Identifying clinical and acute psychological risk factors for PTSD after critical … Wade... · ening illness, a known traumatic stressor that may precede PTSD.4 They undergo treatments

944 MINERVAANESTESIOLOGICA August2013

R E V I E W

Anno: 2013Mese: AugustVolume: 79No: 8Rivista: MINERVA ANESTESIOLOGICACod Rivista: Minerva Anestesiol

Lavoro: titolo breve: IDENTIFYING CLINICAL AND ACUTE PSYCHOLOGICAL RISK FAC-TORS FOR PTSD AFTER CRITICAL CAREprimo autore: WADEpagine: 944-63

Ascriticalcaremedicineadvancesandmorepatientssurvive,attentionhasturnedtothe

qualityoftheirsurvival.Itisnowrecognisedthatphysical and psychological recovery of criticalcarepatientsmaybepoor.1Sincethelate1990stherehasbeenparticularconcernabouttheprev-alenceofpost-traumaticstressdisorder(PTSD)afterintensivecare.2,3PTSDisan“anxiety disor-der that often follows exposure to an extreme stressor that causes injury, threatens life or physical integ-rity”.4Theperson’simmediateresponseinvolvesintensefear,helplessnessorhorror.Thedisorder

is characterised by three clusters of symptoms:re-experiencing, avoidance and hyper-arousal,thatpersistformorethanamonthandcausedis-tressorimpairedfunctioning.Aswellasmentalsuffering,patientswithPTSDaremorelikelytoendureworsephysicalhealth,qualityoflifeandmortality.5

CriticallyillpatientsareathighriskofPTSDforanumberofreasons.Theysufferlife-threat-ening illness, a known traumatic stressor thatmayprecedePTSD.4Theyundergo treatmentsandproceduresthatmaysavelives,butcanalso

IdentifyingclinicalandacutepsychologicalriskfactorsforPTSDaftercriticalcare:asystematicreview

D.WADE1,R.HARDY2,D.HOWELL1,M.MYTHEN3

1TheCriticalCareUnit,UniversityCollegeLondonHospitalsNHSFoundationTrust(UCLH),London,UK;2MRCUnitforLifelongHealthandAgeing,DivisionofPopulationHealth,UniversityCollegeLondon(UCL),UK;3NationalInstituteforHealthResearchBiomedicalResearchCentre,UCL,London,UK

A B S T R A C TBackground.Patientsmaysufferextremepsychologicalreactionsinintensivecareunits(ICU),andpost-traumaticstressdisorder(PTSD)afterleavinghospital.Previoussystematicreviewsofstudiesupto2007foundthatthetrueprevalenceofandconsistentriskfactorsforPTSDafterICUwerenotestablished,duetomethodologicalshortcom-ingsofstudies.Thereforeweaimedtoconductasystematicreviewofobservationalstudiesofpost-ICUPTSDfrom2008-2012,andtocomparethemto1997-2007studies,withregardtoquality,prevalenceestimatesandriskfactors.Methods.Weusedapre-specifiedprotocol,andsystematic,explicitmethodstoidentify,selectandcriticallyap-praisestudies.StudiesingeneralICUsettingswithmixed-diagnosispatients(N.>30)wereincluded.Riskofbiaswasassessed,withlower-riskstudiesgivengreaterweight.Noquantitativesynthesiswaspossibleduetoheterogeneity,thereforerangesofestimatesandfrequenciesofriskfactorswereexamined.Results.Thereviewincluded26papers,13from1997-2007and13from2008-2012.Thereweremorehighqual-itystudiesinthelatterperiod.Therangeofprevalenceestimatesfromhigh-qualitystudieswassimilar;8%to27%(1997-2007)and9%to27%(2008-2012).Clinicalriskfactorsconsistentlyidentifiedoverthetwoperiodswereuseofbenzodiazepines,durationofsedationandmechanicalventilation.PsychologicalriskfactorsincludestressandfearexperiencedacutelyinICU,andfrighteningmemoriesoftheadmission.Conclusion.Thequalityandnumberofpost-ICUPTSDstudieshas increasedover time,andwecanbemoreconfidentintheaccumulatedfindings.Evidencefrombothperiodssuggeststhatupto27%ofICUsurvivorssufferfromPTSD.Thereisalsoincreasingevidencethatuseofbenzodiazepinesanddurationofsedation,alongwithfear,stressanddeliriumintheICUarelikelyriskfactorsforsubsequentPTSD.(Minerva Anestesiol 2013;79:944-63)Key words: Criticalcare-Stressdisorders,traumatic-Riskfactors.

COPYRIGHT© 2013 EDIZIONI MINERVA MEDICA

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IDENTIFYINGCLINICALANDACUTEPSYCHOLOGICALRISKFACTORSFORPTSDAFTERCRITICALCARE WADE

Vol.79-No.8 MINERVAANESTESIOLOGICA 945

beinvasiveanddisturbing,includingintubation,ventilation,catheterisationandhaemofiltration.Patients describe the cumulative stress of pain,thirst,hunger,sleepdeprivation,noiseandlight,inabilitytocommunicate,fearofdyingandlossof control in the intensive care unit (ICU) asoverwhelming.6Furthermore,manypatientsre-ceiveacocktailofpsychoactivedrugsincludingbenzodiazepines, inotropes,anti-psychoticsandcorticosteroids thathavepoorlyunderstoodef-fectsonthebrainandemotionsofacriticallyillpatient.Consequently,patientsmayexperienceanxiety, panic, low mood and delirious symp-tomsincludinghallucinationsandterrifyingde-lusionsduringtheirstayinanICU.7,8

ThreesystematicreviewsofPTSDaftercriti-calcareappraisedstudiesupto2007.Prevalenceofpost-ICUPTSDwasreportedasbeingintherangeof0-64%9,10orashavingamedianpointprevalenceof22%.11Tworeviews9,11identifiedpotentialriskfactorsforPTSDincludingdelu-sional memories of ICU, use of sedation, psy-chiatrichistory,youngerageandfemalegender.Howeverfewriskfactorswereconsistentlyiden-tifiedacrossstudies.

PTSDremainsatopicofinterestinthecriti-calcareliterature,with63articlespublishedin2011-2012,andmorecontinuingtoappearaf-terthisreviewwascompleted.One2012studyfoundthat39%ofpatientsscreenedpositiveforPTSDat12months.12Allwereacuterespiratorydistresssyndrome(ARDS)patients,asub-groupofICUpatientswhomayhavehigherthanaver-age PTSD rates. As well as PTSD in patients,therehasbeenincreasingrecentresearchinterestinPTSDamongrelativesandICUstaff.Symp-tomsofPTSDhavebeendetectedinupto33%offamilymembers13and24%ofICUnurses.14

Since2007therehavealsobeenasmallnumberoftrialsofICUinterventionstopreventPTSD.PatientdiarieswerepioneeredinScandinaviatofill in memory gaps and help patients come toterms with their experience.15 A pan-EuropeanRCT found that patients receiving a diary in-terventionhadasignificantlylowerincidenceofPTSDthanacontrolgroup(5%vs.13%).16An-otherstudyinvestigatedtheeffectofearlysupportbypsychologists in critical care.17The interven-tiongrouphadasignificantlylowerriskofPTSD

(21%vs.57%)at12months,butthestudyhadahistoricalcontrolratherthanRCTdesign.

Asyet thereare too few interventionstudiesto warrant a systematic review. However moreinformationisneededaboutimportant,consist-ent risk factors forPTSDso thathigh-riskpa-tients canbemonitoredand followed-up.Fur-thermore,itisrecognizedthatforpsychologicalinterventions to be successful, they should bedesignedtotargetmodifiableriskfactors.18

Allthreesystematicreviewsto2007concludedthatthestudiestheyreviewedhaddeficienciesindesign, methodology and reporting, as well asconflicting results, that limited the conclusionsthatcouldbedrawnabouteitherprevalenceof,orriskfactorsforpost-ICUPTSD.Forexample,Griffiths et al.10 suggested that more rigorous,largerstudiesfocusingongeneralICUpatients,rather than sub-groups, should be carried out.Theyalsorecommendedcarryingoutlongitudi-nalstudieswithassessmentsovermultipletime-points.Otherrecommendationsfromthereviewswere that studies should examine the effects ofpre-ICU psychopathology, sedation strategies,andin-ICUdeliriumonsubsequentPTSD.9,11

In order to assess whether the evidence onpost-ICUPTSDhadimprovedinthesuggestedwayssincepublicationofthethreesystematicre-views,weaimedtocarryoutasystematicreviewofobservationalstudiespublishedfrom2008to2012.Second,weaimedtocomparethenewerstudies,withthestudiespublishedupto2007,intermsofsizeandmethodologicalquality.Third,unliketheprevioussystematicreviews,whichin-cludedstudiesofsub-groupsandverysmallstud-ies,weaimedtoincludeonlystudiesofgeneralmixed-diagnosis ICU patients and studies withatleast30patients.Finally,ourreviewaimedtodetectnewevidenceaboutclinicalandacutepsy-chologicalriskfactorsfor,aswellasprevalenceofPTSD,since2007.Wewereawarethatincreasedrecognition of psychological stress in the ICU,aswellasimprovementsinICUtherapiesmighthavereducedtheprevalenceofPTSDandalteredriskfactorssince2007.Thequalityofmorerecentstudiesmightbehigherandestimatesmoreaccu-rate.Ouroverallaimwastocompare2008-2012studieswith1997-2007 studies,with regard toPTSDprevalence,riskfactorsandquality.


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WADE IDENTIFYINGCLINICALANDACUTEPSYCHOLOGICALRISKFACTORSFORPTSDAFTERCRITICALCARE


Typesofoutcomemeasures

Studieswereselectediftheyusedreliable,val-idated questionnaires or interviews for PTSD.Studies that used single item measures or un-validatedbespokequestionnairesforPTSDwereexcluded.

Exclusioncriteria:

Studieswereexcludedif:1. theirsamplesizewassmallerthan30par-

ticipants;2. theywerepublishedonlyasconferencepa-

persorabstracts;3. fulltextwasnotavailableinEnglish;4. theywerepublishedpre-1997;5. they were set in neo-natal or pediatric

ICUs.

Search strategy

StudieswereidentifiedonJune28,2012fromthefollowingdatabases:

— Medline(OvidSP1946-present)— Embase(OvidSP,1947-present)— PsycINFO(OvidSP,1806-present)— CinahlPlus(EBSCOHost,1937-present)

TheinitialsearchwascarriedoutonMedlineusing the strategy outlined inTable I. Similarsearcheswerecarriedoutontheotherthreeda-tabases. On September 12, 2012 the searcheswerere-run.TherewereninenewreferencesintheMedlinesearchandnoneintheothers.Onlyonenewstudy20waseligibleandhasbeenaddedtothereview.AfurtherstudywasidentifiedinOctober2012.6

Assessment of risk of bias (quality assessment)

It should be noted that the PRISMA state-ment19 recommends that reviewers shouldusethe phrase “assessment of risk of bias”, ratherthan “quality assessment”. The terms are usedinterchangeably in this review. We based ourqualityassessmentonmethodologychecklists21forstudydesignsincludingcohortstudies.Qual-itycriteriaforrobustnessofoutcomedatawereused.ForexampleastudythatusedtheImpact

Review questions

1. What percentage of survivors of generalintensive care treatment suffers frompost-ICUPTSDinthemonthsafterintensivecare?

2. Whataretheclinicalandacutepsychologi-calriskfactorsforpost-ICUPTSD?

3. Hasthequalityofevidenceregardingthefirsttwoquestionsimprovedbetweenthe1997-2007periodandthe2008-2012period?

Materials and methods

The systematic review was conducted ac-cordingtoPRISMArecommendations;19Itwasbasedonapre-specifiedprotocol,andusedsys-tematicandexplicitmethods to identify, selectandcriticallyappraisestudies.Theriskofbiasinstudies was assessed and higher quality studiesweregivengreaterweight.

Criteria for study selection

Three criteriawereused to select studies forinclusioninthesystematicreview.

Typeofstudies

Prospective cohort studies, retrospective co-hort studies, and cross-sectional surveys wereincluded in the review. Data from the controlgroupsinRCTsofinterventionstoreducepsy-chologicalmorbidityinICUpatientswerealsoconsideredeligible.

Typesofparticipants

Thestudypopulationswereadult,mixed-di-agnosisICUpatientswhoreceivedintensivecare>24hoursingeneral,medicalorsurgicalICUs.StudiesofICUsub-groupssuchaspatientswithARDSorpancreatitiswerenot eligible as theyarenot representative of general ICUpatients.HoweverstudiesofICUpatientsreceivingme-chanical ventilation were included. Patientswho receive mechanical ventilation have manydifferentunderlying conditions so they are ap-proximately representative of the general ICUpopulation.


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assigned to each study based on poor (0), ad-equate(1)andgood(2)ratingsforeachoffourselectedparameters.Thesewere:Representative-nessofthesample(basedoncriteria1and2);Powerofthestudy/samplesize(criterion3),Ro-bustness of outcome assessment (criteria 4-7),andAppropriatenessof statistical analysisused(criteria8-12).Forsamplesize,studieswith30-59participantswereratedpoor/small;studiesof60-150adequate/mediumandstudieswith150or more participants, or that included a pow-er calculation, were good/large. The first threeparameters applied to prevalence estimation;thefourthtoriskfactor-outcomeanalysis.The

of Events-Revised Scale 22 scored more highlythanoneusingtheImpactofEventsScale23asthe latter includes only two of three symptomclustersnecessaryforadiagnosisofPTSD.4An-other criterion – controlling for confoundingfactors– is important inevaluatingthequalityofobservationalstudies.Afurthercriterionwasuseofappropriatestatisticalanalysis.ThequalitycriteriaareshowninTableII.

Using the recommended system,21 the ma-jority of 1997-2007 studies were assessed asmediumquality,withfewpoororhighqualitystudies. To provide better differentiation be-tweenstudies(TableII),numericalscoreswere

TableI.—�Medline search strategy.

1. MEDLINESearchterms1946-Present

#1 Expcriticalcare/#2 (criticalcareorintensivecareorcriticalillnessorICUorITU).ti,ab.#3 1or2#4 (neonatalorpediatricorbabyorbabiesorinfantorPICUorchild).ti,ab.#5 3not4#6 Limit5to(englishlanguageandyr=“1997-Current”and(clinicaltrialorcomparativestudyorjournalarticleor

multicenterstudyorrandomizedcontrolledtrial))#7 Stressdisorders,traumatic/orstressdisorders,post-traumatic/orstressdisorders,traumatic,acute/#8 (PTSDor“posttraumaticstressdisorder”or“post-traumaticstressdisorder”or“posttraumaticstressdisorder”or

“posttraumaticstress”or“post-traumaticstress”or“posttraumaticstress”).ti,ab.#9 7or8#10 6and9

TableII.—�Quality criteria used in assessment of risk of bias.

Thesample1. Acleardefinitionofsourcepopulationandcleareligibilitycriteriaforselectionofsubjectsareused,toensurethesampleis

representative.2. Comparisonismadebetweenfullparticipantsandthoselosttofollowup.3. Apowercalculationisreported.Ifnot,samplesizeissmall,mediumorlarge.Outcome4. Thelikelihoodthatsomesubjectsmighthavetheoutcomeatbaselineisaccountedfor.5. Theoutcomesareclearlydefined.6. Evidenceisusedtodemonstratethatmeasureofoutcomeisvalidandreliable.7. Follow-upislongenoughforoutcometooccur.Riskfactors-outcomeanalysis8. Thestudyaddressesanappropriateandclearlyfocusedquestion.9. Anymeasuresofriskfactorsarereliable.10.Mainpotentialconfoundersareidentifiedandtakenintoaccountindesignandanalysis.11.Confidenceintervalshavebeenprovided.12.Appropriatestatisticalanalyseshavebeencarriedout.OverallassessmentHowwellwasstudydonea)tominimiseriskofbiasandb)toestablishacausalrelationshipbetweenexposureandeffect.?

AdaptedfromScottishIntercollegiateGuidelinesNetworkchecklistforcohortstudies


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Synthesis of extracted evidence

Itwasnotpossibletocarryoutameta-analysisofPTSDoutcomesduetoheterogeneityofbothresultsandmethodsofstudies,aswellaslackofconsistencyinreportingresultsbetweenstudies.Thereforeweexaminedrangesofestimatesandidentifiedreasons forvariation inresults,usingquality(riskofbias)criteria.Synthesisofinfor-mation about risk factors was difficult as fewstudiesreportedresultsinacomprehensiveman-ner,particularlyinthepre-2007period.There-forewesummarisedthenumberof timesasso-ciationswerefoundornotfoundacrossstudies.

Results

A total of 503 papers were retrieved in thesearchoutlinedabove(Figure1).

rangeofscoreswas0-6outof6forprevalence,and0-2outof2fortheriskfactoranalysis.Thisnumerical system was then used to assess the2008-2012studies.

Inter-rater reliability

DWcarriedoutqualityassessmentof1997-2007papersandERof2008-2012papers.Threeotherratersassessedthreepaperseachtoassessinter-rater reliability. There was 100% agree-mentbetweenallratersinthequalityassessmentofthe9papers.

Data extraction strategy

Data were systematically extracted for eachstudyusingadataextractionformbyDWandER.

Figure1.—�Flowchartofreferenceretrieval,exclusionsandinclusions.

Title screening

Abstract screening

Full paper review

Total papers retrieved N.=503

Total without duplicates N.=339

Eligible on title N.=177

Eligible for full paper review N.=49

128 excluded: (Inclusion criteria not met e.g. editorials, reviews, sub-groups of ICU patients)

164 excluded: (Inclusion criteria not met e.g. neonatal/paediatric settings; reviews; PTSD in staff not patients; qualitative methods; end of life patients; physiological or mechanistic studies)

62 duplicates automatically removed; 102 manually removed

Synthesis N.=26

2008-2012 N.=13

1997-2007 N.=13

23 excluded: (Inclusion criteria not met: e.g. abstracts only, editorials, studies of ICU sub-groups, unvalidated PTSD questionnaires used)


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Exclusion

In the earlier period, seven studies excludedpatients forpsychiatricorneurological reasons,butfrom2008almostall(11)studiesexcludedthosepatients(TableIII).

Patient characteristics

Age

Therewaslittledifferencebetweentherangeofmedian/meanageswithinthetwogroupsofstudies; (42-68 years) from 1997 and (48-69years)from2008.

Sex

Therewere largerpercentagesofmen in theearlierstudies(43-76%)comparedwiththelaterstudies(25-68%).

Illnessseverity

MeanormedianApacheIIscoresofcohortsappeared to be similar; (12-25) in 1997-2007studies,versus(13-28)in2008-2012.

LengthofstayinICU

There was a shorter range of average stays(2.5-21days)inthe2008-2012studies,com-paredtoarangeof5-52daysintheearlierpe-riod(TableIII).

Quality assessment of PTSD studies

Accordingtoourqualitycriteria,morerecentstudies(2008-2012)havealowerriskofbiasinestimatingprevalenceofPTSD,thanolderones(1997-2007).Ninenewstudieshadaprevalenceratingoffourormore(outof6),whereasonlyfourold studies scored fourormore,andnineold studies had a high risk of bias (Table IV).Rangesofresponserates(percentageofrecruitedpatients assessed at follow-up) were similar inboth groups of studies (24% to 88% vs. 35%to91%).

Afterremovingduplicates,339titlesandthen177 abstracts were screened, and the full-textversions of 49 potentially eligible papers werereviewed.Of these, 26paperswere eligible forinclusioninthereview;13from1997-2007and13from2008-2012.

Characteristics of included PTSD studies

Therewere13cohortsofpatientsin13stud-ies inthe1997-2007periodand12cohorts in13studiesfrom2008-2012,astwopapers39,40coveredthesamecohortofpatientsatdifferenttime-points. There were 2703 unique patientsfollowedupinthe26studies,andtheseparatetotals(1119in1997-2007,and1584in2008-2012)showthatmorepatientswereassessedinthe latterperiod.Therewereninemedium-size(N.=60-150) or large (N.>150) studies in the2008 group, compared to seven in the earliergroup.

Bothgroupsof studies tookplace inhomo-geneous settings (general, medical or surgicalICUswithpatientsofmixeddiagnoses).Thereweremoremulti-sitestudiespublishedin2008-2012(5vs.3).From1997-2007themajorityofstudies (7) took place in the UK, with five inmainlandEuropeandoneintheUS.Amongthe2008-12studies,sevenwereinEurope,threeintheUK,twoinUSandoneinAustralia.Mostoftheearlierstudieswereprospectivecohortstud-ies (8),withoneRCTand fourotherdesigns.Bythelaterperiod,thereweremoreRCTs(4),fewer prospective cohorts (5) and four others.FurtherdetailscanbeseeninTableIII.

Inclusion/exclusion criteria of included studies

Inclusion

From1997-2007,most studies (11)had in-clusioncriteriaforlengthofstay(LoS,rangingfrom>1 to>6days) ormechanical ventilation(MV, ranging from >1 to >3 days). But six ofthe2008-2102studieshadnoinclusioncriteriaforLoSorMV.IntheothersevenlaterstudiesinclusioncriteriawereLoS(>2to>4days)andMV(>12to>36hours).


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TableIII.—�Characteristics of post-ICU PTSD studies.

Firstauthorandyear NassessedforPTSDsymptoms TypeofICU,country,No.sites Inclusioncriteriainstudy

Exclusioncriteriainstudy(psychological,

neurological)Designofstudy Age(years) Sex(%men) LengthofstayinICU

(days) ApacheIIscore(orsimilar)

1997-2007studiesCapuzzo(2005)24 63 GeneralICU,Italy LoS>3days Psychiatrichistory Prospectivecohort 69(median) 60% 5(median) 14(median)Cuthbertson(2004)25 78 GeneralICU,UK Prospectivecohort 58(median)

18-87(range)56% 6(median)

1-51(range)18(median)4-38(range)

Girard(2007)26 43 MedicalICU,US MV Neurologicdisease,mentaldisability

Prospectivecohort 52(median)39-65(IQR)

47% 10(median)5-13(IQR)

25(median)20-31(IQR)

Griffiths(2006)27 108 GeneralICU,UK LoS>3days,seenatfollowupclinic

Cross-sectional 57(mean)17-85(range)

66% 12(median)2-101(range)

Jones(2001)28 30 GeneralICU,UK LoS>24hMV Psychoticillness,Suicideattempt,head

injury

Case-seriesprospectivecohort

57(median)17-82(range)



Jones(2003)29 44incontrolgroupat6m

GeneralICUs,UK,3sites LoS>48hMV Psychoticillness,neurosurgery

RCT(controlgroup) 59(mean)16(SD)

57% 13(mean)18(SD)

16(mean)5(SD)

Jones(2007)30 238 GeneralICUs,Europe,5sites ICU>48hMV Psychosis,suicide

Prospectivecohort 61(median)17-86(range)



Nickel(2004)31 41 MedicalICU,Germany LoS>24h Cross-sectional 47(mean) 68% 12(mean,maximumscoreobtained)11(SD)

Rattray(2005)32 60at6m80at12m GeneralICU,UK, LoS>24h,emergencies ProspectivecohortRichter(2006)33 37 SurgicalICU,Germany LoS>30days Retrospectivecohort 42(mean)

17(SD)76% 52(mean)

20(SD)20(mean)

7(SD)Samuelson(2007)7 226 GeneralICUs,Sweden,2sites MV>24h Psychosis,suicide,head

injury,mentaldisabilityProspectivecohort 63(mean)

13(SD)52% 6(mean)

6(SD)18(median)

12(IQR)Scragg(2001)34 80 GeneralICU, UK Headinjury,other

injuryRetrospectivecohort 57(median)

19-90(range)47%

Sukantarat(2007)35 51at3m45at9m

GeneralICU,UK LoS>72h Prospectivecohort 57(mean)14(SD)

43% 17(mean)17(SD)

15(mean)6(SD)

2008-2012studiesGarrouste-Orgeas(2012)20 36(twocontrol

groups,pre-andpost-)

Medical-surgicalICU,France LoS≥4days Dementia Non-randomisedtrial:Pre-andpost-controls

Pre-68(mean)14(SD)post-62(mean)16(SD)

52%54%

Pre21(mean)16(SD)Post13(mean)18(SD)

SAPSIIscorePre44(mean)14(SD)Post40(mean)15(SD)

Granja(2008)36 299 GeneralICU,Portugal9sites LoS>48h Cross-sectionalcohort 59(mean)44-71(IQR) 58% 8(median)5-13(IQR) SAPSIIscore37(median)30-46(IQR)

Jackson(2010)37 32at3m25at12m(controlgroup)

MedicalICU,USA MV>12h Neurologicdeficits,neurosurgery

NestedsubstudyofRCT(controlgroup)

68(median)IQR(56-76) 45% 28(median)21-33(IQR)

Jones(2010)16 160(controlgroup) Europe,6sites LoS>72h,MV>24h PsychoticillnessorPTSD.confusion

RCT(controlgroup) 59(mean),16(SD) 62% 13(mean)12(SD) 19(mean)7(SD)

Myhren(2009)38 255 GeneralICU,Norway LoS>24h Psychiatrichistory,severeheadinjury

Cross-sectionalcohort 48(mean)16(SD) 63% 12(mean)10-14(CI) SAPSII37(mean)35-39(CI)

Myhren(2010)39 194 GeneralICU,Norway LoS>24h Asabove Prospectivecohort 48(mean)16(SD) 63% 12(mean)10-14(CI) SAPSII37(mean)35-39(CI)Rattray(2010)40 42 UK,6sites Headinjury,

neurosurgeryProspectivecohort 60(mean)17-84(range) 63.% 7(median)0-63

(range)19(mean)6-34(range)

Treggiari(2009)41 129 MedicalandsurgicalICUs,Switzerland

MV>12h Neurologicconditions,mentaldisability

RCT(bothgroups,lightvdeepsedation)

72.3%

Twigg(2008)42 44 GeneralICUs,UK,2sites Dementia,confusion,overdose

Caseseriescohort 56(median) 45% 11(median)7(median)2sites

16(median)14(median)2sites

VanderSchaaf(2009)43 238 MixedICU,Netherlands LoS>48h Cross-sectionalcohort 59(mean)17(SD) 66% 9(mean)10(SD) 15(mean)6(SD)Wade(2012)6 100 GeneralICU,UK Dementia,persistent

confusioninICUProspectivecohort 57(mean)17(SD) 52% 8(median)85(range) 22(median)7(range)

Wallen(2008)44 100 ICU,Australia Prospectivecohort 63(mean)19(SD) 68% 57h(median)62h(IQR)


Weinert(2008)45 149at2m80at6m Medical/surgicalICUs,US MV>36h Psychosis,cognitiveimpairment

Prospectivecohort 54(mean)45,63(IQR) 52%

ICU:IntensiveCareUnit;LoS:lengthofstay;MV=mechanicalventilation;h=hours;IQR:interquartilerange;RCT:randomisedcontrolledtrial;SD:standarddeviation;SAPS:SimplifiedAcutePhysiologyScore.Ifcellsareempty,datawerenotreportedinstudies.Somestudiesreportedchar-acteristicsofthesampleatbaseline;othersreportedcharacteristicsofthesampleatfollow-up.


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TableIII.—�Characteristics of post-ICU PTSD studies.

Firstauthorandyear NassessedforPTSDsymptoms TypeofICU,country,No.sites Inclusioncriteriainstudy

Exclusioncriteriainstudy(psychological,

neurological)Designofstudy Age(years) Sex(%men) LengthofstayinICU

(days) ApacheIIscore(orsimilar)

1997-2007studiesCapuzzo(2005)24 63 GeneralICU,Italy LoS>3days Psychiatrichistory Prospectivecohort 69(median) 60% 5(median) 14(median)Cuthbertson(2004)25 78 GeneralICU,UK Prospectivecohort 58(median)

18-87(range)56% 6(median)

1-51(range)18(median)4-38(range)

Girard(2007)26 43 MedicalICU,US MV Neurologicdisease,mentaldisability

Prospectivecohort 52(median)39-65(IQR)

47% 10(median)5-13(IQR)

25(median)20-31(IQR)

Griffiths(2006)27 108 GeneralICU,UK LoS>3days,seenatfollowupclinic

Cross-sectional 57(mean)17-85(range)


Jones(2001)28 30 GeneralICU,UK LoS>24hMV Psychoticillness,Suicideattempt,head

injury

Case-seriesprospectivecohort




Jones(2003)29 44incontrolgroupat6m

GeneralICUs,UK,3sites LoS>48hMV Psychoticillness,neurosurgery

RCT(controlgroup) 59(mean)16(SD)

57% 13(mean)18(SD)

16(mean)5(SD)

Jones(2007)30 238 GeneralICUs,Europe,5sites ICU>48hMV Psychosis,suicide

Prospectivecohort 61(median)17-86(range)



Nickel(2004)31 41 MedicalICU,Germany LoS>24h Cross-sectional 47(mean) 68% 12(mean,maximumscoreobtained)11(SD)

Rattray(2005)32 60at6m80at12m GeneralICU,UK, LoS>24h,emergencies ProspectivecohortRichter(2006)33 37 SurgicalICU,Germany LoS>30days Retrospectivecohort 42(mean)

17(SD)76% 52(mean)

20(SD)20(mean)

7(SD)Samuelson(2007)7 226 GeneralICUs,Sweden,2sites MV>24h Psychosis,suicide,head

injury,mentaldisabilityProspectivecohort 63(mean)

13(SD)52% 6(mean)

6(SD)18(median)

12(IQR)Scragg(2001)34 80 GeneralICU, UK Headinjury,other

injuryRetrospectivecohort 57(median)

19-90(range)47%

Sukantarat(2007)35 51at3m45at9m

GeneralICU,UK LoS>72h Prospectivecohort 57(mean)14(SD)

43% 17(mean)17(SD)

15(mean)6(SD)

2008-2012studiesGarrouste-Orgeas(2012)20 36(twocontrol

groups,pre-andpost-)

Medical-surgicalICU,France LoS≥4days Dementia Non-randomisedtrial:Pre-andpost-controls

Pre-68(mean)14(SD)post-62(mean)16(SD)

52%54%

Pre21(mean)16(SD)Post13(mean)18(SD)

SAPSIIscorePre44(mean)14(SD)Post40(mean)15(SD)

Granja(2008)36 299 GeneralICU,Portugal9sites LoS>48h Cross-sectionalcohort 59(mean)44-71(IQR) 58% 8(median)5-13(IQR) SAPSIIscore37(median)30-46(IQR)

Jackson(2010)37 32at3m25at12m(controlgroup)

MedicalICU,USA MV>12h Neurologicdeficits,neurosurgery

NestedsubstudyofRCT(controlgroup)

68(median)IQR(56-76) 45% 28(median)21-33(IQR)

Jones(2010)16 160(controlgroup) Europe,6sites LoS>72h,MV>24h PsychoticillnessorPTSD.confusion

RCT(controlgroup) 59(mean),16(SD) 62% 13(mean)12(SD) 19(mean)7(SD)

Myhren(2009)38 255 GeneralICU,Norway LoS>24h Psychiatrichistory,severeheadinjury

Cross-sectionalcohort 48(mean)16(SD) 63% 12(mean)10-14(CI) SAPSII37(mean)35-39(CI)

Myhren(2010)39 194 GeneralICU,Norway LoS>24h Asabove Prospectivecohort 48(mean)16(SD) 63% 12(mean)10-14(CI) SAPSII37(mean)35-39(CI)Rattray(2010)40 42 UK,6sites Headinjury,

neurosurgeryProspectivecohort 60(mean)17-84(range) 63.% 7(median)0-63

(range)19(mean)6-34(range)

Treggiari(2009)41 129 MedicalandsurgicalICUs,Switzerland

MV>12h Neurologicconditions,mentaldisability

RCT(bothgroups,lightvdeepsedation)

72.3%

Twigg(2008)42 44 GeneralICUs,UK,2sites Dementia,confusion,overdose

Caseseriescohort 56(median) 45% 11(median)7(median)2sites

16(median)14(median)2sites

VanderSchaaf(2009)43 238 MixedICU,Netherlands LoS>48h Cross-sectionalcohort 59(mean)17(SD) 66% 9(mean)10(SD) 15(mean)6(SD)Wade(2012)6 100 GeneralICU,UK Dementia,persistent

confusioninICUProspectivecohort 57(mean)17(SD) 52% 8(median)85(range) 22(median)7(range)

Wallen(2008)44 100 ICU,Australia Prospectivecohort 63(mean)19(SD) 68% 57h(median)62h(IQR)


Weinert(2008)45 149at2m80at6m Medical/surgicalICUs,US MV>36h Psychosis,cognitiveimpairment

Prospectivecohort 54(mean)45,63(IQR) 52%

ICU:IntensiveCareUnit;LoS:lengthofstay;MV=mechanicalventilation;h=hours;IQR:interquartilerange;RCT:randomisedcontrolledtrial;SD:standarddeviation;SAPS:SimplifiedAcutePhysiologyScore.Ifcellsareempty,datawerenotreportedinstudies.Somestudiesreportedchar-acteristicsofthesampleatbaseline;othersreportedcharacteristicsofthesampleatfollow-up.


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TableIV.—�Assessment of risk of bias (quality assessment) of post-ICU PTSD studies.

Qualityscores Ratingsforriskofbiasassessment

Firstauthorandyear NassessedforPTSD Follow-uprate*

1.R

epre

sent

ativ

enes

sof

sam

ple

2.S

ampl

esiz

e†

3.O

utco

me

asse

ssm

ent

4.A

naly

siso

fass

ocia

tion

1.P

reva

lenc

e ‡

ratin

g(m

ax=6

)

2.R

iskfa

ctor

–o

utco

me

anal

ysis

ratin

g(m

ax=2

)

1997-2007studiesCapuzzo(2005)24 63 75% 1 1 0 n/a 2 n/aCuthbertson(2004)25 78 70% 2 1 2 1 5 1Girard(2007)26 43 24% 2 0 1 2 3 2Griffiths(2006)27 108 67% 1 1 1 n/a 3 n/aJones(2001)28 30 unclear 0 0 1 0 1 0Jones(2003)29 44

Controls77% 2 0 1 0 3 0

Jones(2007)30 238 78% 1 2 2 2 5 2Nickel(2004)31 41 n/a 1 0 2 0 3 0Rattray(2005)32 60at6m

80at12m55%73%

2 1 1 n/a 4 n/a

Richter(2006)33 37 n/a 1 0 2 0 3 0Samuelson(2007)7 226 72% 2 2 2 2 6 2Scragg(2001)34 80 n/a 1 1 1 0 3 0Sukantarat(2007)35 51at3m

45at9m100%88%

1 0 1 0 2 0

2008-2012studiesGarrouste-Orgeas(2012)20 36(sumof2

controlgroups)35%41%

1 0 1 1 2 1

Granja(2008)36 299 n/a 2 2 1 1 5 1Jackson(2010)37 32(3m)

25(12m)38%29%

1 0 1 n/a 2 n/a

Jones(2010)38 160(controlgroup) 91% 2 2 2 n/a 6 n/aMyhren(2009)38 255 n/a 1 2 1 1 4 1Myhren(2010)39 194 76% 2 2 1 2 5 2Rattray(2010)40 42 41% 1 0 0 n/a 1 n/aTreggiari(2009)41 129 94% 2 2 1 2 5 2Twigg(2008)42 44 79% 1 0 2 n/a 3 n/aVanderSchaaf(2009)43 238 n/a 2 2 1 n/a 5 n/aWade(2012)6 100 64% 2 2 2 2 6 2Wallen(2008)44 100 88% 1 1 2 2 4 2Weinert(2008)45 149at2m

80at6m54%29%

2 1 2 1 5 1

NBRiskofbiasassessmentratingswerecalculatedaccordingtocriteriarelevantforthisreview.Theydonotreflectthequalityofotheraspectsofthestudies,whichmayhaveotherprimaryobjectives.*Follow-uprate:%ofthoseenrolledwhocompletedPTSDfollow-up(deathsareincludedinlosstofollow-up).Norategivenifstudycross-sectional.†Qualityscores:0(poor);1(adequate);2(good).Samplesizescores;0(small):30-59,1(medium):60-150,2(large):>150(orpowercalculationdone)‡Prevalenceratingwascalculatedbyaddingtogetherqualityscores1-3.Riskfactor-outcomeanalysisratingissimplybasedonqualityscore4.


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TableV.—�Prevalence of post-ICU PTSD.

Firstauthorandyear

TimefromICUdischarge

tooutcomeassessment

NassessedforPTSD

PTSDmeasure Resultsasreported Interpretationofresults

Prev

alen

cera

ting

(low

estr

isk=

6)

(1997-2007studies,arrangedinorderofprevalenceratings)Samuelson(2007)7

2morlater

226 IES-R 8≥30%onIES-R(95%CI:4.8,12)

8%borderlinePTSD 6

Jones(2007)30

3m 238 PTSS-14,PDS 9%(95%CI:5.5,12.9)

hadPTSDusingPDS

9%diagnosisofPTSD 5

Cuthbertson(2004)25

3m 78 DTS 22%>27onDTS(95%CI:12.8,31.2)12%>40onDTS(95%CI:0.8,19.2)

22%possiblePTSD12%likelyPTSD

5

Rattray(2005)32

6m12m

6080

IES 27≥35%onIES(95%CI :17.7,36.3)

24≥35%onIES(95%CI:15,33)

27%likelyat6m24%likelyat12m

4

Richter(2006)33

35m 37 Semi-structuredpsychiatricinterview.

32%(5/6criteria)(95%CI:17,47)19%(6criteria)(95%CI:4,34)

32%sub-syndromalPTSD19%fulldiagnosisofPTSD

3

Scragg(2001)34

Variable:3-21m

80 IES 30%>unknowncut-off(95%CI:20,40)15.6%>30onIES

(95%CI:7.7,23.6)

30%possiblePTSD16%borderlinePTSD

3

Nickel(2004)31

Variable:3-15m

41 PTSS-10.SCID

17%≥35onPTSS-10(95%CI:5.5,28.5)9.76%withSCID(95%CI:0.7,18.9)

17%likelyPTSD10%fulldiagnosisofPTSD

3

Griffiths(2006)27

3m 108 Traumascreeningchecklist

52%“PTSD”(95%CI:42.6,61.4)on

TSC

52%possiblePTSD 3

Girard(2007)26

6m 43 PTSS-10 25≥27%onPTSS-10(95%CI:12,37.9)

14≥35%onPTSS-10(95%CI:3.6,24.4)

25%possiblePTSD14%likelyPTSD

3

Jones(2003)29

6m 44(controlgroup)

IES 48>19%onIES(95%CI:33.2,62.8)

48%someimpact 3

Capuzzo(2005)24

3m 63 ICUmemorytoolIES

0%onIESsubscales 0%PTSD 2

Sukantarat(2007)35

3m9m

51

45

IES 35>26%onIES(95%CI:21.1,48.9)

62>26%onIES(95%CI:47.8,76.2)

35%possiblePTSD62%possiblePTSD

2

Jones(2001)28

2m 30 IES 23>19%onIES(95%CI:7.9,38.1)

23%someimpact 1

(2008-2012studies,inorderofprevalenceratings)Jones(2010)16

3m 160(controlgroup)

PDS 13%(95%CI:7.8,18.2)IdentifiedbyPDS

13%diagnosisPTSD 6

Wade(2012)6

3m 100 PDS 27%(95%CI:18.3,36)PDS

severityscore>18

27%likelyPTSD 6


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TableV.—�Prevalence of post-ICU PTSD.

Firstauthorandyear

TimefromICUdischarge

tooutcomeassessment

NassessedforPTSD

PTSDmeasure Resultsasreported Interpretationofresults

Prev

alen

cera

ting

(low

estr

isk=

6)

Treggiari(2009)41

4weeks 129(wholecohort)

IES-Rfor25%ofpatientsPCL

for75%ofpatients

9-10%(95%CI:4.1,13.9)metsymptomcriteriaforapresumptivediagnosis

9-10%diagnosisPTSD 5

Granja(2008)36

6m 299 PTSS-14 18%(95%CI:13.75,22.25)withPTSS-14score>49

18%highriskforPTSD 5

Myhren(2010)39

12m 194 IES 27%(95%CI:20.8,33.2)withIESscore>35

27%likelyPTSD 5

vanderSchaaf(2009)43

12m 238 IES 18%(95%CI:13.3,22.7)withIESscore>35

18%likelyPTSD 5

Weinert(2008)45

2m6m

14980

PDS 17%(95%CI:11,23)

15%(95%CI:7.2,22.8)met

diagnosticcriteria

17%diagnosis15%diagnosis

5

Wallen(2008)44

1m 100 IES-R 13%(95%CI:6.4,19.6)

withIES-Rscore>33

13%likelyPTSD 4

Myhren(2009)38

4-6weeks 255 IES 27%(95%CI:21.6,32.4)withIESscore>35

27%likelyPTSD 4

Twigg(2008)42

3m 44 PDS,IES,PTSS-14

16%sixcriteria(95%CI:5,27)

27%fivecriteriaPDS(95%CI:13.9,40.1)

16%diagnosisPTSD27%likelyPTSD

3

Garrouste-Orgeas(2012)20

12m 36(sumoftwo

controlgroups)

IES-R 65%pre-group(95%CI:50.4,80.6)

≥22ascut-off74%post-group

(95%CI:60.3,88.3)≥22ascut-off

65%and75%ofpatientswithsomePTSDsymptoms

2

Jackson(2010)37

3m12m

32(controlgroup)

25

PTSS-10 10%>35(95%CI:-0.4,20.4)

24%>35(95%CI:7.6,40.4)

10%likelyPTSD24%likelyPTSD

2

Rattray(2010)40

2m6m

4242

IES 36%>35(95%CI:21.5,50.5)

24%>35(95%CI:11.1,36.9)

36%likelyPTSD24%likelyPTSD

1

PTSDmeasuresused:DTS:DavidsonTraumaScale;47IES:ImpactofEventsScale;23IES-R:ImpactofEventsScale-revised(IES-R);22PCL:PTSDChecklist;48PDS:Posttraumatic Diagnostic Scale;46 PTSS-10: Post-traumatic Stress Syndrome 10-Questions Inventory;49 PTSS-14: UK Post-traumatic StressSyndrome14-QuestionsInventory;42SCID:StructuredClinicalInterviewforDSM-IVAxisIDisorders;51TSQ:TraumaScreeningQuestionnaire.50

TableV.—�Continues from previous page.


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vs.3)foundthatgenderwasnotariskfactorforPTSD.Ageandsexwerelesslikelytobeidenti-fiedas risk factors forPTSD in the later stud-iesthantheearlierones.Psychiatrichistorywasfoundtobeariskfactorinfivestudies(includ-ingonewhere resultswereunclear)butnot inthree. Three studies investigated an associationbetween time since discharge from ICU andPTSD,andfoundnoeffect.

Theclinicalriskfactorsmostconsistentlyde-tectedwereaspectsof sedationandmechanicalventilation(TableVI).From1997to2007stud-ies, lorazepam dose,26 administration of mida-zolam6anddurationofsedation30wereassoci-atedwithPTSDinthreestudies.Anotherstudyfound no effect of duration of sedation,33 andonestudyfoundnoeffectoftotalmidazolamortotalpropofoldose.26From2008to2012stud-ies,daysofsedationanduseofbenzodiazepineswereassociatedwithPTSDinonestudy.6Lightvsdeepsedation41anddegreeofsedation45hadnoeffectintwootherstudies.Mechanicalven-tilationwasmorefrequentlyidentifiedasariskfactorbetween2008-12 than1997-2007,withsmalleffectsizes.One2008studyfoundanon-linear association between wakefulness duringventilationandPTSD(withlowerPTSDintheleastandmostawake).45

Other clinical risk factors were identified inonestudyeach:physicalrestraint,30administra-tionofinotropes/vasopressors;administrationofantipsychotics;TherapeuticInterventionScoringSystem(TISS)score;numberoforganssupport-ed,daysofcardiovascular supportandnumberofpsychoactivedruggroupsgiven.6Diagnosticgroupings,illnessseverityscoressuchasApacheIIandLoSintheICUwerenotidentifiedasriskfactorsforPTSDineitherperiod(TableVI).

Acute psychological risk factors were fre-quently identified as risk factors for PTSD,with28associationsfoundacrossbothperiods(Table VII). In studies focusing on memoryanddelirium,factorsmeasuredweretraumaticmemories(associationfoundin1study),26painmemories(associationin2studies),38,39factualmemories (2 associations),38, 39 delusional/de-liriousmemories(associationin6;noassocia-tionin2),intrusivememories(associationin2studies),6,36amnesiainICUorpre-ICU(asso-

Outcome assessment of PTSD studies

Inthe1997-2007groupofstudies,outcomeswere assessedat varying timepoints from2 to35monthsafterICUdischarge(TableV).From2008-2012 outcomes were assessed at between1and12months.SeveralPTSDmeasureswereused in the 26 studies, including self-reportquestionnaires suchas thePosttraumaticDiag-nosticScale(PDS),46theImpactofEventsScale(IES),23theImpactofEventsScale-revised(IES-R),22theDavidsonTraumaScale(DTS),47andthePTSDChecklist (PCL);48 screening instru-ments such as the Post-traumatic Stress Syn-drome10-QuestionsInventory(PTSS-10),49theUK Post-traumatic Stress Syndrome 14-Ques-tions Inventory,42 and the Trauma ScreeningQuestionnaire(TSQ),50andaclinicalinterview-theStructuredClinicalInterviewforDSM-IVAxisIDisorders(SCID).51

PTSD prevalence estimates (1997-2007)

The range of PTSD prevalence estimatesfoundwas0to62%across13studies(TableV).Ifonlystudieswithalowerriskofbias(scoring4-6)wereincludedintheassessment(N.=4),therangeofprevalencerateestimateswasnarrower,at 8% to27%.Medianprevalence of the fourlow-riskstudieswas13%.

PTSD prevalence estimates (2008-2012)

TherangeofPTSDprevalenceestimateswas9%to75%across13studies.Whenonlystud-ieswith lower risk of bias (4-6)were included(N.=9),therangeofestimateswas9%to27%.Medianprevalenceof thenine low-risk studieswas18%.

Risk factors for PTSD

There were eight studies with a low or me-diumriskofbias (1-2) for risk factor-outcomeanalysis in 2008-2012 versus four from 1997-2007 (Table VI). Pooling data from the twoperiods,TableVIIshowsthatfivestudiesiden-tifiedage(usuallyyoungerage)asariskfactor,whereas seven studiesdidnot.Most studies (7


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studies using the same measure used differentcut-pointsdenotingdifferentmeanings(suchaslikely PTSD, possible PTSD, probable PTSD,borderlinePTSDanddiagnosedPTSD).Forex-ample in studies using the IES,23 some used acut-pointof19,someof26andothersof30or35.Clearlythiswouldresultindifferentpreva-lence rates being calculated. There was morestandardisationwithregardstocut-pointsinthelaterstudies.Forexampleall2008-2012studiesusingtheIESusedacut-pointof>35.

Whenstudieswerearrangedinorderoftimetofollow-up(tablenotshown)nopatterncouldbediscerned.Ofnote,inspiteoftherecommen-dationofearliersystematicreviews,fewlongitu-dinalstudieswithPTSDassessmentatmultipletime-points were carried out. Therefore thereis still no clarity about the likely trajectory ofPTSD in ICU survivorsover time.Onexami-nation, themost important sourceofvariationforPTSDresultswas in thequalityof studies.Therefore, table 5 showing PTSD prevalenceandtable6showingriskfactorsforPTSDwererankedinorderofqualityscoreswithinthetwotimeperiods.

The likely interpretation of the 2008-2012data(basedona largernumberofhighqualitystudies)isthat9%-15%ofICUsurvivorswouldfulfilalldiagnosticcriteriaforPTSD,while13%to27%arehighlylikelytohavePTSDormeetmostdiagnosticcriteria.Themedianprevalencesuggeststhataroundoneinfivecriticalcarepa-tients develop high levels of PTSD symptomsafterintensivecare.

Interventions to reduce PTSD prevalencewould clearly be desirable 52 and in the UK,NationalInstituteofHealthandClinicalExcel-lence guidelines recommend that support andrehabilitation be made available to prevent fu-turepsychologicalmorbidity.53However,tode-signeffectivepreventative interventions,aclearpictureofimportantriskfactorsisneeded.18

Acrossthe26studies,therewasevidenceforandagainsttheimportanceofsocio-demograph-ic risk factors such as younger age and femalesex,butfewerrecentstudiesfoundassociationswiththosefactors(TableVI).Nostudiesintheearlier,andveryfewinthelaterperiod,investi-gatedtheroleofethnicityorsocio-economiccir-

ciationin2studies,6,36nonein1study),45anddelirium (association in 1 study;6 no associa-tioninanother).26Mood,stress,fear,agitation,panic, loss of control and inability to expresswishesintheICU,alongwithpessimism,peri-traumatic dissociation and illness perceptionswereotherpsychologicalriskfactorstested(in6 studies). All had positive associations withPTSD,withtheexceptionofperitraumaticdis-association.20

Discussion

In this systematic review, 13 eligible studiesof post-ICU PTSD were retrieved from 1997-2007and13studiesfrom2008-2012.Thissug-gests an increasing interest in post-critical carePTSDinthelastfouryears.Comparedto1997-2007,the2008-12periodincludedmoremulti-sitestudies,moremediumto largestudies, lessrestrictive inclusion criteria, more RCTs and alarger number of patients overall. More of thelaterstudieswereofhighquality(i.e.hadalowerriskofbias)thanearlierstudies.

There was a remarkable concordance aboutthe prevalence of PTSD, based on the higherqualitystudiesfrombothperiods(TableV).Therange of estimates for PTSD from 1997-2007was8-27%with13%asthemedianprevalence.From2008-2012studies,PTSDwasestimatedbetween 9-27% with a median prevalence of18%.Variationinresultsmayberelatedtodif-ferencesinICUpopulations,differentmeasuresused with different diagnostic thresholds anddifferentlengthsoffollow-up.

Itshouldbenotedthateightoutof26stud-iesused the (unrevised) IES23 as ameasureofPTSD.TheIESisagoodmeasureofdistressre-latedtolifeeventsbutisnotameasureofPTSD,as it includes only two of the three clusters ofPTSDsymptoms.4OthersusedscreeningtoolsthatcannotconfirmthepresenceofPTSD,suchasthePTSS-1049orTSQ.50Inthe2008period,more studies (four vs one) used the PDS,46 aquestionnairethatconformstocurrentdiagnos-tic criteria forPTSD.4A further three (vs. onefrom1997-2007),usedtheIES-R,22which in-cludesthethreeclustersofPTSDsymptoms.

In the early period, it was problematic that


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Exactly why sedation factors should be linkedto longer-term PTSD is not yet obvious. Cer-tainlytherehaslongbeenconcern,andindeedcontroversy,aboutreportsthatextendedperiodsofbenzodiazepineusageinthecommunity,par-ticularlyamongolderpatients,maybelinkedtopoor long-term neuropsychiatric outcomes in-cludingcognitivedecline,psychoticsymptoms,anxiety and depression.54, 55 These effects havebeen attributed to benzodiazepine-associatedbrain damage,56 or deficiencies in serotonin,noradrenaline anddopamine causedbybenzo-diazepines.54

OtherstudieshavefoundthatbenzodiazepineuseintheICUisassociatedwithagreaterlike-lihood of delirium.30, 57 This is possibly due totheeffectsofthesedrugsonlevelsofneurotrans-mitterssuchasdopamineoracetylcholine,par-ticularly in critically ill patients with derangedphysiology, whose ability to excrete drugs mayalso be impaired. It may be that patients suf-fering delirium, especially if hallucinations andparanoid delusions are among their delirioussymptoms,aremorelikelytodevelopPTSD.Butalthough a number of studies have shown thatpatients who have memories of paranoid delu-sionsshortlyafterleavingtheICUaremorelikelytodevelopPTSD,anassociationbetweenacutedelirious symptomsandPTSDwasonly foundinoneofthe26studiesreviewedhere.6Anotherlikelyexplanatorymechanismmaybethatben-zodiazepinesareknowntocauseamnesiaaswellas sedation.58 Patients who have long periodsof amnesia for real events that occurred in theICU, while remembering terrifying delusionalmemories,maybemorepronetodevelopPTSD.Whiletheseexplanationsremainintherealmsofhypothesis,theclinicalimplicationsofthestud-iesthatmeasuredsedationasariskfactor,arethatreducingtheuseofbenzodiazepinesand lengthoftimeapatientissedatedwherepossible,couldreducetheirriskofICU-relatedPTSDinfuture.

Use of mechanical ventilation and durationof MV were found to be risk factors in 3 outof4 later studies (2008-2012),butnoassocia-tionswithdays of ventilationwere found in3outof4earlierstudies(1997-2007).Itisknownthatmechanicalventilation,particularly ifpro-longed, can be a highly stressful, invasive and

cumstances inpost-ICUPTSD.6,38,39Theim-portanceofpreviouspsychiatrichistoryremainsuncertainasveryfew2008-12studiestesteditasariskfactor,althoughtheearliersystematicre-viewshadstronglyrecommendedthatitshouldbeincludedinfuturestudies.

Similarto1997-2007studies,the2008-2012studies found that clinical factors such asdiag-nostic group, illness severity scores such as theApache II and length of stay in the ICU werenot risk factors for PTSD. Of note, one 2012study6foundassociationswithbothTISSscoreand number of organs supported and PTSD.Thesevariablesmaybeabetterreflectionofill-nessseverityduringanadmissionthanApacheIIscoresmeasuredwithin24hoursofadmission.InfactTISSscoreisameasureofnumberandtypeofinterventionsreceived;itispossiblethereforethatincreasing,moreinvasiveinterventionsrath-erthanillnessseverityareariskfactorforPTSD.

Otherclinicalfactorssuchassedationandme-chanicalventilationcontinuedtobeinvestigated(TableVI),asrecommendedbyearlierreviews.Between1997and2012,7studiesinvestigateda link between sedation and PTSD. Between1997-2007 3 high-quality studies found posi-tiveassociationsbetweenPTSDandlorazepamdose,26administrationofmidazolam,7anddura-tion of sedation and opiates;30 while one low-quality, small study (N.=37) foundno associa-tionwithdurationof sedation.33Oneof thesestudies(alsosmall,N.=43)26alsofoundnoposi-tive association between other sedatives (apartfromlorazepam)andPTSD.From2008-2012,only one high-quality study found positive as-sociations with both duration of sedation andadministrationofbenzodiazepines,andPTSD.6However another high-quality study found noassociation between depth of sedation (heavyvs light) andPTSD41while amedium-qualitystudy45 didnotfind an associationwith seda-tion intensity score (average sedative exposureperhour)andPTSD.

Althoughevidenceisnotdefinitive,thesere-sults suggest that receivingbenzodiazepines forsedation,orbeingsedatedforlonger,areriskfac-tors forPTSD.Howeverthedepthofsedationoraverageamountof sedativedrugreceived inagiventimedonotappeartoincreasetherisk.


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TableVI.—�Risk factors for post-ICU PTSD.

1stauthor/year Statisticalanalysisofriskfactors Age/othersocio-demographics Sex Severityof

illnessPrior

psychologicalhistory

Clinical/otherfactors

Psychological/neuro-cognitive

factors*Diagnosis

groupsLoS

inICURiskfactor

analysisrating

1997-2007studiesinorderofqualityratingGirard200726 Multivariable

logisticregressionAgeY

(youngerpeopleatgreaterrisk)Y

(femalesatgreaterrisk)N TotallorazepamdoseY

MidazolamNPropofolNDaysofMVN

DaysofdeliriuminICUNMeasuredat6m:TraumaticmemoriesY

N 2

Jones200727 Structuralequationmodelling Y ProlongedsedationYPhysicalrestraintY

Measuredat1-2weeks:DMsY

N2

Samuelson20077 Multivariablelogisticregression AgeYyounger

Yfemale

N UseofmidazolamYDaysofMVN

AgitationinICUYMeasuredat5days:ICUfearYICUstressYDMsNAmnesiaN

N 2

Cuthbertson200425 Univariable(Spearman’scorrelations)

AgeYyounger

N N Y DaysMVY N N 1

Scragg200134 Multivariablelinearregression AgeN N TimesincedischargeN N 0Jones200128 T-test,

ANOVAN Measuredat2weeks:

DMsYN

0Nickel200431 MannWhitneytest N Y

?unclear0

Richter200633 T-test,MannWhitneytest AgeN N N?unclear

DurationMVNDurationofsedationNTimetofollow-upN

N N 0

Jones200329 ANOVA Measuredat2weeks:DMsY

0

Sukantarat200735 Univariable(Spearman’scorrelations) AgeN N 02008-2012studiesinorderofqualityMyhren201039 Multivariablelogisticregression AgeN

Educationlevel,lowYUnemployedY

N N TimeofoutcomeassessmentN

Measuredat4-6w:PessimismYPainmemoriesYLackofcontrolYFMsYDMsN

N N 2

Treggiari200941 T-test LightvsdeepsedationN 2Wade20126 Multivariablelinearregression AgeN

Socio-economicNEthnicityN

N N Y DaysofsedationYBenzodiazepinesYInotropes/vasopressorsYAntipsychoticsYTISSscoreYNumberorgansYDaysMVYDaysCVsupportYNumberdruggroupsY

MeasuredinICU:MoodYIMYIllnessperceptionYStressYDeliriumYAmnesiainICUY

N N 2

Wallen200844 Multivariablelogisticregression AgeY(younger)

N Y N N 2

Garrouste-Orgeas,201220

Kruskal-Wallis,chisquare

AgeN Yfemale

N N ReceivingendotrachealMVY

Measuredat3m:PeritraumaticdissociationN

N N 1

Granja200836 Multivariablelogisticregression AgeN N N Measuredat6m:DMsYPanicYIMYAmnesiaforpre-ICUhospitalstayY

N N 1

Myhren200938

(4-6weeks)Multivariablelinearregression AgeY

(older)UnemployedY

N N MVreceivedYDurationofMVN

Measuredat4-6w:PessimismYPainmemoriesYLackofcontrolYInabilityexpressneedsYDMsYFMsY

N N 1

Weinert200845

(2mand6m)T-test,ANOVA,correlations WakefulnessinMVN

(non-linear;lowerPTSDinmostandleastawake)DegreeofsedationN

Measuredat2m:ICUamnesiaNDMsY

1

Y:associationfound,N:noassociationfound;MV:mechanicalventilationRiskfactoranalysisrating:2=lowestriskofbias.1=moderateriskofbias0:highestriskofbias*Amongpsychologicalfactors,FMs=factualmemories,DMs:delusional/deliriousmemories,IMs:intrusivememories


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TableVI.—�Risk factors for post-ICU PTSD.

1stauthor/year Statisticalanalysisofriskfactors Age/othersocio-demographics Sex Severityof

illnessPrior

psychologicalhistory

Clinical/otherfactors

Psychological/neuro-cognitive

factors*Diagnosis

groupsLoS

inICURiskfactor

analysisrating

1997-2007studiesinorderofqualityratingGirard200726 Multivariable

logisticregressionAgeY

(youngerpeopleatgreaterrisk)Y

(femalesatgreaterrisk)N TotallorazepamdoseY

MidazolamNPropofolNDaysofMVN

DaysofdeliriuminICUNMeasuredat6m:TraumaticmemoriesY

N 2

Jones200727 Structuralequationmodelling Y ProlongedsedationYPhysicalrestraintY

Measuredat1-2weeks:DMsY

N2

Samuelson20077 Multivariablelogisticregression AgeYyounger

Yfemale

N UseofmidazolamYDaysofMVN

AgitationinICUYMeasuredat5days:ICUfearYICUstressYDMsNAmnesiaN

N 2

Cuthbertson200425 Univariable(Spearman’scorrelations)

AgeYyounger

N N Y DaysMVY N N 1

Scragg200134 Multivariablelinearregression AgeN N TimesincedischargeN N 0Jones200128 T-test,

ANOVAN Measuredat2weeks:

DMsYN

0Nickel200431 MannWhitneytest N Y

?unclear0

Richter200633 T-test,MannWhitneytest AgeN N N?unclear

DurationMVNDurationofsedationNTimetofollow-upN

N N 0

Jones200329 ANOVA Measuredat2weeks:DMsY

0

Sukantarat200735 Univariable(Spearman’scorrelations) AgeN N 02008-2012studiesinorderofqualityMyhren201039 Multivariablelogisticregression AgeN

Educationlevel,lowYUnemployedY

N N TimeofoutcomeassessmentN

Measuredat4-6w:PessimismYPainmemoriesYLackofcontrolYFMsYDMsN

N N 2

Treggiari200941 T-test LightvsdeepsedationN 2Wade20126 Multivariablelinearregression AgeN

Socio-economicNEthnicityN

N N Y DaysofsedationYBenzodiazepinesYInotropes/vasopressorsYAntipsychoticsYTISSscoreYNumberorgansYDaysMVYDaysCVsupportYNumberdruggroupsY

MeasuredinICU:MoodYIMYIllnessperceptionYStressYDeliriumYAmnesiainICUY

N N 2

Wallen200844 Multivariablelogisticregression AgeY(younger)

N Y N N 2

Garrouste-Orgeas,201220

Kruskal-Wallis,chisquare

AgeN Yfemale

N N ReceivingendotrachealMVY

Measuredat3m:PeritraumaticdissociationN

N N 1

Granja200836 Multivariablelogisticregression AgeN N N Measuredat6m:DMsYPanicYIMYAmnesiaforpre-ICUhospitalstayY

N N 1

Myhren200938

(4-6weeks)Multivariablelinearregression AgeY

(older)UnemployedY

N N MVreceivedYDurationofMVN

Measuredat4-6w:PessimismYPainmemoriesYLackofcontrolYInabilityexpressneedsYDMsYFMsY

N N 1

Weinert200845

(2mand6m)T-test,ANOVA,correlations WakefulnessinMVN

(non-linear;lowerPTSDinmostandleastawake)DegreeofsedationN

Measuredat2m:ICUamnesiaNDMsY

1

Y:associationfound,N:noassociationfound;MV:mechanicalventilationRiskfactoranalysisrating:2=lowestriskofbias.1=moderateriskofbias0:highestriskofbias*Amongpsychologicalfactors,FMs=factualmemories,DMs:delusional/deliriousmemories,IMs:intrusivememories


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Emotional reactions measured in or imme-diatelypost-ICUwere found topredictPTSDintwohighqualitystudies,onefromeachtimeperiod.6, 7 In one study acute emotional reac-tionsconfoundedmostotherriskfactors.6LossofpsychologicalcontrolandthepersonalitytraitofpessimismwerealsoassociatedwithPTSDintwolaterhighqualitystudiesofthesamecohortofpatients.38,39Itislikelythatacutepsychologi-calorneuro-cognitivefactorssuchastheimpactofdelusionsanddelirium,andemotionalstressintheICU,areimportantriskfactorsforPTSD,butstillmoreresearchisneededtoconfirmthesefindings

The experience of hallucinations and delu-sions,alongwith the threat to life fromcriticalillness,andthestressfulandinvasiveproceduresitnecessitates, is likely to lead to extreme reac-tionssuchasanxiety,panicattacksandlowmoodin critical care patients. Without psychologicalsupporttodealwiththesesymptoms,thepatientmaycontinuetobetraumatizedaftertransfertoamedicalorsurgicalward.AsrelativesmayalsosufferfromPTSD,13theremaybeconflictwithinfamiliesafterICU,causingfurtherstressduringapatient’srecoveryperiodathome.Theseexperi-encesmaypredisposepatientstodevelopmentalhealthdisorderssuchasPTSDaftertheICU.

Strengthsofthisreviewarethatitwasbasedonaprespecifiedprotocolandusedsystematicand

terrifying procedure. It is associated with life-threateningillnesssuchasrespiratoryfailureandthe inability to breathe independently, factorsthatwouldbeexpectedtocauseanxiety.There-foreitwouldnotbeunusualiftheexperienceofMVweretotriggerananxietydisordersuchasPTSD.Neverthelessinthreeofthefourstudieswhichdetectedtheassociation,itwasfoundtohaveasmalleffectsizeinaunivariableanalysis.ThissuggeststhatMVisnotastrongriskfactorforPTSD,anditseffectmaybeexplainedbytherelatedfactorofsedation,asthetwoclinicalfac-torstendtooccurtogether.

Judgedby thenumberofassociations foundacrossstudies,28psychologicalreactionstoICUwouldbethemostimportantgroupofriskfac-tors for PTSD. However there are problemswithinterpretingtheseassociations.From1997-2007,anumberofstudiesshowedthattraumat-icordelusionalmemorieswereassociatedwithPTSD. These were measured at times between2 weeks and 6 months after ICU, and couldthereforebesymptomsofdisorder(acutestressdisorder or PTSD) rather than risk factors foradisorder.Thepicture is even less clear in the2008to2012studies,asmanytypesofmemory(delusional/delirious memories, factual memo-ries, pain memories, intrusive memories, ICUamnesia,pre-ICUamnesia)wereinvestigatedatdifferenttimepointsinoneortwostudieseach.

TableVII.—�Summary table of post-ICU PTSD risk factors.

Studies

Age

Sex

Soci

o-ec

onom

ic

posit

ion

ore

thni

city

Psyc

hiat

rich

istor

y

Dia

gnos

isin

ICU

Illne

ssse

v erit

y

Day

sin

ICU

S eda

tion

MV

Type

sofm

emor

yan

dde

lirio

us

sym

ptom

s

Oth

erp

sych

olog

ical

fa

ctor

s‡

1997-2007(n=10)

Y(3)N(3)

Y(2)N(2)

Y(0)N(0)

Y(4)N(2)

Y(0)N(4)

Y(0)N(6)

Y(0)N(5)

Y(3)N(2)

Y(1)N(3)

Y(5)*N(3)

Y(2)N(0)

2008-2012(n=8)

Y(2)N(4)

Y(1)N(5)

Y(3)N(2)

Y(1)N(1)

Y(0)N(6)

Y(1)N(5)

Y(0)N(6)

Y(2)N(2)

Y(3)N(1)

Y(12)†N(2)

Y(9)N(1)

Total Y(5)N(7)

Y(3)N(7)

Y(3)N(2)

Y(5)N(3)

Y(0)N(10)

Y(1)N(11)

Y(0)N(11)

Y(5)N(4)

Y(4)N(4)

Y(17)N(5)

Y(11)‡N(1)

Y:significanteffectfoundforfactor(x)numberoftimesN:nosignificanteffectfoundforfactor(x)numberoftimes*traumaticmemories,deliriousmemoriesoramnesia†painmemories,factualmemories,delusionalmemories,intrusivememories,delirium,amnesiainICUandpre-ICU‡Stress,agitation,fear,panic,mood,lossofcontrol,inabilitytoexpressneedsinICU.Alsopessimism,peritraumaticdissociationandillnessper-ceptions


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References 1. Desai SV, LawTJ, Needham DM. Long-term complica-

tionsofcriticalcare.CritCareMed2011;39:371-9. 2. PerrinsJ,KingN,CollingsJ.Assessmentoflong-termpsy-

chological well-being following intensive care. IntensiveCritCareNurs1998;14:108-16.

3. SchellingG,StollC,HallerM,BriegelJ,ManertW,Hum-melT et al.Health-relatedqualityoflifeandposttraumaticstressdisorderinsurvivorsoftheacuterespiratorydistresssyndrome.CritCareMed1998;26:651-9.

4. AmericanPsychiatricAssociation:DiagnosticandStatisti-calManualofMentalDisorders.4th edition.WashingtonDC:Author;1994.

5. DedertEA,CalhounPS,WatkinsLL,SherwoodA,Beck-hamJC.Posttraumatic stressdisorder,cardiovascular, andmetabolicdisease:areviewoftheevidence.AnnBehavMed2010;39:61-78.

6. WadeDM,HowellDC,WeinmanJA,HardyRJ,MythenMG,BrewinCRet al.Investigatingriskfactorsforpsycho-logicalmorbiditythreemonthsafterintensivecare,apro-spectivecohortstudy.CritCare2012;16:R192.

7. SamuelsonKA,LundbergD,FridlundB.Stressfulmemo-riesandpsychologicaldistressinadultmechanicallyventi-lated intensivecarepatients -a2-month follow-upstudy.ActaAnaesthesiolScand2007;51:671-8.

8. ElyEW,SiegelMD,InouyeSK.Deliriumintheintensivecareunit:anunder-recognizedsyndromeoforgandysfunc-tion.SeminRespirCritCareMed2001;22:115-26.

9. Jackson JC, Hart RP, Gordon SM, Hopkins RO, GirardTD,ElyEW.Post-traumaticstressdisorderandpost-trau-maticstresssymptomsfollowingcritical illness inmedicalintensivecareunitpatients:assessingthemagnitudeoftheproblem.CritCare2007;11:R27.

10. GriffithsJ,FortuneG,BarberV,YoungJD.TheprevalenceofposttraumaticstressdisorderinsurvivorsofICUtreat-ment:asystematicreview.IntensCareMed2007;33:1506-18.

11. DavydowDS,GiffordJM,DesaiSV,NeedhamDM,Bien-venuOJ.Posttraumaticstressdisorderingeneralintensive

explicitmethodstoidentify,selectandappraisestudies.Assessmentofriskofbias(qualityassess-ment)wascarriedout.Nostudiesofdiagnosticsub-groupsofICUpatientswere included,andtherefore estimates of prevalence were not in-flatedbypatientgroupswithexceptionallyhighrates. The review included studies of mechani-callyventilated ICUpatients.Asventilatedpa-tientshavemanyunderlyingconditions,theyarebroadlyrepresentativeoftheICUpopulation.

Alimitationofthereviewwasthatnostatisti-calaggregationofresultswaspossibleduetohet-erogeneityofmethodsandresults.ThereforewehavepresentedmediansandrangesofestimatesofPTSD.Wecouldnotcarryoutameta-anal-ysis,andthereforecouldnottestquantitativelyforpublicationbias,whichisacommonlimita-tionof systematic reviews.Wedidnot includeunpublishedresultsorresultspublishedonlyinabstractsorconferencepapers.Thisreviewalsocarriestheriskofbiasduetopossibleselectivere-portingofassociationswithinstudies.Itislikelytherewasunder-reportingofnullassociations.

Conclusions

Evidencefromthissystematicreviewsuggeststhat at least one in five patients may developPTSD after intensive care. The most consist-ent risk factors identified were clinical (ben-zodiazepine use and duration of sedation) andacutepsychological (relating to stress, deliriumand memory problems associated with ICU).Althoughmorestudiesandhigherqualitystud-ieshavebeenpublishedsince2008thanbefore,theevidencebaseforprevalenceandriskfactorsforPTSDafterICUcanstillnotbeconsidereddefinitive.Inthemeantime,clinicalimplicationsoftheevidencetodatearethattheuseofben-zodiazepines and duration of sedation shouldbelimitedifclinicallyfeasible,andpsychologi-calsupportshouldbeprovidedbothduringandfollowingICUadmissionstomitigatetheeffectof delusions, delirium and emotional stress inICU,andreducelonger-termPTSD.Addition-ally,thereis limitedevidencethatreducingtheamountofinvasiveICUmedicalinterventions,ifclinicallyfeasible,mightalsoreducethetrau-maticstresssufferedbyICUpatients.

Key messages

— Up to 27% of ICU survivors sufferfrom PTSD up to a year after leaving theunit, with likely serious consequences fortheirhealthandwell-being.

— The most important known clinicalrisk factors for post-ICU PTSD are use ofbenzodiazepinesanddurationofsedationintheICU.

— Extreme stress reactions, delirioussymptoms and memory problems in theICUareriskfactorsforPTSD,buthavenotbeeninvestigatedinaconsistentway.

— Thequality andquantityof evidenceaboutprevalenceofandriskfactorsforpost-ICU PTSD have improved over time, butcannotyetbeconsidereddefinitive.


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Acknowledgments.—WeareverygratefulforthecontributionofElijahRhone(ER),whocarriedoutdataextractionofthe2008-12studies,andKateCheneytheUCLlibrarianwhoadvisedonthesearchstrategy.WewouldalsoliketothankRosalindRaineandJohnWeinmanfortheirsupportinsupervisingtheearlystagesofworkonthissystematicreview.Funding.—DWisfundedby,andDHandMMreceiveaportionoftheirfundingfrom,theUCLH/UCLNationalInstituteofHealthResearchBiomedicalResearchCentre.RebeccaHardyissupportedbytheMRC.Therearenoconflictsofinterest.ReceivedonOctober8,2012–AcceptedforpublicationonMarch25,2013.Correspondingauthor:Dr.D.Wade,HealthPsychologist,TheCriticalCareUnit,UCLHNHSFoundationTrust,235EustonRd,Lon-donNW12BU,UK.E-mail:[email protected]

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