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Intracranial haemorrhage in infective endocarditis
Erwan Salaün, Anissa Touil, Sandrine Hubert, Jean-Paul Casalta, Frederique
Gouriet, Emmanuelle Robinet-Borgomano, Emilie Doche, Nadia Laksiri,
Caroline Rey, Cecile Lavoute, et al.
To cite this version:
Erwan Salaün, Anissa Touil, Sandrine Hubert, Jean-Paul Casalta, Frederique Gouriet, et al..
In-tracranial haemorrhage in infective endocarditis. Archives of cardiovascular diseases, Elsevier/French
Society of Cardiology, 2018, 111 (12), pp.712-721. �10.1016/j.acvd.2018.03.009�. �hal-02006737�
ArchivesofCardiovascularDisease(2018)111,712—721
Availableonlineat
ScienceDirect
www.sciencedirect.com
CLINICAL
RESEARCH
Intracranial
haemorrhage
in
infective
endocarditis
Hémorragie
intracrânienne
dans
l’endocardite
infectieuse
Erwan
Salaun
a,∗,
Anissa
Touil
a,
Sandrine
Hubert
a,b,
Jean-Paul
Casalta
a,b,
Frédérique
Gouriet
a,b,
Emmanuelle
Robinet-Borgomano
c,
Emilie
Doche
c,
Nadia
Laksiri
c,
Caroline
Rey
c,
Cécile
Lavoute
a,
Sébastien
Renard
a,
Hervé
Brunel
d,
Anne-Claire
Casalta
a,
Julie
Pradier
a,
Jean-Franc
¸ois
Avierinos
a,
Hubert
Lepidi
a,b,
Laurence
Camoin-Jau
b,e,
Alberto
Riberi
a,b,
Didier
Raoult
b,
Gilbert
Habib
a,baCardiologyDepartment,laTimoneHospital,AP—HM,boulevardJean-Moulin,13005
Marseille,France
bMEPHI,IRD,IHU-MéditerranéeInfection,AixMarseilleUniversity,AP—HM,13005Marseille,
France
cNeurologyDepartment,laTimoneHospital,AP—HM,13005Marseille,France
dRadiologyDepartment,laTimoneHospital,AP—HM,13005Marseille,France
eDepartmentofHematology,AixMarseilleUniversity,laTimoneHospital,AP—HM,13005
Marseille,France
Received13December2017;receivedinrevisedform23January2018;accepted16March2018 Availableonline5June2018
KEYWORDS Infective endocarditis; Intracranial haemorrhage; Summary
Background.—Althoughintracranialcerebralhaemorrhage(ICH)complicatinginfective endo-carditis(IE)isacriticalclinicalissue,itscharacteristics,impact,andprognosisremainpoorly known.
Aims.—Toassesstheincidence,mechanisms, riskfactorsandprognosisofICH complicating left-sidedIE.
Abbreviations: ICH,intracranial cerebral haemorrhage;IE, infective endocarditis; TOE, transoesophageal echocardiography; TTE, transthoracicechocardiography.
∗Correspondingauthor.
E-mailaddress:[email protected](E.Salaun).
https://doi.org/10.1016/j.acvd.2018.03.009
Mycoticaneurysm; Neurological complication; Cerebralbleeding
Methods.—Inthissingle-centrestudy,963patientswithpossibleordefiniteleft-sidedIEwere includedfromJanuary2000toDecember2015.
Results.—Sixty-eight(7%)patientshadanICH(meanage57±13years;75%male).ICHwas classifiedintothreegroupsaccordingtomechanism:rupturedmycoticaneurysm(n=22;32%); haemorrhageafterischaemicstroke(n=27;40%);andundeterminedaetiology(n=19;28%). FivevariableswereindependentlyassociatedwithICH:plateletcount<150×109/L(oddsratio [OR]2.3,95%confidenceinterval[CI]1.01—5.4;P=0.049);severevalveregurgitation(OR3.2, 95%CI1.3—7.6;P=0.008);ischaemicstroke(OR4.2,95%CI1.9—9.4;P<0.001);other symp-tomatic systemicembolism (OR14.1, 95%CI 5.1—38.9;P<0.001);and presenceofmycotic aneurysm(OR100.2,95%CI29.2—343.7;P<0.001).Overall,237(24.6%)patientsdiedwithin 2.3(0.7—10.4)months offollow-up.ICH wasnotassociatedwithincreasedmortality(Pnot significant).However,the1-yearmortalityratedifferedaccordingtoICHmechanism:14%,15% and45%inpatientswithrupturedmycoticaneurysm,haemorrhageafterischaemicstrokeand undeterminedaetiology,respectively(P=0.03).InpatientswithanICH,mortalitywashigher innon-operatedversusoperatedpatientswhencardiacsurgerywasindicated(P=0.005).No operatedpatienthadneurologicaldeterioration.
Conclusions.—ICHisacommoncomplicationofleft-sidedIE.Theimpactonprognosisis depen-dentonmechanism(haemorrhageofundeterminedaetiology).Weobservedahighermortality rateinpatientswhohadconservativetreatmentwhencardiacsurgerywasindicatedcompared withinthosewhounderwentcardiacsurgery.
©2018ElsevierMassonSAS.Allrightsreserved.
MOTSCLÉS Endocardite infectieuse; Hémorragie intracrânienne; Anévrysme mycotique; Complication neurologique; Saignementcérébral Résumé
Contexte.—Leshémorragiesintracrâniennes(HIC)compliquantlesendocarditisinfectieuses (EI)sontunesituationcliniquecruciale,cependantleurscaractéristiques,impacts,etpronostic restentmalconnus.
Objectifs.—Analyserl’incidence,lesmécanismes,lesfacteursderisque,etlepronosticdes HICcompliquantlesEI.
Méthodes.—Cetteétude monocentriqueainclus963 patientsavec uneEI du cœurgauche possibleoucertaineentrejanvier2000etdécembre2015.
Résultats.—Soixante-huit (7 %) présentaient une HIC (âge moyen de 57±13 ans et 75 % d’hommes).L’HICétaitclasséeselontroismécanismes:ruptured’anévrysmemycotique(n=22, 32%)patients,hémorragiesecondaireàunaccidentischémiquecérébral(n=27,40%), étiolo-gienondéterminée(n=19,28%).Cinqparamètresétaientassociésàl’HIC:thrombopénie(OR 2,3,IC95%1,01—5,4;p=0,049),fuitesévèrevalvulaire(OR3,2,IC95%1,3—7,6;p=0,008), accidentischémiquecérébral(OR4,2,IC95%1,9-9,4;p<0,001),autreemboliesystémique symptomatique(OR14,1,IC95%5,1—38,9;p<0,001),etlaprésenced’unanévrysme myco-tique(OR100,2,IC95%29,2—343,7;p<0,001).Laprésenced’uneHICn’étaitpasassociéeà unesurmortalité(p=NS).Cependant,letauxdedécèsàunanétaitdifférentselonle mécan-isme:14%,15%et45%respectivementencasderuptured’anévrysmemycotique,hémorragie secondaireàunaccidentischémiquecérébral,etd’étiologieindéterminée(p=0,03).Chezles patientsprésentantuneHIC,la mortalitéétaitplusélevéeavecuntraitementconservateur malgrél’indicationdechirurgiecardiaqueparrapportàceuxquienbénéficiaient(p=0,005). Aucunedétérioration neurologique n’est survenuechez les patients ayant bénéficiés d’une chirurgiecardiaque.
Conclusions.—L’HICreprésenteunecomplicationcommuneauxEI.L’impactpronostiqueest dépendantdumécanismedel’HIC(étiologieindéterminée).Nousobservonsunesurmortalité encasdetraitementconservateurlorsqu’ilexisteuneindicationchirurgicalecardiaque. ©2018ElsevierMassonSAS.Tousdroitsr´eserv´es.
Background
Infectiveendocarditis(IE)isacomplexanddeadlydisease, whichassociatescardiacinfectivelocationandmultiorgan
complications[1,2].Neurological complications relatedto IEaremultiple(ischaemic,haemorrhagic,infective),occur in17—82%ofpatientswithleft-sidedIE[3,4]andare glob-allyassociated with an excess of mortality [5]. However,
714 E.Salaunetal.
Figure1. Studyflowchart.IE:infectiveendocarditis.*The diag-nosis ofinfective endocarditis was established accordingto the modifiedDukecriteriabytheendocarditisteamforeachpatient, andduringtheperiodfromJanuary2000toDecember2015.
differenttypesofneurologicalcomplicationsandtheir pre-sentation may affect the clinical course of IE differently
[6,7].The impactof ischaemicstrokeiswell known[5,7], andclear recommendations existconcerningthe manage-ment of ischaemic lesions [1]. Conversely, the impact of intracranialcerebral haemorrhage (ICH) and the resulting managementislessdescribed[1].Moreover,several mech-anismsmayleadtoICHduringIE[6,7],andnolargestudy hasdescribedthecharacteristicsofthesedifferentlesions andtheirimpact.
Ourobjectivesweretoassesstheincidenceand mecha-nismsofICHinpatientswithleft-sidedIE,theriskfactors for itsdevelopment,the associatedrisk of deathandthe managementofpatientsafterICH.
Methods
Inclusion
criteria
This studyincluded patients consecutivelydiagnosed with possibleordefiniteIE,accordingtothemodifiedDuke cri-teria [8], in a single-centre, and who were registered in a dedicated database between January 2000 and Decem-ber2015(n=1235).Theexclusioncriteriawereright-sided IE (n=203) and incomplete data (n=69) (Fig. 1). Writ-teninformed consentwas obtained fromall participating patients, as required by the institutional review board under an approved protocol. Blood cultures, serologi-calassessment, transthoracicechocardiography(TTE)and transoesophagealechocardiography(TOE) wereperformed systematically within 48hours of admission. A cerebral computed tomography scan wasperformed onadmission, and was repeated if indicated clinically. Complementary cerebral imaging (cerebral magnetic resonance imaging and catheter-based cerebral angiography) was performed depending on the neurological presentation, and after advice from neurological specialists and the endocarditis team,includingthecardiologists,thecardiacsurgeonsand theinfectiousdiseasespecialist.
Clinical
and
echocardiographic
data
The following criteria were collected prospectively: age; sex; previous valve surgery (mechanical valve or bio-prostheticvalve/homograft/valverepair);intravenousdrug abuse;diabetes;hypertension;historyofatrialfibrillation; coronaryarterydisease;historyofischaemicstroke; Charl-son Index score; oral anticoagulant or platelet inhibition therapies; creatinine serum concentration; haemoglobin concentration; platelet count; C-reactive protein serum concentration; andsymptomatic systemic embolismother thancerebral.
TTE and TOE were performed as reported previously
[9].Echocardiographicdataincludedpresenceofvegetation andperiannularlesion(definedasthepresenceofabscess and/orpseudoaneurysmand/orfistula)[1].Thevegetation length was measured in various planes, and the maximal lengthwasused.Valvularregurgitationswerequantified fol-lowingcurrentrecommendations[10,11].
Definitions
Neurological vascular complications were classified into two categories: isolated ischaemic stroke; and ICH. An experienced neurological specialist confirmed the diag-nosis of all neurological vascular complications. Isolated ischaemicstroke(i.e.withnosignofcerebralhaemorrhage) includedischaemicstrokewithapersistentdeficit,transient ischaemicattackandsilentcerebralembolismconsideredas recentoncerebralimaging.Ischaemicstrokewitha persis-tentdeficitwasdefinedasthepersistencefor>24hoursofa focalneurologicdeficitcausedbyalteredcirculationofthe cerebralhemispheres,brainstemorcerebellum.Transient ischaemic attack wasdefined asfocal neurological symp-tomsofsuddenoccurrenceandrapidresolution(<24hours), related to altered circulation of the brain. Silent cere-bralembolismwasdetectedbycerebralimagingperformed afteradmission.Themechanism ofICHwasestablishedby expertconsensusbetweentheneurologistand neuroradiol-ogistafterclinicalandimagingexaminations,andICHwas classifiedas:ICHsecondarytorupturedmycoticaneurysm; haemorrhage afteran acuteischaemic stroke; andICH of undeterminedaetiology.
Haemorrhage after an acute ischaemic stroke was definedbybothchronologicalandimagingcriteria. Undeter-mined aetiologyincluded necroticvessel aetiologyand/or undiagnosedotherlesionintheimagingassessment. Mana-gement of the neurological vascular complication was performed accordingtotheguidelines[12,13].As microb-leedshavenotbeenassociatedwithICHandpostoperative neurological complications in theliterature [1], the pres-enceofmicrobleedswasnotconsideredinourstudy(also becausecerebralmagneticresonanceimagingwasnot per-formedinallpatients).
Indication
for
cardiac
surgery
Theindicationforcardiacsurgerywasbasedonthe guide-lines for the management of IE [1,14,15], in patients with high-risk features. The three main indications were heart failure, uncontrolled infection and prevention of
embolic events. The final decision to perform cardiac surgerywasmadebytheendocarditisteam,inagreement withtheneuroradiologists,neurologistsandneurosurgeons. When cardiac surgery was performed, the timing was dichotomized according to the period of antibiotic ther-apy(i.e.duringoraftertheactivephaseoftheantibiotic therapy)ordisplayedaccordingtothedelaywithICH.
Mortality
and
follow-up
The primary endpoint was death from any cause during thefollow-up.Thesecondaryendpointswere:death imme-diately related to ICH, defined by death as a result of neurologicalfailureafew hoursafterthe ICH;and neuro-logicaldeteriorationaftercardiacsurgeryinpatientswith anICH,definedbyclinicalneurologicaldeteriorationand/or worseningofthe ICHand/ornewICH.Follow-up informa-tionwasobtainedduringandafterthehospitalization,with scheduledvisitsat1month,3months,6monthsand1year. Ifapatientmissedascheduledvisit,supplemental follow-upinformationwasobtained bycontactingthe patientor thepatient’sphysicians.
Statistical
analysis
Continuousdataareexpressedasmeans±standard devia-tionsormedians[interquartileranges],andwerecompared withanalysisofvariance andTukey’srangetest. Categor-icaldata areexpressedasnumbers and percentages, and were compared by use of the 2 test or Fisher’s exact test. Time-to-event curveswere obtained by the Kaplan-Meiermethod,andwerecomparedwiththelog-ranktest. TheCoxproportionalhazardsmodelwasusedtocalculate adjusted hazard ratios andtheir 95% confidence intervals (CIs). The final model included clinically relevant varia-blesand/orvariableswithaP-value<0.10intheunivariate analysis.The multivariableCox modeltopredict midterm mortalityincluded:age;sex;diabetes;hypertension; coro-nary disease;history of cardiac surgery;creatinine serum concentration;ischaemicstroke;ICH;lengthofvegetation; periannularlesion;severeregurgitation;andcardiacsurgery for IE during the first year. An exploratory multivariable analysis by logistic regression wasperformed to evaluate the predictors of ICH.The final model included clinically relevantvariablesand/orvariableswithaP-value<0.10in theunivariateanalysis.Theresultsarereportedasadjusted oddsratios(ORs)withassociated95%CIs.AvalueofP<0.05 wasconsidered statisticallysignificant. Statistical analysis wasperformedusingJMPsoftware,version13(SASInstitute, Cary,NC,USA).
Results
Neurological
vascular
complications
and
patient
characteristics
Among the963 patients withleft-sidedIE included in the study, 68 (7%) had an ICH, 157 (16%) had an isolated ischaemicstrokeand738(77%)hadnoneurological vascu-larcomplications.Baselinepatientfeaturesarereportedin
Table1forpatientswithanICH,patientswithanisolated
ischaemicstroke andpatients withnoneurological vascu-larcomplications.PatientswithanICHhadameanageof 57±13years,and75%weremale;theywereyoungerthan patients withnoneurological vascular complications, and hadahigherrateof intravenousdrugabusethanpatients withisolatedischaemicstrokeandthosewithno neurolog-icalvascularcomplications.Diabetesoccurredsignificantly morefrequentlyinpatientswithisolatedischaemicstroke. Echocardiographic findings were similar, except for a higherrateofvegetationintheICHandisolatedischaemic stroke groups, with longer vegetation in the isolated ischaemicstroke groupthanin patientswithno neurolog-icalvascular complications. Ahigher rate of severe valve regurgitationwasobservedintheICHgroup.Staphylococci were more frequent in patients with an ICH or isolated ischaemicstrokethaninpatientswithnoneurological vas-cular complications. Patients with an ICH had a higher rateofothersymptomaticsystemicembolismsandmycotic aneurysm.Norelationshipwasobservedbetweenthe occur-renceofanyneurologicalvascularcomplicationandtheuse ofantithrombotictherapy.
Mechanisms
of
ICH,
and
patient
characteristics
Among patients withan ICH, 19 (28%) had undetermined aetiology, 22 (32%) had ruptured mycotic aneurysm and 27(40%)hadhaemorrhageafterischaemicstroke.Patients withrupturedmycotic aneurysmwereyounger(51.5±2.7 years;P=0.03)andmorefrequentlymale(n=21,95%male;P=0.001) than those with haemorrhage after ischaemic stroke(57.8±2.4years;52%male,n=14)andICHof unde-termined aetiology (61.9±2.8 years; 84% male, n=16). Ratesofintravenousdrugabuseweresimilarinpatientswith haemorrhageafterischaemicstroke(15%),ICHof undeter-minedaetiology(16%)andrupturedmycoticaneurysm(18%) (Pnotsignificant).Otherhistoryvariableswerealsonot sig-nificantlydifferentbetweenthethreetypesof ICH;these included diabetes, hypertension, history of atrial fibrilla-tion,coronarydisease,historyofischaemicstroke,Charlson Indexscore,oral anticoagulanttherapy,plateletinhibition therapyandpresenceandtypeofpreviouscardiacsurgery (Pnotsignificantforall).
Regardingcerebralimaging,lesionsof ischaemicstroke werefound concomitantlyin five patients withan ICHof undeterminedaetiologyandinfourpatientswithruptured mycotic aneurysm. Five patients with haemorrhage after ischaemicstrokehadunrupturedmycoticaneurysm.
The location and severity of cardiac lesions were not significantlydifferentaccordingtothe mechanismof ICH, includingvalvelocation,periannularlesion,severe regurgi-tationandpresenceorlengthofvegetation(Pnotsignificant for all). Patients with ruptured mycotic aneurysm had morestreptococci(n=13,59%;P=0.03)thanothers(seven patients[37%]withan ICHof undeterminedaetiology;six patients [22%] withhaemorrhage after ischaemic stroke). Therates ofstaphylococci, enterococciandother biologi-calvariables werenot significantly different according to the mechanism of ICH (P not significant for all). Table 2 shows clinical signs, timing and methods of diagnosis for eachmechanismofICH.
716 E.Salaunetal.
Table1 Comparison of patients with intracranial cerebral haemorrhage, ischaemic stroke or with no neurological vascularcomplication. Variables ICH (n=68) Isolatedischaemic stroke (n=157) Noneurological complication (n=738) Pa
Demographicsandmedicalstatus
Age,(years) 57±13b 61±18 64±15 <0.001
Male 51(75) 110(70) 529(72) 0.8
Diabetes 13(19) 36(23)c 106(14) 0.02
Arterialhypertension 21(31) 42(27) 224(30) 0.7
Coronarydisease 7(10) 17(11) 69(9) 0.8
Historyofischaemicstroke 1(1.5) 10(6) 37(5) 0.3
Intravenousdrugabuse 11(16)d 9(6) 55(7) 0.02
Historyofatrialfibrillation 18(27) 36(23) 154(21) 0.5
Previousvalvesurgery 18(27) 46(30) 227(31) 0.7
Mechanicalvalve 5(7.5) 11(7) 72(10) 0.5
Bioprostheticvalve/homograft/valve repair
13(19) 35(23) 160(22) 0.7
Anticoagulanttherapy 18(27) 34(22) 175(24) 0.7
Plateletinhibitiontherapy 12(18) 28(18) 140(19) 0.9
CharlsonIndexscore 3[1—4] 3[2—5] 3[1—5] 0.9
Echocardiographicfindings
Affectedvalve 0.5
Aortic 35(51) 63(40) 324(44)
Mitral 22(32) 61(39) 256(35)
Aorticandmitral 11(16) 30(19) 116(16)
Vegetation 59(87)b 134(85.5)c 534(73) <0.001
Vegetationlength(mm) 14[8—20] 15[10—19]c 12[8—17] <0.01
Periannularlesion 22(32) 51(32.5) 199(27) 0.3
Severeregurgitation 53(78)d 61(39) 253(34) <0.001
Leftventricularejectionfraction(%) 62[60—65]b 60[55—65] 60[55—65] 0.045
Biologicalfindings
Haemoglobin(g/dL) 10.2[0.94—12] 10.8[0.98—12] 10.8[0.96—12] 0.4 Plateletcount(109/L) 220[141—308] 246[153—317] 252[171—332] 0.2 C-reactiveproteinserum
concentration(mg/L)
73[(37—179] 109[(53—182]c 71[31—136] <0.001
Creatinineserumconcentration (mol/L)
86[71—130] 86[73—138] 95[76—140] 0.2 Microbiologicalfindings
Positivebloodculture 64(94)b 134(85.5) 596(81) 0.01
Staphylococci 25(37)b 57(36)c 165(22) <0.001
Streptococci 26(38) 42(27) 225(30) 0.2
Enterococci 8(12) 23(14.5) 103(14) 0.8
Complicationsandsurgery
Othersymptomaticsystemicembolism 25(37)d 5(3) 23(3) <0.001
Cerebralmycoticaneurysm 27(40)d 5(3)c 2(0.3) <0.001
Indicationforcardiacsurgery 60(88) 129(82) 593(80) 0.1
Cardiacsurgerye 38(63) 95(74) 433(73) 0.4
Cardiacsurgeryduringversusafterthe activephase
<0.001 ‘‘Duringtheactivephase’’f 21(55)d 87(91) 376(87)
‘‘Aftertheactivephase’’f 17(44)d 8(9) 57(13)
Dataareexpressedasmean±standarddeviation,number(%)ormedian[interquartilerange].ICH:intracranialcerebralhaemorrhage.
aP-valueforthecomparisonbetweenthethreegroupsofpatients. b P<0.05for‘‘ICH’’versus‘‘noneurologicalcomplication’’.
c P<0.05for‘‘ischaemicstroke’’versus‘‘noneurologicalcomplication’’.
d P<0.05for‘‘ICH’’versus‘‘ischaemicstroke’’andversus‘‘noneurologicalcomplication’’. ePercentagescalculatedamongpatientswithindicationsofcardiacsurgery.
Table2 Clinicalsigns,timingandmethodsofdiagnosisaccordingtothetypeofintracranialcerebralhaemorrhage. Variables Undetermined aetiology (n=19) Rupturedmycotic aneurysm (n=22) ICHsecondaryto ischaemicstroke (n=27) P
TimingofICHdiagnosis
Inauguraldiagnosis 6(32)a 10(45)b 20(74) 0.01
DiagnosisinthecourseofIE 13(68)a 11(50)b 7(26) 0.01
TimebetweenIEandICH diagnosis(days)
12[6—25] 7[4—21] 3[2—14] 0.2
MethodofICHdiagnosis
Computedtomography 19(100) 21(95) 27(100) 0.3
Cerebralmagneticresonance imaging 7(37) 12(55) 14(52) 0.5 Catheter-basedcerebral angiography 6(32)c 18(82)b 12(44) 0.003 Clinicalsigns Asymptomatic 2(11) 5(23) 3(11) 0.4 Paresisorplegia 5(26)c 7(32) 16(59) 0.04 Aphasia 2(11) 4(18) 7(26) 0.4 Clonicconvulsion 2(11) 1(5) 1(4) 0.6 Disorientation 4(21) 2(9) 1(4) 0.2
Visualfielddeficits 0(0) 0(0) 2(7) 0.2
Headache 4(21) 7(32)b 1(4) 0.03
Ataxia 0(0) 0(0) 1(4) 0.5
Vigilancereduction 8(42) 4(18) 6(22) 0.2
GlasgowComaScale 14[10—15] 14[13—15] 15[12—15] 0.4
Dataareexpressedasnumber(%)ormedian(interquartilerange).ICH:intracranialcerebralhaemorrhage;IE:infectiveendocarditis.
a P<0.05for‘‘undeterminedaetiology’’versus‘‘ICHsecondarytoischaemicstroke’’. b P<0.05for‘‘rupturedmycoticaneurysm’’versus‘‘ICHsecondarytoischaemicstroke’’. c P<0.05for‘‘undeterminedaetiology’’versus‘‘rupturedmycoticaneurysm’’.
Table3 Univariateandmultivariableanalysis,accordingtothepresenceofintracranialcerebralhaemorrhage.
Univariate Multivariable
Oddsratio(95%CI) P Oddsratio(95%CI) P
Age,peroneincrease 1.02(1.01—1.02) <0.001 — 0.35
Intravenousdrugabuse 2.6(1.3—5.3) 0.006 — 0.71
Presenceofvegetation 2.2(1.1—4.6) 0.03 — 0.82
Presenceofsevereregurgitation 2.2(1.1—4.6) 0.03 3.2(1.3—7.6) 0.008 Plateletcount<150×109/L 2.5(1.5—4.6) 0.001 2.3(1.01—5.4) 0.049
Staphylococci 1.7(1.05—3) 0.03 — 0.31
Streptococci 1.5(0.8—2.4) 0.1 — 0.43
Ischaemicstroke 5.3(3.2—8.8) <0.001 4.2(1.9—9.4) <0.001 Mycoticaneurysm 97.5(38.2—249.4) <0.001 100.2(29.2—343.7) <0.001 Othersymptomaticsystemicembolism 18(9.7—33.5) <0.001 14.1(5.1—38.9) <0.001
CI:confidenceinterval.
Determinants
and
management
of
ICH
By multivariable analysis (Table 3), five variables were associatedwiththeoccurrenceofICHinpatientswith left-sidedIE:plateletcount<150×109/L;severeregurgitation; cerebralischaemic embolism;othersymptomatic systemic embolism;andpresenceofmycoticaneurysm.
In patients with an ICH, 13 patients (19%) underwent endovascular therapy, consisting of occlusion of ruptured mycoticaneurysmineightpatientsandoftheaffected ves-sels in five patients with an ICH secondary to ischaemic strokeorundeterminedaetiology(Fig.2).Neurosurgerywas performedinanothertenpatients (15%),andconsistedof
718 E.Salaunetal.
Figure2. Managementandoutcomesinpatientswithintracranialcerebralhaemorrhage(ICH)andinfectiveendocarditis.
removalof the underlying cause by clipping the affected vessel/aneurysm in five patients; the other five patients underwentsurgerytoremovethebloodclotand/ortreatthe masseffect(bystandardcraniotomyinthreepatients,and byminimallyinvasivesurgicalevacuationintwopatients).
Impact
of
ICH
on
mortality
The median follow-up of the whole cohort was 15.9 [5.6—29.8] months; 237 (24.6%) patients died within a medianof2.3[0.7—10.4]monthsafterIEdiagnosis. Cumu-lativemortalityratesat1month,6monthsand1yearwere: 12%,23%and23%inthegroupwithanICH;10%,23%and26% inthegroupwithisolatedischaemicstroke;and7%,16%and 18%inthegroupwithnoneurologicalvascularcomplication, respectively.Mortalityfromanycauseduringfollow-upwas notsignificantlydifferentbetweenthethreegroups(Fig.3). The independent predictors of mortality during follow-up were:age(HR1.02,95%CI1.01—1.04;P=0.07); periannu-larlesion(HR2.5,95% CI1.6—3.7;P<0.001);andcardiac surgeryforIEduringthefirstyearafterIE(protectoreffect, HR0.3,95%CI0.17—0.43;P<0.001).
ICH was not associated with increased mortality (P not significant). However, when considering the mecha-nismof ICH,the 1-year mortalityrate was 14%, 15% and 45% in case of ruptured mycotic aneurysm, haemorrhage afterischaemic strokeandICHofundeterminedaetiology, respectively.Patientswithrupturedmycoticaneurysmhad a similar risk of death to those with haemorrhage after ischaemicstroke(HR0.7,95%CI0.14—2.89;P=0.6). How-ever, patientswithan ICH ofundeterminedaetiology had ahigherriskofdeaththanpatientswithrupturedmycotic aneurysm(HR4.4,95%CI 1.23—20.39;P=0.02)and those withhaemorrhage after ischaemic stroke (HR 3.1,95% CI 1.01—10.69; P=0.04) (Fig. 4). Finally, death immediately related toICH occurred in three patients with an ICH of undeterminedaetiology,versusonepatientinthegroupwith haemorrhageafterischaemicstrokeandonepatientinthe group withruptured mycotic aneurysm (P not significant) (Fig.2).
Figure 3. Time-to-event curves for death from any cause in patients with left-sided infective endocarditis complicated by intracranialcerebralhaemorrhageorisolatedischaemicstroke,or inpatientswithnoneurologicalvascularcomplication.
ICH
and
cardiac
surgery
Among the 60 patients withan ICHand an indication for cardiac surgery (Fig.2), 38 underwent cardiac surgery (a median34[20—78]daysaftertheICH).Inpatientswithan indication for cardiac surgery andwithout death immedi-atelyrelatedtoICH,conservativetreatmentwasassociated with a higher mortality rate during follow-up compared withcardiacsurgery(HR5.90,95%CI1.54—28.1;P=0.01) (Fig.5).Noneurologicaldeteriorationoccurredinpatients whounderwentcardiacsurgery;especiallyinthe17patients
Figure 4. Time-to-event curves for death from any cause in patientswithintracranialcerebralhaemorrhage(ICH), according tothemechanismofbleeding.
Figure 5. Time-to-event curves for death from any cause in patientswithintracranialcerebralhaemorrhage,accordingto con-servativetreatmentorcardiacsurgerywhenindicated.
whounderwentcardiacsurgeryduringthefirstmonthafter theICH(amedian20[15—25]daysaftertheICH).
Discussion
Inthislargecohortofpatientswithleft-sidedIE,totalICH showed no significant impact on mortality during follow-up. However, different mechanisms of ICH may affect the clinical course differently. Patients with an ICH of undetermined aetiology had a significant excess of mor-talitycomparedwiththosewithobviousrupturedmycotic aneurysm or haemorrhage after ischaemic stroke. Five variables were associated with the occurrence of ICH: platelet count<150×109/L; severe valve regurgitation; cerebralischaemicembolism;othersymptomaticsystemic embolism;andpresenceofmycoticaneurysm.Weobserved thatcardiacsurgery, whenindicated, wasassociated with abetterprognosisthanconservativetreatmentinpatients withanICH,andnoneurologicaldeteriorationoccurredin patientswhounderwentcardiacsurgery.
Population
characteristics
and
predictors
of
ICH
The incidence of cerebral complications in left-sided IE is high [4,7,16]. Embolic aetiology is the most frequent cause [5], but ICH complicates 5—7% of cases of IE [17]. Asinprevious studies[5,6,18,19],morestaphylococciand a higher incidence and size of vegetation are common trendsin neurological vascular complications. In our pop-ulation,patientswithanICHwereyoungerandhadahigher rateof intravenous drugabuse. Forthefirst time,a spe-cificrelationshipbetweenrupturedmycotic aneurysmand streptococcalinfectionwasdemonstrated.Recently, Mon-teleoneetal.describedsuchanassociationinasmallcohort ofpatients withmycotic aneurysm(fiveof sevenpatients hadviridans-groupstreptococcalinfection) [20]. Concern-ing the potential role of antithrombotic therapy, Garcia etal.showed ahigherriskof ICHin patientswith antico-agulanttherapy [7]. In our cohort,anticoagulant therapy and platelet inhibition therapy were not associated with an excess of ICH. Outwith the particular context of IE, thrombocytopeniaisalreadyassociatedwithhaemorrhagic transformation of cerebral infarction and other cerebral haemorrhage[21,22].Forthefirsttime,wehavefoundthat thrombocytopeniaisapredictorofICHinpatientswith left-sidedIE.
Various
mechanisms,
but
one
spectrum:
embolism,
‘‘micro’’
and
‘‘macro’’
It is not surprising that patients with an ICH had more mycoticaneurysms.However,asdescribedbyThunyetal.
[6], several patients with isolated ischaemic stroke also hadconcomitant unrupturedmycotic aneurysm.Moreover, amongthe27patientswithmycoticaneurysmandICH,this vascularlesionwasruptured,andwastheoriginoftheICH inonly 22 patients.This can beexplainedby the similar-ities between the mechanisms of cerebral embolism and bleedingduringIE. The mechanism of ischaemic stroke is amigrationof a‘‘macro’’ fragmentor the whole vegeta-tion in the cerebral arteries [17]. The mycotic aneurysm arisesfrom‘‘microemboli’’ tothevasavasorum, butalso secondarytobacterialescapefromaseptic‘‘macroemboli’’
720 E.Salaunetal. that has occluded a vessel [23]. As for ICH of
undeter-minedaetiology,itcanalsoresultfromsepticarteritis,with erosionof the vessel wallcaused by ‘‘microemboli’’,but withoutawell-delineatedaneurysm[17,18].Thisconfirms the hypothesis of a continuum of arterial injury, ranging from‘‘microemboli’’ withpyogenic necrosis and mycotic aneurysmto ‘‘macroemboli’’ in ischaemic stroke. This is concordantwiththeexcessofsystemicembolisminpatients withanICH[5],andpromotestheuseofaccurateimaging (computedtomography and magnetic resonance angiogra-phy—andcatheter-basedangiography,ifnecessary)forthe diagnosisofneurologicalevents.
Impact
of
ICH
and
its
mechanisms
on
clinical
course
Thepresenceofanacuteneurologicalcomplication[5,24], especiallyanICH[7],hasbeenassociatedwithanincreased riskofin-hospitalmortalityinpreviousstudies.Althoughthe 1-monthmortalityratewashigherinpatients withan ICH thaninpatientswithnoneurologicalvascularcomplications (12% versus 7%), the difference in mortality during fur-therfollow-up wasnotstatistically significant. This result isconcordantwiththestudybyWilbringetal.inacohortof 495patientsoperatedonforleft-sidedIE,whoalsoreported thata preoperative neurologicaleventwasa predictorof in-hospital mortality, but was not a predictor of mortal-ityduringfurtherfollow-up[24].Inalargecohortof2523 surgicalcases ofIE,Eishietal. foundnohighermortality rateinpatientswithcerebralcomplicationscomparedwith thosewithout, andin patientswithcerebralhaemorrhage comparedwiththosewithacerebralinfarction[25].
Theimpactshouldalsobeseeninrelationtothe mech-anismofICH.Undeterminedaetiologywasassociatedwith asignificant higherrate of deathcomparedwithICH sec-ondarytoobviousrupturedmycoticaneurysmorischaemic stroke.Inaddition,diagnosticandtherapeuticinterventions remaindifficulttoperforminthissubgroupofpatientswith necroticvessel[18].
ICH
and
cardiac
surgery
ICH is the most debated cerebral complication in terms of management of IE and the risk of neurological deteri-oration during cardiac surgery [17]. The recent European SocietyofCardiologyguidelinesrecommendthat,afterICH, surgeryshouldgenerallybepostponed for ≥1 month[1]. Aninterestingobservationinourstudywasthat conserva-tivetreatmentwhensurgerywasindicatedwasdramatically associatedwithanexcessofmortality,whilenoneurological deteriorationwas observed when surgerywas performed, especiallywhen performedearlyaftertheICHinselected patients. Yoshioka et al. previously reported a low risk of postoperativeneurological deteriorationresulting from exacerbationof ICH,evenin patients with IEwho under-wentsurgerywithin2weeksofICHonset[26].Theoptimal management remains the case-by-case approach by the endocarditisteamandneurologicalspecialists,adaptedto themechanismandseverityoftheICH,andthepossibility ofpostponingthecardiacsurgery.However,theprognostic
benefitofcardiacsurgeryshouldnotbesetasideinrelation tothemanagementofneurologicalcomplications.
Study
limitations
This was a single-centre study based on data collected prospectively, but witha retrospective analysis. Cerebral magnetic resonance imaging and catheter-based cerebral angiographywere notperformed systematically,and clas-sification of each type of ICH may be dependent on the accuracy of imaging. Cerebralcomputed tomography had alowerdiagnosticvaluethanmagneticresonanceimaging forthediagnosisofmycoticaneurysm,andcatheter-based cerebralangiographyremainsthegoldstandard[23]. More-over,mycotic aneurysmsaresometimesobliteratedbythe haemorrhagesthattheyproduce,sotheirarteriographicand evenpathologicaldemonstrationisnotalwayspossible[18]. Other neurological complications, such as abscess and meningitis, were not considered. The impact of cardiac surgery in patients with an ICH should be interpreted withcautioninthisobservationalstudy.Casesselectedfor surgerymayhavehiddenbiases.Thisstudywasperformed inareferencecentreforthetreatmentofIE,andmaynot reflectthemanagementandprognosisofICHinother cen-tres.
Conclusions
ICHis acommoncomplicationofleft-sidedIE.Theimpact onprognosisisdependentonthemechanism(haemorrhage ofundeterminedaetiology).Weobservedahighermortality rateinthegroupofpatientswhohadconservativetreatment whencardiacsurgerywasindicated,comparedwithinthose whounderwentcardiacsurgery.
Funding
None.
Disclosure
of
interest
Theauthorsdeclarethattheyhavenocompetinginterest.
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