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Pleasecitethisarticleinpressas:CalsavaraAJC,etal.Post-sepsiscognitiveimpairmentandassociatedriskfactors:Asystematicreview. AustCritCare(2017),http://dx.doi.org/10.1016/j.aucc.2017.06.001

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Contents lists available atScienceDirect

Australian

Critical

Care

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / a u c c

Review

Paper

Post-sepsis

cognitive

impairment

and

associated

risk

factors:

A

systematic

review

Allan

J.C.

Calsavara

a,b,_∗

Vandack

Nobre

b

Tatiana

Barichello

c,d

Antonio

L. Teixeira

b,d

a_School_of_Medicine,_Universidade_Federal_de_Ouro_Preto,_Ouro_Preto,_MG,_Brazil

b_Postgraduate_Program_in_Health_Sciences:_Infectology_and_Tropical_Medicine,_School_of_Medicine,_Universidade_Federal_de_Minas_Gerais,_Belo_Horizonte,

MG,Brazil

c_Universidade_do_Extremo_Sul_Catarinense,_Criciúma,_SC,_Brazil

d_{Translational}_Psychiatry_Program,_Department_of_Psychiatry_and_Behavioral_Sciences,_Medical_School,_The_University_of_Texas_Health_Science_Center_at

Houston,Houston,TX,USA

a

r

t

i

c

l

e

i

n

f

o

r

m

a

t

i

o

n

Articlehistory: Received13July2016

Receivedinrevisedform10May2017 Accepted 4 June 2017

Keywords: Cognition

Neuropsychologicaltests Sepsis

Sepsis-associated encephalopathy

a

b

s

t

r

a

c

t

Introduction:Post-sepsiscognitiveimpairmentisoneofthemajorsequelaeobservedinsurvivorsof

sepsis.Thiscognitiveimpairmentcanbeglobalormayaffectspecificdomains.Abetterunderstanding ofthesedeficitsandassociatedriskfactorscouldinfluencethecareofpatientswithsepsis.

Objective:Toperformasystematicreviewtoinvestigatethepresenceofcognitiveimpairmentandits

associatedriskfactorsamongpatientswhosurvivedsepsis.

Methods:ThesearchwasconductedinMEDLINE(1966toMarch2017)andEMBASE(1988toMarch2017).

Weincludedstudieswithindividualswhowere18yearsorolderwithpost-sepsiscognitiveimpairment.

Results:Weanalysed 577articles.Sixteenstudiesmettheinclusioncriteria.Morethan74,000,000

patientswereevaluatedintheselectedstudies.Significantvariationwasobservedinthedefinition ofsepsisandcognitiveimpairment.TwelvestudiesusedACCP/SCCMcriteriaforsepsis,while cogni-tiveimpairmentwasdefinedpertestused.Post-sepsiscognitiveimpairmentwasobservedin12.5to 21%ofsurvivorsofsepsis.Attention,cognitiveflexibility,processingspeed,associativelearning,visual perception,workmemory,verbalmemory,andsemanticmemorywerethespecificdomainsaffected. Depressivesymptoms,centralnervoussysteminfection,lengthofhospitalisationduetoinfection,and temporalproximitytothelastperiodofinfectionwereassociatedwithcognitiveimpairment.

Conclusion:Thestudiesareheterogeneous,andthereisurgentneedforacommonlanguage,

includ-ingdeﬁnitionsandneuropsychologicaltests,fortheinvestigationofpost-sepsiscognitiveimpairment. Despitethis,thereismountingevidencefortheclinicalrelevanceofpost-sepsiscognitiveimpairment.

Systematicreviewregistration:PROSPEROCRD42017054583(www.crd.york.ac.uk/PROSPERO).

1. Introduction

Sepsis isa systemic inﬂammatory response of thehostto a pathogenicmicroorganism.Sepsisisamajorhealthproblem,with datademonstratinganincreaseinincidencerate1–4_and_mortality incertaingroups.5_A_recent_global_study_showed_that_one_third_of patientswithsepsisdiebeforeleavingthehospital.6_Furthermore,

∗ Correspondingauthor.Permanentaddress:EscoladeMedicina,Universidade FederaldeOuroPreto,CampusMorrodoCruzeiro,OuroPreto,MGCEP35400-000, Brazil. Fax: +55 3135591001.

E-mailaddress:allancalsavara@medicina.ufop.br(A.J.C. Calsavara).

accordingtotheGlobalSepsisAlliance,atleast20%ofsurvivorsof sepsishavesomeformofsequelae,7_such_as_physical_or_cognitive impairment,mooddisorders,andpoorqualityoflife.8

Cognitive dysfunctionin patientswho survivesepsis can be characterized by new deficits (or exacerbations of preexisting mild deficits) in global cognitionor executive function.9 _Septic associatedencephalopathy(SAE)maybedefinedasacognitive dys-functionassociatedwithsepsis,withoutthepresenceofinfection, inthecentralnervoussystem(CNS)orstructuralbraininjuryafter excludingmetaboliccauses.SAEmaybeacute,subacute,orchronic. SAEmanifestedonlyduringthecourseofthediseasewith improve-mentafteritscontrolcanbeclassifiedasacute.10_Symptoms_that

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lastweekstomonthscanbeconsideredsubacute,whilesymptoms thatpersistoverayeararecategorizedaschronic.Subacuteand chronicdeﬁcitselicit substantialinterestas affectedindividuals mayrequirerehabilitationorhomecare.

Recently,therehasbeenaprogressiveincreaseofstudies evalu-atingcognitivechangesassociatedwithsepsis.Duetothepotential negativeimpactofsuchamendments,thereisgreatinterestfrom thescientiﬁccommunity,healthmanagers,andpatients’families onthesubject.Conductingasystematicreviewonthetopiccould summarizethestudiescarriedoutsofar,providethereaderwith thebestavailableevidence,andindicatethegapsthatstillexist.We conductedasystematicreviewtodeterminecognitiveimpairment anditsassociatedriskfactorsamongpatientswhosurvivedsepsis.

2. Methods

2.1. Typesofparticipants

Individuals who were 18 years or older with post-sepsis cognitive impairment were included in this study. Post-sepsis referstoanytime afterthediagnosisofsepsis. Sepsisis a life-threatening organ dysfunction caused by a dysregulated host responsetoinfection.11_Patients_with_human_{immunodeﬁciency} virus(HIV)infectionwereexcludedasimmunosuppressionanduse ofantiretroviraldrugscouldhaveinﬂuencedthecourseofsepsis andcognitionoftheseindividuals.12,13_Individuals_under₁₈_were alsoexcludedduetoneurodevelopmentalfeaturesthatmustbe takenintoconsiderationwhenstudyingchildrenandadolescents.

2.2. Studyselectioncriteria

Publicationsselectedforreviewwerecase-control,cohort,and clinicaltrialsstudieswritteninEnglish,Spanish,orPortuguese. Tobeincluded,studiesneededtohaveassessedtheassociation betweencognitivedysfunctionandsepsisand/oratleastone poten-tialriskfactorfortheoccurrenceofSAE.Therewasnorestriction regardingdateofpublicationandtimeoffollow-upofeachstudy. Studiesthatreportedsubjectivemeasuresofcognitiveoutcome, suchastheopinionsofthestaffregardingthecognitivestateof patientswereexcluded.Singlecasereports,unpublishedstudies, scientiﬁcmeetingabstracts,reviewstudies,commentsandletters totheeditorwereexcluded.

2.3. Outcomemeasures

Theprimaryoutcomemeasureforthisreviewwasthecognitive performanceofpost-sepsisindividualsasmeasuredbycognitive tests,scales,orbatteriessuchas,butnotlimitedto,theWechsler AdultIntelligenceScale,Boston NamingTest,WechslerMemory Scale,TrailMakingTest(TMT),InformantQuestionnaireon Cogni-tiveDeclineintheElderly,andMini-MentalStateExamination.

2.4. Searchstrategy

The search was conducted in the databases MEDLINE (1966–present)andEMBASE(1988–present)(seeAppendixA, Sup-plementarydata). ThesearchwasﬁrstconductedonMay10th, 2015,andwasupdatedonOctober17th,2015,andonMarch20th, 2017.Theinformationthatcouldnotbeextractedbyreadingthe articleswasrequestedbye-mailfromthecorrespondingauthor.

2.5. Studyselection

Twoinvestigatorsindependentlyreviewed thesearchresults toidentifyrelevantstudies.Disagreementswereresolvedby con-sensus,andifnecessaryathirdinvestigatorwasconsulted.First, studieswereexcludedbasedonthetitle;titlesthatwerenotrelated tothesubjectsepsisorcognitionwereexcluded.Inthenextstage,

studieswereevaluatedbyreadingtheabstracts;studiesthatdid notexaminecognitioninthecontextofsepsiswereexcluded.After readingtheabstracts,selectedstudieswerethoroughlyread;atthis laststage,studiesthatmetalltheeligibilitycriteriadescribedabove wereincludedinthereview.TheNewcastle-Ottawaformassignsa maximumoffourpointsforselection,twopointsforcomparability andthreepointsforexposureoroutcome.Inthecurrentstudy,we consideredastudyawardedsevenormorepointsasahigh-quality study.14

2.6. Dataextractionprocessandliteraturequalityassessment

WedevelopedadataextractiontablebasedontheCochrane template.15 _One _investigator _(A.J.C.C) _extracted _the _data _and _a second(A.L.T.)veriﬁedtheextracteddata.Inaddition,two inves-tigators(A.J.C.C.andA.L.T.)independentlycross-checkedtherisk ofbiasusingtheNewcastle-OttawaScaleforobservationalstudies. Anydisagreementbetweeninvestigatorswasresolvedby consen-sus,andifnecessaryathirdinvestigator(V.N.)wasconsulted.

2.7. Dataitems

Thefollowinginformationwastakenfromeachselectedstudy: (1)countrywherethestudywasconducted,(2)typeofstudy,(3) follow-upperiod,(4)samplesize,(5)characteristicsofthestudy population(meanage,sex,eligibilitycriteria,classificationsused, anddatacollectionlocation),(6)primaryandsecondaryoutcome, (7)cognitiveoutcomeevaluated,and(8)mainresultsofthestudy. Otherdatasuchas(1)thedefinitionofsepsisused,(2)definition ofcognitiveimpairmentused,(3)cognitiveimpairmentassociated withsepsisfound,and(4)riskfactorsassociatedwithpost-sepsis cognitiveimpairmentwerealsoextracted.

Ingeneral,studiesthathavenotincorporatedmultivariate tech-niquestoidentifyriskfactorshavelittlevalue.Forthepurposesof thissynthesis,onlyvariablesforwhichatleastonestudyreported eitherariskratio(RR)orodds ratio(OR)(regardlessof statisti-calsigniﬁcancereported)orastatisticallysigniﬁcantassociation (regardlessoftheOR/RRreported)wereconsidered.

3. Results

3.1. Descriptionofstudies

ThesearchresultsarepresentedinFig.1.Fivehundred seventy-sevenpotentiallyrelevantarticleswereidentiﬁed.Afterexclusion of57duplicatestudies,byjudgingthetitleandabstract,490articles wereexcluded,astheydidnotmeettheinclusioncriteria.Thirty articleswereretainedforin-depthinspection.Sixteenarticleswere retainedfor thissystematic review.Therewas100% agreement betweenreviewersintheselectionofarticlesthatmettheinclusion criteriaofthestudy.

3.2. Characteristicsofincludedstudies

Thesixteenselectedstudiescomprisedsixprospectivecohort withcontrolgroup,8,16–20_six_prospective_cohort_without_control group,21–26_three_{retrospective}_cohort_without_control_group,27–29 andonecase-controlstudy.30_No_clinical_trials_met_the_inclusion criteria.

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Please cite this article in press as: Calsavara AJC, et al. Post-sepsis cognitive impairment and associated risk factors: A systematic review. Aust Crit Care (2017), http://dx.doi.org/10.1016/j.aucc.2017.06.001

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AUCC-376; No. of Pages 11 A.J.C. Calsavara et al. / Australian Critical Care xxx (2017) xxx–xxx 3 Table1

Characteristics of studies included.

Reference (country)

Typeofstudy Follow-upperiod Samplesize Studypopulation Measurements

Götzetal.20

(Germany)

Prospectivecohort study with control group

Severesepsisorseptic shock: until 10–15 months after ICU discharge Cirrhosis: not followed up Healthy:until12months afterhospitaldischarge

Severesepsisorseptic Shock: 36

Cirrhosis: 24 Healthy: 23

Patientssurvivedseveresepsisorsepticshock,patientswithcirrhosisand healthy individuals discharged from a University Hospital.

Mean age: severe sepsis or septic shock: 58.9 ±2, cirrhosis: 55.4 ± 6,

healthy: 58 ± 2.

Theauthorsdidnotindicatethemeaneducationallevel.

Visualevokedresponsesusinga set of familiar vs. unfamiliar pictures measured with magnetoencephalography.

Pierrakos et al.26

(Belgium)

Prospective cohort study

1 year 28 patients with sepsis, 14 withcognitivedecline(CD) and14withoutCD

Consecutive patients with sepsis discharged from the ICU between January 2013andJanuary2014.

Meanage:CD:69±15,No-CD:65±16.

Didnotprovidedataoneducationallevel.

Pulsatility index and cerebral blood ﬂowindexmeasurebytranscranial DopplerinpatientswithCDand without-CD.

Götzetal.19

(Germany)

Prospectivecohort studywithcontrol group

Severesepsisorseptic shock:until10–15months afterICUdischarge Healthy:until12months afterhospitaldischarge

Severesepsisorseptic Shock:36

Healthy:30

Patientsthathadsurvivedseveresepsisorsepticshock,andhealthy individualsdischargedfromaUniversityHospital.

Meanage:severesepsisorsepticshock:58.9±2,healthy:50.9±3.

Theauthorsdidnotindicatethemeaneducationallevel.

Peakrestingactivity(frequency andpower)measuredby magnetoencephalography.

Azabouetal.25

(France)

Prospectivecohort study

Untilday28of

hospitalisationoruntilICU discharge

110patientswithsepsis included(45septicshock, 37severesepsisand28 sepsis)

PatientsadmittedtotheICUforsepsisbetweenNovember2011andApril 2014.

Meanagewas63.8years.

The authors did not indicate the mean educational level.

ICUmortalityandrelationship betweenEEGabnormalitiesand occurrenceofdelirium.

Benrosetal.29

(Denmark)

Retrospectivecohort Frombirthtoage19 161,696individuals CognitiveabilitydatafromDanishConscriptionRegistryofmenover18, borninDenmarkbetween1976and1994.

Mean age of patients was 19.4 years. Mean educational level was not provided.

Cognitiveperformanceusingthe DanishConscriptionRegistry database.

Pierrakosetal.24

(Belgium)

4months 38patients Patientsdiagnosedwithsepsiswithin24-hfromonset.

Mean age of patients with pulsatility index (PI) <1.29 was 62 years and PI >1.3 was 72 years.

Data on educational level was not provided.

PulsatilityIndexmeasuredwith transcranial Doppler in patients with and without SAE.

Lahariya et al.18

(India)

Prospective cohort study with control group

Until occurrence of delirium or ICU discharge

309 patients (81 with delirium and 228 without delirium)

Patients admitted to the cardiology ICU between May and June 2010 who had delirium during hospitalisation.

Mean age in the group with delirium was 61.69 and 77.01 in the group withoutdelirium.

Meaneducationallevelinthegroupwithdeliriumwas7.87yearsandin thegroupwithoutdelirium9.7years.

Incidence and prevalence of delirium in the population studied, risk factors, and mortality associatedwithdelirium.

Merlietal.16_(Italy) _Prospective_cohort

studywithcontrol group

Threemonthsafter dischargeforcirrhotic patientsandcontrolswith cognitivechangesduring the infectious condition

231(150patientswith cirrhosisand81patients withoutliverdisease)

PatientswithcirrhosishospitalizedbetweenOctober2008andJune2009 (meanage63.4years)andpatientswithoutcirrhosis,betweenJanuary 2010andDecember2010(meanage58years).Eachgroupwasdivided into3subgroups:withoutsepsisorinfection,withinfectionwithout systemic inﬂammatory response syndrome, and with sepsis. The mean educational level was not indicated by the authors.

Measurementofpsychometric parameters.

Semmleretal.17

(Germany)

Prospectivecohort studyintwocenters withcontrolgroup

From6to24monthsafter ICUdischarge

44patients(25with sepsis/severesepsisand19 withoutsepsis)

PatientsadmittedtotheICUbetweenJanuary2004andAugust2006with sepsisorseveresepsis.

Meanageofpatientswithsepsis:55.64yearsandnon-septic:52.15years. Dataoneducationallevelwerenotprovided.

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Please

cite

this

article

in

press

as:

Calsavara

AJC,

et

al.

Post-sepsis

cognitive

impairment

and

associated

risk

factors:

A

systematic

review.

Aust

Crit

Care

(2017),

AR

TICLE IN PRESS

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AUCC-376;

No.

of

Pages

11

4

A.J.C.

Calsavara

et

al.

/

Australian

Critical

Care

xxx

(2017)

xxx–xxx

Table 1 (Continued)

Reference (country)

Typeofstudy Follow-upperiod Samplesize Studypopulation Measurements

Iwashynaetal.27

(USA)

Retrospectivecohort studywithoutcontrol group

From1996to2008 34,782,442and39,337,348 Medicarebeneﬁciariesin 1996and2008, respectively

Beneﬁciariesofhealthinsuranceolderthan65yearsthatgenerated servicepaymenttaxbetween1996and2008.

Theaverageageinthestudiedpopulationin1996was73years,with59% women and in 2008 the average age was 73 years, with 57% women. Data on educational level were not provided.

Threeyears’survivalrateafter admissionforseveresepsis, evaluationoffunctionalstatusby combined score for activities of daily living (ADL) and instrumental activities of daily living (IADL), and degreeofcognitiveimpairment.

Guerra et al.28

(USA)

Retrospective cohort study without control group

3 years (2006– 2008) 25,368 individuals Cohort of 5% of all Medicare beneﬁciaries older than 65 years, who were admitted to the ICU and survived to hospital discharge, with no prior cognitiveimpairmentorhistoryofcardiacsurgery.

Meanage76.6years.

Dataoneducationallevelwerenotprovided.

Dementia presence.

Davydowetal.21

(USA)

Until2006ordeath, whicheveroccurredﬁrst

447individuals ParticipantsintheHealthandRetirementStudy(HRS)withatleastone evaluationbetween1998and2004withoutcognitiveimpairment,and whowereregisteredforseveresepsishospitalizationintheMedicare databasebetween1998and2005,andhadatleastoneevaluationfor depression after sepsis.

Mean age: 76.1 years.

38.5% of patients to complete high school, 34.8% with incomplete higher educationand26.7%withcollegeeducation.

Classiﬁcationintomildor moderatetoseverecognitive impairment.

Arinzon et al.23

(Israel)

Prospective cohort study

To full or partial recovery from delirium, unchanged delirium,ordeath

92 patients Patients aged 65 or more admitted to a geriatric medical center between January 2000 and December 2002 for a week or longer, who had delirium. Averageageof79.86years

Dataoneducationallevelwerenotprovided.

Risk factors associated with delirium, delirium duration, and mortalityrate.

Iwashyna et al.8

(USA)

Prospective cohort studywithcontrol group

Until 2006 or death, whicheveroccurredﬁrst

5033 patients (516 survivingrespondentswith sepsisand4517surviving respondentswithout sepsis)

Data from patients aged over 50 years from the Medicare database with baselinecognitiveassessmentbetween1998–2004andsubsequent hospitalizationduetoseveresepsis;orpatientswithoutsepsisbetween 1998–2003thatsurvivedtoconductonefollow-upvisit.

Patientssurvivingsepsis:meanage76.9years.

19% of patients with severe cognitive impairment, 20% with mild to moderate and 30% without cognitive impairment had completed higher education.

Measurement of functional status (combinedscoreofADLsandIADL) anddegreeofcognitive

impairment.

Lazosky et al.30

(Canada)

Case-control study 1–4 years 23 (8 with sepsis and 15 with acute myocardial infarction – AMI), On retiredsubgroup evaluated:5septicand8 AMI

Patients with sepsis or acute myocardial infarction (AMI) (matched by age) from one to four years prior to selection and who answered the

administered questionnaire.

Averageage:49.6yearsinthesepticgroupand58.5yearsintheAMI group.

Themeaneducationallevelinthesepticgroupwas12.6yearsand13 yearsintheAMIgroup.

Health status of survivors of sepsis and number of new

neuropsychological issues (problemsolving,language, speech,mathskills,nonverbal skills,concentrationand awareness,memory,motorand coordination, sensory, physical and behavioural).

Regazzonietal.22

(Argentina)

1year 116patients Patientsfrombothgendersover69yearsadmittedbetweenSeptember 2002 and August 2003.

Mean age: 80.81 years.

Data on educational level were not provided.

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Bibliographic search: MEDLINE (n= 317) EMBASE (n= 260)

Excluded by duplicity (n= 57)

Arcles evaluated based on tle Combinaon of search results (n= 520)

Excluded (n=358)

Not related to sepsis OR cognion (n= 241) Individuals under 18 (n= 82)

Studies in animals (n= 11)

Comment, leer, editorial or meeng abstract (n= 2) Paents with HIV (n= 17)

Studies with LPS injecon (n=5) Included (n= 162)

Arcles evaluated based on abstract

Excluded (n=132)

Not related to sepsis AND cognion (n=74) Individuals under 18 (n=1)

Studies sll in progress (n= 2) Review (n= 34)

Case Report (n=3) Studies in animals (n=2) Paents with HIV (n= 1) Arcle not available (n=2)

Comment, leer, editorial or meeng abstract (n= 8) Arcles in languages other than English, Portuguese or Spanish (n=4)

Studies with LPS injecon (n=1) Included (n=30)

Arcles evaluated bythe full–text reading

Excluded (n=14)

Not related to sepsis AND cognion (n= 10) Subjecve cognive assessment (n=4) Included (n=16)

Fig.1. Searching results.

Whileconsideringformaleducationdata,onlyfourstudies indi-catedtheaveragelevelofeducationofpatients.8,18,21,30_Two_studies indicatedtheaverageschoolingoftheirpatientsas7.918_and_12.6 years.30 _The _others _referred _to_the _patients’ _education_level _by categorizingthemintohavinggraduatedornotfromSecondary educationandhavinggraduatedornotfromHighereducation8,21 (Table1).

Thequalityofthestudieswasassessedwiththe Newcastle-OttawaScoreandtheresultsarepresentedinTables2and3.Four studieswereclassiﬁedashighquality.8,17,21,29_The_mean_value_for thesixteenstudiesassessedwas5.3indicatingalowoverallquality.

3.3. Definitionofsepsis,severesepsis,andsepticshock

There was variation in the deﬁnition of sepsis, severe sep-sis,and septicshock among the selected studies.The majority of studies used as reference the criteria of the American

College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM).8,16,17,19–22,24,25,27,28,30_Others_used_the_{International} StatisticalClassiﬁcationofDiseases(ICD-8and/orICD-10).29,31

NoreferencewasmadetothedeﬁnitionofsepsisbyLahariya etal.18_,_Arinzon_et_al.23_and_Pierrakos_et_al.26

3.4. Definitionofcognitiveimpairmentpatients

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Table2

Newcastle-Ottawaqualityassessmentscaleforcohortstudiesincludedinthisreview.

Firstauthor Year Selectiona

Compara-bilityb

Outcomea _Overall

qualityscorec

Representa-tivenessof theexposed cohort

Selectionof the non-exposed cohort

Ascertainment ofexposure

Outcomeof interestnot presentat start of study

Assessment ofoutcome

Adequacyof durationof follow-up

Adequacyof complete-nessof follow-up

Götz20 ₂₀₁₇ _⋆ ₀ _⋆ ₀ _⋆⋆ _⋆ _⋆ ₀ ₆

Götz19 ₂₀₁₆ _⋆ ₀ _⋆ ₀ _⋆⋆ _⋆ _⋆ ₀ ₆

Pierrakos26 ₂₀₁₆ _⋆ _⋆ _⋆ ₀ _⋆ _⋆ ₀ ₀ ₅

Azabou25 ₂₀₁₅ _⋆ ₀ _⋆ ₀ ₀ _⋆ _⋆ ₀ ₄

Benros29 ₂₀₁₅ _⋆ _⋆ _⋆ ₀ _⋆ _⋆ _⋆ _⋆ ₇

Pierrakos24 ₂₀₁₄ _⋆ ₀ _⋆ ₀ _⋆ _⋆ ₀ ₀ ₄

Lahariya18 ₂₀₁₄ _⋆ _⋆ ₀ ₀ ₀ _⋆ ₀ _⋆ ₄

Merli16 ₂₀₁₃ _⋆ _⋆ _⋆ ₀ ₀ _⋆ _⋆ ₀ ₅

Semmler17 ₂₀₁₃ _⋆ _⋆ _⋆ ₀ _⋆⋆ _⋆ _⋆ _⋆ ₈

Iwashyna27 ₂₀₁₂ _⋆ ₀ _⋆ ₀ ₀ _⋆ ₀ ₀ ₃

Guerra28 ₂₀₁₂ _⋆ ₀ _⋆ _⋆ ₀ _⋆ _⋆ _⋆ ₆

Davydow21 ₂₀₁₂ _⋆ ₀ _⋆ _⋆ _⋆⋆ _⋆ _⋆ ₀ ₇

Arinzon23 ₂₀₁₁ _⋆ ₀ ₀ ₀ ₀ _⋆ ₀ ₀ ₂

Iwashyna8 ₂₀₁₀ _⋆ _⋆ _⋆ ₀ _⋆⋆ _⋆ _⋆ ₀ ₇

Regazzoni22 ₂₀₀₈ _⋆ ₀ _⋆ _⋆ _⋆ _⋆ _⋆ ₀ ₆

Mean 5.3

a_A_study_can_be_awarded_a_maximum_of_one_star_for_each_numbered_item_within_the_Selection_and_Outcome_categories. b _A_maximum_of_two_stars_can_be_given_for_{Comparability.}

c _Maximum_of₉_points.

Table3

Newcastle-Ottawaqualityassessmentscaleforcasecontrolstudiesincludedinthisreview.

Firstauthor Year Selectiona

Compara-bilityb

Exposurea _Overall

quality scorec

Isthecase deﬁnition adequate?

Representa-tivenessof the cases

Selectionof controls

Deﬁnitionof controls

Ascertainment ofexposure

Samemethod of ascertain-ment for cases and controls

Non-response rate

Lazosky30 ₂₀₁₀ _⋆ ₀ ₀ _⋆ _⋆ _⋆ _⋆ ₀ ₅

a_A_study_can_be_awarded_a_maximum_of_one_star_for_each_numbered_item_within_the_Selection_and_Exposure_categories. b _A_maximum_of_two_stars_can_be_given_for_{Comparability.}

c _Maximum_of₉_points.

AdiagnosisofcognitiveimpairmentwasmadebyMerlietal.16 withtheTrailMakingTestA,BoraDigit-SymbolTestZ-score33 greaterthantwostandarddeviationsfromthemeanofahealthy Italianpopulation,adjustedforageandeducation.34

Semmleretal.17_calculated_a_composite_Z-score_for_cognition usingtheNeuroCogFX,Trail-makingTestsAand BandMultiple ChoiceWordTest-B.Thescoreconsideredtheresultsofapplied cognitivetestsaftersepsis(NeuroCogFXandTrail-makingTestsA andB),andMultipleChoiceWordTest-BGermanvocabularytest, whichaimistoquantifythepatients’premorbidcognitivestatus. AZ-scorebetween₋1.5and₋2.0wasconsidereddenotingmild cognitiveimpairment.

Otherstrategiestodeﬁnecognitiveimpairmentweretheuse ofthe“ConfusionAssessmentMethodintheIntensiveCareUnit” (CAM-ICU),18,23–26_an_MMSE_score_less_than_24,26_Glasgow_Coma Score<8despiteresolutionofsepsisafterexclusionofany under-liningpathologythatcouldexplainthis state,26 _abnormal_Clock DrawingTest,26_or_searching_{predetermined}_{International} Classiﬁ-cationofDiseases(ICD-9-CM)codes35_in_databases.28

Althoughmoststudies didnotstate this, alltools described in this section toassess cognitive impairment had been previ-ouslyvalidated.36–45 _The _{neurocognitive} _outcomes _reported _by eachauthorwereassessedandarepresentedinTable5.

Somestudiesdidnotexplaintheircategorizationmethodsor cutoffpointsusedtodeﬁnecognitiveimpairment.19,20,22,29,30

3.5. Post-sepsisglobalcognitiveimpairment

Analysingtheselected studiesinthis review, wefoundthat Iwashynaetal.27_showed_moderate _to_severe_cognitive impair-mentafter3yearsin16.7%(95%CI:12.3,21.0%)ofpatientswho survivedsepsis.Thesameauthorhadfoundanoddsratio(OR)of 3.34formoderatetoseverecognitiveimpairmentaftersepsisina studypublishedtwoyearsearlier.8_In_a_study_by_Davydow_et_al.,21 cognitiveimpairmentrangedfrom14to20%,with60%of individu-alsbeingclassiﬁedasmoderatelytoseverelyimpaired.Itwasalso shownbyBenrosetal.29_that_hospital_contact_due_to_any_infectious conditionworsenedglobalcognitiveperformance,assessedbya DanishIntelligenceTestby76%(95%conﬁdenceinterval,61–92%), sepsiswasassociatedwithameanscoreof1.60-unitslower cogni-tiveability.

3.6. Post-sepsisspecificcognitivedomainsimpairment

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Table4

Deﬁnitions,changes,andriskfactorsassociatedwithpost-sepsiscognitiveimpairment.

Reference Deﬁnitionofcognitiveimpairment Cognitiveimpairmentassociatedwithsepsis found

Riskfactorsassociatedwithcognitiveimpairment

Götzetal.20 _The_cutoff_points_for_the_DemTect_and_Clock_Drawing_Test

(CDT)werenotspeciﬁed.

Notassessed ImpairedresponsetoperiodicvisualstimulationwasassociatedwithDemTect andCDTsumscoresinpatientswithsepsis.Non-affectingfactors:APACHEII, CRP,lengthofstayintheICU,andmonthsafterICUdischarge.

Pierrakosetal.26 _Persistent_coma_(Glasgow_Coma_Score_<8),_despite

resolutionofsepsisandafterexclusionofanyunderlying pathologythatcouldexplainthisstate,positiveCAM-ICU ondischarge,MMSE<24,abnormalClockDrawingTest.

Notassessed Univariateanalysis:deliriumandpulsatilityindexonﬁrstdaywereassociated withcognitivedecline(CD).Multivariateanalysis:onlydeliriumwas associatedwithCD.

Götzetal.19 _The_cutoff_points_for_DemTect_and_CDT_were_not_speciﬁed. _Not_assessed _Within_sepsis_group_peak_resting_frequency_increase_with_time_after_ICU

dischargeandwithDemTectandCDTsumscoreanddecreasewithage. Non-affectingfactorsAPACHEII,CRP,andlengthofstayintheICU.

Azabouetal.25 _Delirium_was_deﬁned_by_the_CAM-ICU_and_coma_was

deﬁnedinnon-sedatedpatientsbyGCS≤8andinsedated

patientsbyRASS≤4.

Notassessed DeliriuminsepticpatientswasassociatedwithSAPS-IIscore,septicshock,and deltafrequencydominant,Synekgrade≥3andYounggrade≥1inearlyEEG.

Benrosetal.29 _No_cut_off_point_was_given_for_the_test_applied. _Infection_was_associated_with_poor_overall

cognitiveperformanceassessedbytheBørge Prienstest.(OR:−1.76,95%CI:−1.92,−1.61).

Centralnervoussysteminfectionwasassociatedwithgreaterdeclinein cognitiveability.Otherassociatedfactors:numberofvisitstohospitaldueto infection,temporalproximitytothelastinfection,lengthofstay,andfamily historyofinfection.Non-affectingfactors:age,historyofpsychiatricdisorders or substance abuse, history of cancer, and normal weight at birth.

Pierrakosetal.24 _CAM-ICU_for_delirium. _Not_assessed _No_association_was_found_between_age_or_APACHE_II_with_positive_CAM-ICU.

Lahariyaetal.18 _CAM-ICU_for_delirium._IQCODE_score_greater_than

3.31–3.38asanindicationofsuspecteddementia.

Sepsiswasassociatedwiththedevelopmentof deliriumasdiagnosedwiththeCAM-ICU.

PatientswithcognitiveimpairmentmeasuredbytheIQCODEshowed increasedriskofdevelopingdelirium.Otherriskfactorsassociatedwiththe developmentofdelirium:hypokalemia,SOFAscores,using>3drugs, cardiogenicshock,historyofcoronaryarterybypassgrafting,ejectionfraction <30, use of opioids, age >65 years, diabetes, a history of seizures, congestive heart failure, percutaneous transluminal coronary angioplasty, atrial ﬁbrillation, current depression, use of benzodiazepines, warfarin, ranitidine, steroids,orNSAIDs,polypharmacy,increasedcreatinine,anemia,

hypoglycemia,APACHEII,andtheComorbidityIndexofCharlson.

Merli et al.16 _Z-score_>2_SD_of_healthy_Italian_population,_adjusted_for

ageandeducation.

Patients with cirrhosis and sepsis showed changesintheTrail-MakingTestsAandBand Digit-SymbolTest.Patientswithoutcirrhosis withsepsishadpoorerperformanceonthe TrackTestsandDigitSymbolthanthegroup without infection (39% of septic individuals had subclinical cognitive impairment damage, remaining unchanged).

In the cirrhotic subgroup, the MELD score, albumin, and creatinine were not foundtobeindependentriskfactorsforcognitiveimpairment.Sepsiswasthe onlyriskfactorfound.Riskfactorswerenotevaluatedinthecontrolgroup.

Semmler et al.17 _Z-score_compared_to_the_historical_norm._Composite_score

for cognition through the simple average of the

NeuroCogFX and Trail Making Test A and B Z-scores, minus theestimatedpremorbidverbalabilitybytheMultiple ChoicesWordTestZ-score.

Patients with sepsis post-ICU hospitalization had poor performance on the Digit Span test, 2-Back Test, alertness, GoNoGo, verbal memory,andphoneticverbalﬂuency.Patients withoutsepsispost-ICUhadlowperformance intheDigitSpantest,2-Backtest,interference, andphoneticverbalﬂuency.

Cognitive deﬁcits were not inﬂuenced by the length of stay in the ICU, time after ICU discharge, number of days on mechanical ventilation, APACHE II, and SOFA scores.

Iwashyna et al.27 _The_cutoff_point_for_m-TICS_was_not_speciﬁed._The_cutoff

point for IQCODE was 4.59–5.00, denoting moderate to severecognitiveimpairment,accordingtotheauthors.

Hospitalisation for severe sepsis was associated with a 3.34-fold increased risk of developingmoderatetoseverecognitive impairment.

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as:

Calsavara

AJC,

et

al.

Post-sepsis

cognitive

impairment

and

associated

risk

factors:

A

systematic

review.

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Crit

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(2017),

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TICLE IN PRESS

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Table4(Continued)

Reference Deﬁnitionofcognitiveimpairment Cognitiveimpairmentassociatedwithsepsis found

Riskfactorsassociatedwithcognitiveimpairment

Guerra et al.28 _ICD-9-CM_codes:_{290.0–290.4,}_294.0,_294.1,_294.8,_331.0,

331.1,331.2,331.7,and797.Xrecordedfrom fee-for-serviceclaimsinthesubsequentthreeyearsof follow-up.

Neuropsychological tests were not applied. Risk factors associated with post-ICU dementia: a critical illness with infection,especiallyifseveresepsis,acuteneurologicdysfunctionduringICU stay,anduseofrenalreplacementtherapy(increasedriskonly6monthsafter discharge),patientswithhospitalisationduetoclinicalcausesandpatients withprevioushospitalization.Notassociated:mechanicalventilation,organ dysfunction, length of stay in the ICU and total hospital stay.

Davydowetal.21 _{Categorisation}_of_cognitive_function_as_mild,_and_moderate

tosevereusingthem-TICS.

17%ofpatientswithseveresepsisshowed globalcognitiveimpairmentassessedbythe TICS; most had moderate to severe deﬁcits.

Pre-sepsisdepressivesymptomswereariskfactorforpost-sepsiscognitive impairment.

Arinzonetal.23 _CAM-ICU_for_diagnosis_of_delirium_and_Delirium_Rating

Scale(ascorehigherthan10–12pointsindicatedpatients with delirium).

Theincreaseinthedurationofdeliriumwas associatedwiththeoccurrenceofsepsis.

Sepsiswasassociatedwiththedurationofdeliriumandincreasedmortalityin patientswithdelirium.

Iwashynaetal.8 _The_cutoff_points_for_the_m-TICS_and_IQCODE_were_not

speciﬁed.

AnORof3.34,95%CI:1.53–7.25wasfoundfor moderatetoseverecognitiveimpairment after-sepsis. No moderate to severe cognitive impairment was found after hospitalisation for reasons other than sepsis.

Notassessed

Lazoskyetal.30 _Number_of_new_problems_identiﬁed_in_the_‘Adult

Neuropsychological History form’.

Therewerenocognitivechangesinthe evaluated samples.

None

Regazzonietal.22 _There_was_no_{categorisation}_or_cutoff_point_deﬁnition_for

theMMSE.

Globalcognitivestatusevaluatedwiththe MMSEdidnotpredictin-hospitalmortality after sepsis. In a univariate analysis, the MMSE predicted mortality after 1 year; however, in a COXmodelthiseffectwasnotmaintained.

Notassessed(cognitionascovariate)

Table5

Reportedneurocognitiveoutcomesbyauthor.

Reference EEG MEG CAM-ICU GCS MMSE m-TICS IQCODE TMT Digit-Symbol Test

Multiple Choice Word Test-B

Neuro-CogFxa

Auditory Verbal Learning Test

Rey Complex Figure Test

Børge Prien’s Prøveb

Delirium Rating Scale

ICD Adult Neuropsy-chological History form

DemTectc _Clock

Drawing Test

Götz et al.20 √ √ √

Pierrakos et al.26 √ √ √ √ √

Götz et al.19 √ √ √

Azabouetal.25 √ √ √

Benrosetal.29 √

Pierrakosetal.24 √

Lahariyaetal.18 √ √

Merli et al.16 √ √ √

Semmler et al.17 √ √ √ √ √

Iwashyna et al.27 √ √

Guerraetal.28 √

Davydowetal.21 √

Arinzonetal.23 √ √ √

Iwashynaetal.8 √ √

Lazosky et al.30 √

Regazzoni et al.22 √ √ √

a_NeuroCogFx_(Digit_Span,_2-back-test,_alertness,_go-no-go,_{interference,}_verbal_memory,_ﬁgural_memory,_phonetic_verbal_ﬂuency).

b _A_Danish_intelligence_test.

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processingspeed,visualperception,andworkingmemoryassessed bytheDigitSymbolTestwasalsolowerinpatientswithsepsis.16

Semmleretal.17_found_long_term_mild_cognitive_impairments_in attention,verbalﬂuency,executivefunction,andverbalmemoryin survivorsofsepsiswhencomparedtotheirpreviouslyestimated intelligencelevel.

A long-term visual processing impairment in patients with sepsispost-infectionwasobservedbyGötzetal.with magnetoen-cephalographicmeasurements.20

3.7. Associationsbetweensepsisandcognition

Moststudiesassessedtheassociationbetweencognitive impair-mentandsepsis(Table4).8,16,17,21,27,29,30_Some_studies_showed_that sepsisisariskfactorforworseningcognitiveperformanceafterICU discharge28_or _demonstrated_an_association_between_sepsis _and delirium,aclinicalsyndromethatencompassesseveralcognitive changes.18,23–25

Thepresenceofpre-sepsisdepressivesymptomswas consid-eredariskfactorforpost-sepsiscognitiveimpairment.21_Infection in the CNS, number of hospital visits due to infection, length of hospitalization due to infection, family history of infection, and temporal proximitytothe latestepisodeof infectionwere identiﬁedasriskfactorsforcognitiveimpairmentobservedafter infectiousconditions.29_Critical_illness_in_the_presence_of_infection, especiallyseveresepsis,wasidentiﬁedasoneoftheriskfactorsfor thesubsequentdiagnosisofdementiawithinthreeyearsofhospital discharge.28

Sepsis was a risk factor for the development18 _and _longer duration23_of_delirium._Moreover,_Arinzon_et_al.23_showed_that_a diagnosisof sepsisincreasedthemortalityrateinpatientswith delirium.

Severalriskfactorswereevaluatedintheincludedstudies,but manydidnotaffecttheoutcomeevaluated(Table4).Forinstance, itwasfoundthatcognitivedeﬁcitsrelatedtosepsiswerenot inﬂu-encedbythelengthofstayintheICU,ICUdischargetime,number ofdaysonmechanicalventilation,APACHEII,andSOFAscores.17 Thepatient’s age,familyhistory of psychiatricillness,and sub-stanceabusesimilarlydidnotaffectcognitiveperformanceafter infection.29

3.8. Workuponsepsisassociatedencephalopathy

Thediagnosisofsepsis-associated cognitivedysfunctionwas additionallyevaluatedbytheselectedstudies.17,24,25

AnassociationbetweenSAEandelectroencephalography(EEG) parameterswasobserved;astheoccurrenceofcognitive impair-mentinthedaysafterEEGrecordingwasassociatedwithprevious EEGfindings,suchasdeltafrequencydominantEEG,absenceof EEGreactivity,Synekgrade_≥3(anEEGclassificationwith prog-nostic valuefor comatose patientthat range from0 to5), and Younggrade_≥1(anECGclassificationforsepticencephalopathy thatrangesfrom0to4).25

ThediagnosisofSAEwiththepulsatilityindex,anindicatorof cerebrovascularresistance,measuredbytranscranialDopplerwas evaluated.Apulsatilityindexgreaterthan1.3at24-hpostsepsis diagnosiscorrelatedwithSAE(OR:5.66,95%conﬁdenceinterval: 1.1–29.11).24_Although_no_correlation_between_cognitive dysfunc-tionaftersepsisandpulsatilityindexwasfound,whenmultivariate analysiswasperformedinanotherstudybythesameauthor.26

Magnetoencephalographic (MEG) techniques were used to studythe long-termbrain electrophysiologychanges after sep-sis.CombiningMEGdatawithneuropsychologicaltests,suggested abnormalthalamocorticaldynamics19_and_a_disruption_in_neural networking,especiallycomplexnetworking,inpatientswith long-termpost-sepsis.20

Computerized volumetric techniques of magnetic resonance imagesshowedsigniﬁcantdifferencesinleftandtotal hippocam-palvolumesbetweenpatientswithsepsisand healthycontrols. Thehippocampalvolumeinpatientswithoutsepsisadmittedin theICUwasbetweenthatofpatientswithsepsisandhealthy con-trols.Acorrelationanalysisbetweencognitiveperformanceand hippocampalvolumewasnotperformed.17

4. Discussion

Tothebestofourknowledge,thisistheﬁrstsystematicreview toidentifyand synthesize thebestavailable evidenceon post-sepsis cognitiveimpairment. Theanalysed studies showedthat sepsiscanworsencognitiveperformanceintheshort,medium,and longterms.Theavailablestudiesdidnotproviderobustevidenceto determinetheriskfactorsthatmodulatetheassociationbetween sepsisandcognitiveimpairment.Regardingthegreat heterogene-ityinthedeﬁnitionofcognitiveimpairmentandtheuseofseveral cognitivetests,thecomparisonamongstudieswasimpaired.

Theuseofbatteriesandtestsevaluatingglobalcognitive func-tionwasmostfrequentlyemployed.Thisstrategyisinlinewith the theory that sepsis causes wide brain function alterations. The cognitive test batteries Telephone Interview for Cognitive Status(m-TICS),8,21,27_NeuroCogFx,17_MMSE,16,22,23,26_Clock Draw-ingTest,26_Adult_{Neuropsychological}_History_form,30_{BØrge-Priens} test,29_IQCODE,8,18,27_and_DemTect19,20_were_used_for_global cogni-tiveassessment.SometestsastheSymbol-Digittest,16_Trail_Making TestAandB,16,17_Rey_Complex_Figure_Test17_provided_more_specific informationaboutcognitivedomains.Onlyonestudy,by Semm-ler et al.,17 _showed_changes _in _certain_cognitive_domains, _such asattention,verbalfluency,executivefunction,andverbal mem-ory.Semmler etal.17 _proposed_that_an _asymmetric_distribution ofneurotransmittersinthehumanbrainwouldleadtoincreased vulnerabilityofthelefthemispheretoinflammatoryinsults.

Inacohortstudyperformedwithpatientswithcriticalillness byPandharipandeetal.9_the_cognitive_sequelae_ranged_between₂₄ to40%dependingonthetimingofcognitiveevaluation.Thisstudy usedtheRepeatableBatteryfortheAssessmentof Neuropsycho-logicalStatus(RBANS)thatwasnotusedinthestudiesincludedin thisreview.Asshown,ouranalysissuggeststhatequallyimportant totimingisthechoiceoftestingmeans,forcognitiveevaluation. Tocomparetheincidenceandprevalenceofcognitivedysfunction betweenpatientswithsepsisandpatientswithotherdiseasesit isnecessarytoachieveaconsensusontheappropriatedtesttobe used,beforehand.

Mostoftheevaluatedstudieswereconductedwithpatientsover theageof60years.8,18,21–28_Despite_sepsis_increased_incidence_and mortalityintheelderlycomparedtoyoungerpatients,46_it_is impor-tanttoevaluatetheimpactof sepsisonyoungindividualswho arestillpartoftheworkforce.Whereascognitivereservehasbeen identiﬁedasaprotectivefactorforcognitiveimpairmentinseveral studies,47–49_the_possibility_of_young_patients_exhibiting_less_post sepsisdeﬁcitscouldbeexplainedatleastinpartbytheirhigher cognitivereserve.

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developed,and,fortheﬁrsttime,therecommendedprimaryICD-9 andICD-10codesandaframeworkforimplementationfor cod-ingandresearchinanattempttofacilitateresearchandincrease accuracyofcoding.11

Thecriteriausedtoclassifyindividualsaspresentingwith cog-nitiveimpairmentalsodifferedamongstudies,evenwhenusing thesame cognitivetests.The choiceof cut-offsdepends onthe authors’choicebetweenhigherspecificityandhighersensitivity. Whenthegoalis toidentifyindividuals withcognitive impair-ment,testswithgreatersensitivity arepreferred,butwhenthe objectiveistodeterminetheexactnatureofthepatient’sdeficit, specifictestsarepreferable.Amethodtocomparetheperformance ofteststhatmeasuredifferentcognitiveabilitiesisthrough stan-dardizedscores,suchastheZ-score. Onlytwostudiesreported cognitivedatathroughstandardizedscores,16,17 _their_scarce_use maybeduetolackofgoodqualitystandardizeddataorevenlack ofsufficientdatainthestudiedpopulation,especiallyamongethnic minorities.50

Wedidnotlocatestudieswithadesignthatrobustlyassessed theriskfactors associatedwiththedevelopmentof post-sepsis cognitiveimpairment.Factorssuchaspre-sepsisdepressive symp-toms,infectionintheCNS,lengthofstay,andtemporalproximity tothelatestepisodeofinfectionseemtobeinvolvedincognitive impairment associated withsepsis. Studieswith patients post-ICUhospitalizationhavesuggestedtheinﬂuenceofsomefactors oncognition,suchassedativesandanalgesics,51_{antipsychotics,}52 antibiotics,53_glycemic_control,54_{corticosteroids,}55_and_cognitive reserve.56_The_inﬂuence_of_these_factors_must_be_better_investigated infuturestudies.

InastudypublishedbyLarsonetal.,56_cognitive_reserve associ-atedwiththemagnitudeofcognitiveimpairmentinpatientswith acuterespiratorydistresssyndrome.Inthissystematicreview,the issuewasnotexplored.InthestudyofSemmleretal.,17_although theauthor estimatedcognitivereservewithneuropsychological testing, a correlational analysis between cognitive reserve and post-sepsiscognitiveperformance wasnot performed.Lahariya etal.18_used_the_IQCODE_score_to_evaluate_the_{pre-morbidity} cog-nitivereserveinasample,ﬁndingthatpatientswithlowcognitive reserve(i.e. IQCODE>3.3)had an odds ratioof 10.81for delir-ium.

Ourstudyhadanumberoflimitations.Thesearchconducted didnotinvolveacomprehensivelistofsearchterms.The hetero-geneityofthetestsandcutoffpointsusedinthestudiesanalyzed didnotprovidethenecessarydataforperformingameta-analysis. Therewasnoconsensusamongtheauthorsregardingthebesttests toevaluatepost-sepsiscognitivechanges.Thelimitednumberof availablestudies,themarkeddifferencesamongthepopulations studied,andthediversityofoutcomescomplicatedthe general-isabilityof thestudyﬁndings. Thequalityof thestudiesvaried widely.

Ourreviewrevealedseveralgapsintheaccumulatedknowledge onpost-sepsiscognitiveimpairment.We observedthatthere is needforstudiestoassessthemostappropriateneuropsychological testsandtocompareglobalcognitiveassessmentteststodomain speciﬁctests(e.g.attentionandmemory).Furthermore,the assess-mentofpost-sepsiscognitiveimpairmentinsubgroupsofyoung andelderlypatientscouldprovidecluesabouttheroleofcognitive reserveonpost-sepsiscognitiveimpairment.Studieswith cogni-tiveimpairmentbiomarkers(e.g.neurotrophic,neurodegenerative, inﬂammatory,andoxidativestressbiomarkers)andneuroimaging havealsobeenperceivedasmissingorsparse.

Inconclusion,thissystematicreviewdemonstratesthatthere isincreasingevidencefor theexistenceofpost-sepsiscognitive impairment.Duetolackofconsistentﬁndings,thesamecannot bestatedaboutitsassociatedriskfactors.

Funding

Thisresearchdidnotreceiveanyspeciﬁcgrantfromfunding agenciesofthepublic,commercial,ornot-for-proﬁtsectors.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound, intheonlineversion,athttp://dx.doi.org/10.1016/j.aucc.2017.06. 001.

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