beingdiagnosedwithanyarrhythmia whichrequiredimplantationofacardiacpacemakeror defibril-latorwithinonemonth,pulmonaryembolism,cerebrovascular accident, hemorrhage or profound anemia requiring blood transfusion,andany returnstoEDwithin onemonth which requiredurgentsurgicalorendoscopicintervention.The find-ingsthatpredictedthelikelihoodofabove-mentionedadverse outcomesincluded:

1)Brainnatriureticpeptide>300pg/mL. 2)Stoolpositiveforoccultblood.

3)Oxygensaturation<94%onroomaironinitialpresentation. 4)Hemoglobin<90g/L.

5)Chestpainatthetimeofsyncope.

6)Bradycardia(heartrate<50beatsperminute).

Ofthestudypopulation,7.1%metwithanendpointattheend ofonemonth.ThesensitivityandspecificityofRoserulewere estimatedtobe87.2%and65.5%,respectively.

3)TheBostonstudy

Thisstudyincludedatotalof293patientswhowerefollowed for30daysaftertheirinitialpresentationtoEDwithsyncope, lookingforoccurrenceofadverseoutcomessuchasdeath, seri-ousillnessthatrequiredhospitalizationoracuteinterventions [20].

Sixty-eight(23%)patientsmetwithanadverseoutcome.The riskfactorsidentifiedinthisstudythatpredictedthelikelihood ofanadverseeventincludedthefollowing:

1)Acutecoronarysyndrome(ACS). 2)Conductionsystemdisease. 3)Historyofcardiacdisease. 4)Valvularheartdisease. 5)Familyhistoryofsuddendeath. 6)AbnormalvitalsignsinED. 7)Volumedepletion.

8)Primarycentralnervoussystemevent.

Thesensitivityandspecificityofthisstudyare97%and62%, respectively.

4)STePSstudy

A total of 676 patients were included in this study after screeningatotalof2700patientswithpresumedsyncope[21]. Theadverseoutcomeswithin10daysofinitialpresentationwith syncopewereassessed.Thestatisticallysignificantriskfactors predictiveofadverseoutcomeswere:

1)Age>65years. 2)Malegender.

3)Structuralheartdisease. 4)Heartfailure.

5)Trauma.

6)Absenceofsymptomsofimpendingsyncope. 7)AbnormalECG.

Thestudy,however,hadalowpositivepredictivevalueofonly 11–14%duetoalowrateofadverseevents.

Theabove-mentionedstudiestriedtoidentifytheriskfactors thatpredictedthelikelihoodofanadverseoutcome.Theriskfactors identifiedinthesestudiestendedtohaveahighsensitivitybut notspecificity.However,toidentifythehigh-riskpatientswhowill needprompthospitalizationuponinitialevaluation,theknowledge fromthesestudiescanbesummarizedasfollows.

High-riskmarkersofshort-termadverseoutcomes

Thefollowingriskfactorswerenotedtobeconsistently asso-ciatedwithincreasedriskofadverseoutcomesinallthestudies andwhenidentifiedaspartoftheinitialevaluationalmostalways resultinhospitalizationofthepatient.

1)ACSorsymptomssuggestiveofACSassociatedwithsyncopei.e. chestpainorshortnessofbreath.

2)EvidenceofCHFatthetimeofpresentationorahistoryofit. 3)Historyofstructuralheartdisease.

4)AbnormalECG. 5)Anemia.

6)Hemodynamicinstability.

TheESCguidelinesonmanagementofsyncopelistedthecriteria forhospitalizationofpatientspresentingwithsyncope. Hospital-izationofpatientsisadecisionthatshouldbemadecarefullyasone shouldbemindfulofnotonlypatientinconvenienceandanxiety butalsoahighlevelofavoidablehealthcareexpenditure.

Long-termrisk

Long-termriskisdefinedastheriskofanadverseeventinone yearorlongerafterinitialpresentationwithsyncope.Several stud-ieshaveattemptedtoestablishthelong-termriskfactors;several ofthesearesummarizedbelow.Table3summarizesthefindings fromthesestudies.

1)Martinetal.

Thisprospectivecohort studyfromtheUniversityof Pitts-burghconsistedoftwogroups [22].Thefirst groupincluded 252patientswithsyncope whoweremade apartof a risk-assessmentscheme(derivationcohort).Inthisgroup,thedata fromthepatient’shistory,physicalexamination,andECGdone intheEDwereusedtoidentifypredictorsofarrhythmiasor mor-talitywithinthefirstyear.Thesecondgroupconsistedof374 patientswithsyncopeinordertovalidatethesystem(validation cohort).Theobjectivewastoidentifythepredictorsofadverse outcomes(deathorseriousarrhythmias)at1-yearfollow-up. Fourmultivariateriskfactorswereidentifiedinthisstudy: 1)Abnormal ECG [odds ratio (OR) 3.2, 1.6–6.4] defined as

rhythm abnormalities, conduction disorders, hypertrophy, oldmyocardialinfarction,oratrioventricularblock.

2)Historyofventriculararrhythmia(OR4.8,1.7–13.9). 3)Historyofcongestiveheartfailure(OR3.1,1.3–7.4). 4)Age>45years(OR3.2,1.3–8.1).

Table3

Longer-term.

Study Clinicalmarkers

Martinetal.[22] AbnormalECG,CHF,SOB,ventriculararrhythmia,age >45years

OESILscore[23] AbnormalECG,age>65years,historyofcardiovascular disease,nowarning

EGSYS[24] Palpitationbeforeevent,abnormalECGorheart disease,syncopeduringeffort,syncopesupine ECG,echocardiography;CHF,congestiveheartfailure;SOB,shortnessofbreath.

Inpatientswithoutanyriskfactors,adverseeventswhichare definedasdeathorarrhythmiasoccurredin7.3% ofpatients inthederivationcohort and4.4%inthevalidationcohort.In patientswiththree tofourriskfactors,theabove-mentioned adverseeventsoccurredin80.4%ofpatientsinthederivation cohortand57.6%inthevalidationcohort.

2)STePSstudy

Atotalof676patientswereincludedinthisstudy[21]. Long-termadverseoutcomesweredefinedasdeathortheneedfor majortherapeuticprocedures.Adverseoutcomesoccurredin 9.3%ofthestudypopulationwhichincluded40(6%)deathsand 22patientsrequiringmajortherapeuticprocedures.

Five risk factors identified through a multivariate analysis wereassociated withadverseoutcomesin this study,which included:

1)Age>65years. 2)Historyofneoplasm. 3)Cerebrovasculardisease. 4)Structuralheartdisease. 5)Ventriculararrhythmia.

Mortalitywasnotedtobehigher(p<0.05)at1yearinpatients whowere admittedtothe hospital(14.7%) compared tothe patientswhoweredischarged(1.8%).

3)OESILstudy

Theriskfactorsidentifiedtobepredictiveof1-yearmortality inthisstudy[23]included:

1)Age>65years.

2)Historyofcardiovasculardisease. 3)Lackofprodromes.

4)AbnormalECGdefinedasrhythmabnormalities,conduction disorders,hypertrophy,oldmyocardialinfarction,possible acuteischemia,oratrioventricularblock.

One-yearmortalityinthisstudyincreasedprogressivelyfrom 0%inpatientswithnoneoftheabove-mentionedriskfactors,to approximately57%inpatientswith4riskfactors.

4)EGSYSscore

ThesixriskfactorsidentifiedintheEGSYSstudythatwere predictiveofadverseoutcomes[24]are:

1)Historyorevidenceofischemicheartdisease. 2)Valvularheartdisease.

3)Cardiomyopathy. 4)Congenitalheartdisease. 5)CHF.

6)Abnormal ECG (sinus bradycardia, atrioventricular block greaterthanfirstdegree,bundlebranchblock,acuteorold myocardialinfarction,supraventricularorventricular tachy-cardia, evidence of left or right ventricular hypertrophy, ventricularpreexcitation,longQT,orBrugadapattern). Themortalityat2yearswasnotedtobe2%inpatientswitha score<3and21%forascore>3.

Riskstratificationbasedoncardiacversusnon-cardiac causesofsyncope

Syncopefromacardiaccausehasbeennotedtobeassociated with both short- and long-term risk of adverse outcomes.The comparison ofmorbidityand mortalityinpatientswithcardiac syncopeandnon-cardiacsyncopehasbeenthesubjectofseveral studies.

1)Soteriadesetal.

Atotalof7814patientswereincludedinthisstudywhich evaluatedtheincidenceand prognosisamong participantsin theFraminghamheartstudyfrom1971to1998[25].Syncope occurredin822patients.Cardiaccausewasconsideredbythe

investigatorstobetheetiologyin9.4%andvasovagalin21.2%.In 36.6%thecauseofsyncoperemainedunknown.The multivari-atehazardratiosformortalityfromanycauseandstrokewere notedtobesignificantlyhigherinpatientswithpresumed car-diaccauseofsyncopewhencomparedtopatientswithsyncope fromothercauses.Thestudy,however,hadinherentweakness ofitsdiagnosticclassificationmainlyduetothelimitednature ofcollectedclinicalinformation.

2)Kapooretal.

Thisstudyassessedthemorbidityandmortalityattheendof5 yearsinatotalof433patientswhopresentedwithsyncope[26]. Initialhistory,physicalexamination,ECG,andprolongedcardiac monitoringwerehelpfulinassigningthecauseofsyncope,but onlyin22%ofthestudypopulation.Themortalityattheendof 5yearswasnotedtobesignificantlyhigher(50.5%)inpatients withcardiaccauseofsyncopewhencomparedtopatientswith non-cardiacorunknowncauseofsyncope(24.1%).Inaddition, theincidenceofsuddencardiacdeathwasnotedtobe signifi-cantlyhigher(33.1%)inpatientswithcardiaccauseofsyncope whencomparedtonon-cardiac(4.9%)orunknowncause(8.5%). 3)Ungaretal.

This recent study which included a relatively older set of patients(age66+20years)examinedtheriskofcardiovascular mortalityamongthepatientsenrolledinEvaluationof Guide-linesinSyncopeStudy2(EGSYS2)study[27].Atotal of380 patientswereincludedinthisstudywhichexaminedboth short-term(1month)andlong-term(2years)mortality.Atotalof35 (9.2%)deathsoccurredattheendof2years.Thedeathswere significantlyhigher(82%)inpatientswhowereolderandwho hadcardiacriskfactors,abnormalECGorahistoryofstructural heartdiseaseandsustainedinjuries relatedtosyncopewhen comparedtopatientswithoutabnormalECGorstructuralheart disease(3%).

4)Numerosoetal.

Inthisrecentstudyatotalof200patientspresentingwith syn-copewerefollowedtoevaluateincidenceofbothshort-term (1month)andlong-term(1year)adverseeventswhichwere definedasdeath,recurrenceofsyncope,cardiovascularevents, andmajorprocedures[28].Cardiacsyncopewasassociatedwith both greatershort-andlong-termoccurrence ofatleastone adverseevent.

Issyncopeamarkerofincreasedriskofcardiovascular morbidityandmortality?

Thisimportant question remains unresolved. A large recent population-basedstudy from Denmark [29] suggested that the occurrence of syncopein patientswithout anyprior history of co-morbiditiesmayconferanincreasedriskofcardiovascular mor-bidity and mortality. A total of 37,017 (median age 47 years) patientsadmittedtohospitalwithafirstsyncopeeventbetween 2001and 2009 were identified fromnationwide registries and approximatelyfivetimesthenumber(n=185,085)werechosen fromtheDanishpopulationascontrolsubjects(withoutsyncope) whowerematchedforageandsex.MultivariableCoxregression analysisdemonstrated a significantlyhigher all-causemortality andcardiovascularhospitalizationandeventrate(recurrent syn-cope,stroke,andplacementofICDorpacemaker)inpatientswith syncopewhencomparedtothecontrolsubjectswithoutsyncope. Thestudydidhaveamajorlimitationinthatthestudy popula-tionwashospitalizedpatientswithsyncopeandtheothercauses necessitatinghospitalizationwerenotcontrolled.Thefindingsin thisstudyhoweverdoemphasizetheimportanceofcarefulinitial evaluationofallpatientswithsyncopeandtheneedfordiligent riskstratification.

Table4

CriteriaforhospitalizationorintensiveevaluationbasedonEuropeanSocietyof Cardiology2009guidelines.

Severestructuralheartdiseaseorcoronaryheartdisease:

-Heartfailure

-Lowleftventricularejectionfraction -Previousmyocardialinfarction

Clinicalfeaturessuggestiveofarrhythmicsyncope:

-Syncopeinsupineposition -Syncopeduringexertion

-Palpitationsassociatedwithsyncope -Familyhistoryofsuddencardiacdeath

Electrocardiographicfindingssuggestingarrhythmicsyncope:

-Nonsustainedventriculartachycardia

-Bifascicularblock(leftbundlebranchblockorrightbundlebranchblock combinedwithleftanteriorofposteriorfascicularblock)

-OtherintraventricularconductionabnormalitieswithQRScomplex duration>120ms

-Inadequatesinusbradycardia(<50bpm)orsinoatrialblockinabsenceof negativechronotropicmedications(e.g.beta-blockersor

nondihydropyridinecalciumchannelblockers)orphysiologicbradycardia associatedwithphysicaltraining

-Pre-excitedQRScomplex -ProlongedorshortQTinterval

-RightbundlebranchblockpatternwithSTelevationinleadsV1–V3 (Brugadapattern)

-NegativeTwavesinrightprecordialleads,epsilonwavesandventricular latepotentialssuggestiveofarrhythmogenicrightventriculardysplasia

Importantco-morbidities:

-Severeanemia -Electrolyteabnormalities

Conclusion

Understandingthevariouscausesofsyncopeand differentiat-ingsyncopefromothercausesofTLOCarecriticalelementsinthe assessmentof patientswhopresent with‘collapse’. Inaddition, riskstratificationisanindispensablepartoftheinitialevaluation ofpatientspresentingwithsyncopeasitprovidesanopportunity to identify and protect the patients at immediate risk of life-threateningeventsbyprompthospitalization.Riskstratification, whenoptimal, alsoofferstheopportunitytoavoidunnecessary hospitalizationoflow-riskpatients,therebyreducingthe health-careexpenditure.Consequently,theneedtodevelopoptimalrisk assessmenttoolsandtrainfront-lineprovidersintheirusecannot beover-emphasized.

Atthepresenttime,whileaconsensusrisk-stratification instru-mentremainsinevolution, short-termriskstratificationstudies providecompellingevidencetohospitalizesyncopepatientswith a suspected cardiac cause (structural or arrhythmic). All the long-termstudiesunequivocally emphasizetheneedforcareful evaluationandmanagementofunderlyingheartdiseaseinthese patients.

Currently,the2009ESCTaskForceGuidelinesformanagement ofsyncopeprovideausefulandrelativelyup-to-datesummaryof currentcriteriaforhospitalization[1](Table4).Theseguidelines stronglyencouragethedevelopmentwithinmajormedical cen-tersofdedicated‘syncopeclinics,’staffedbyamultidisciplinary teamofinterestedmedicalprofessionals (cardiology,neurology, internalmedicine,psychiatry).Suchunitsmayactasaresourcefor acceleratingeffectiveassessmentofin-hospitalpatients,buteven moreimportantlyprovideareadilyaccessiblesitefortimely outpa-tientevaluationsofsyncope/collapsepatientswhodidnotrequire urgenthospitalization.

Acknowledgment

Thisworkwassupportedinpartbya grant fromtheEarlE BakkenFundforHeart–BrainResearchattheMinnesotaMedical Foundation.

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