Clinical Practice Guidelines for the Prevention and Manageme...

The 2018 Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) (PADIS) guideline builds on this mission by ... SCCM PediatricCriticalCareMedicine CriticalCareExplorations SCCM PediatricCriticalCareMedicine CriticalCareExplorations September2018-Volume46-Issue9 Previous Article Next Article ArticleasEPUB ExportAllImagestoPowerPointFile AddtoMyFavorites Colleague'sE-mailisInvalid YourName:(optional) YourEmail: Colleague'sEmail: Separatemultiplee-mailswitha(;). Message: Thoughtyoumightappreciatethisitem(s)IsawatCriticalCareMedicine. Sendacopytoyouremail Yourmessagehasbeensuccessfullysenttoyourcolleague. Someerrorhasoccurredwhileprocessingyourrequest.Pleasetryaftersometime. 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OnlineSpecialArticleDevlin,JohnW.PharmD,FCCM(Chair)1,2;Skrobik,YoannaMD,FRCP(c),MSc,FCCM(Vice-Chair)3,4;Gélinas,CélineRN,PhD5;Needham,DaleM.MD,PhD6;Slooter,ArjenJ.C.MD,PhD7;Pandharipande,PratikP.MD,MSCI,FCCM8;Watson,PaulaL.MD9;Weinhouse,GeraldL.MD10;Nunnally,MarkE.MD,FCCM11,12,13,14;Rochwerg,BramMD,MSc15,16;Balas,MicheleC.RN,PhD,FCCM,FAAN17,18;vandenBoogaard,MarkRN,PhD19;Bosma,KarenJ.MD20,21;Brummel,NathanielE.MD,MSCI22,23;Chanques,GeraldMD,PhD24,25;Denehy,LindaPT,PhD26;Drouot,XavierMD,PhD27,28;Fraser,GillesL.PharmD,MCCM29;Harris,JocelynE.OT,PhD30;Joffe,AaronM.DO,FCCM31;Kho,MichelleE.PT,PhD30;Kress,JohnP.MD32;Lanphere,JulieA.DO33;McKinley,SharonRN,PhD34;Neufeld,KarinJ.MD,MPH35;Pisani,MargaretA.MD,MPH36;Payen,Jean-FrancoisMD,PhD37;Pun,BrendaT.RN,DNP23;Puntillo,KathleenA.RN,PhD,FCCM38;Riker,RichardR.MD,FCCM29;Robinson,BryceR.H.MD,MS,FACS,FCCM39;Shehabi,YahyaMD,PhD,FCICM40;Szumita,PaulM.PharmD,FCCM41;Winkelman,ChrisRN,PhD,FCCM42;Centofanti,JohnE.MD,MSc43;Price,CarrieMLS44;Nikayin,SinaMD45;Misak,CherylJ.PhD46;Flood,PamelaD.MD47;Kiedrowski,KenMA48;Alhazzani,WaleedMD,MSc(MethodologyChair)16,49AuthorInformation 1SchoolofPharmacy,NortheasternUniversity,Boston,MA. 2DivisionofPulmonary,CriticalCareandSleepMedicine,TuftsMedicalCenter,Boston,MA. 3FacultyofMedicine,McGillUniversity,Montreal,QC,Canada. 4RegroupementdeSoinsCritiquesRespiratoires,RéseaudeSantéRespiratoire,Montreal,QC,Canada. 5IngramSchoolofNursing,McGillUniversity,Montreal,QC,Canada. 6DivisionofPulmonaryandCriticalCareMedicine,DepartmentofPhysicalMedicineandRehabilitation,SchoolofMedicine,JohnsHopkinsUniversity,Baltimore,MD. 7DepartmentofIntensiveCareMedicine,BrainCenterRudolfMagnus,UniversityMedicalCenter,UtrechtUniversity,Utrecht,TheNetherlands. 8DepartmentofAnesthesiology,DivisionofAnesthesiologyCriticalCareMedicine,VanderbiltUniversityMedicalCenter,Nashville,TN. 9DivisionofSleepMedicine,VanderbiltUniversityMedicalCenter,Nashville,TN. 10DivisionofPulmonaryandCriticalCare,BrighamandWomen’sHospitalandSchoolofMedicine,HarvardUniversity,Boston,MA. 11DivisionofAnesthesiology,PerioperativeCareandPainMedicine,NewYorkUniversityLangoneHealth,NewYork,NY. 12DivisionofMedicine,NewYorkUniversityLangoneHealth,NewYork,NY. 13DivisionofNeurology,NewYorkUniversityLangoneHealth,NewYork,NY. 14DivisionofSurgery,NewYorkUniversityLangoneHealth,NewYork,NY. 15DepartmentofMedicine(CriticalCare),McMasterUniversity,Hamilton,ON,Canada. 16DepartmentofHealthResearchMethods,ImpactandEvidence,McMasterUniversity,Hamilton,ON,Canada. 17TheOhioStateUniversity,CollegeofNursing,CenterofExcellenceinCriticalandComplexCare,Columbus,OH. 18TheOhioStateUniversityWexnerMedicalCenter,Columbus,OH. 19DepartmentofIntensiveCareMedicine,RadboudUniversityMedicalCenter,Nijmegen,TheNetherlands. 20DivisionofCriticalCare,LondonHealthSciencesCentre,London,ON,Canada. 21SchulichSchoolofMedicine&Dentistry,UniversityofWesternOntario,London,ON,Canada. 22CenterforQualityAging,DivisionofAllergy,PulmonaryandCriticalCareMedicine,DepartmentofMedicine,VanderbiltUniversityMedicalCenter,Nashville,TN. 23CenterforHealthServicesResearch,VanderbiltUniversityMedicalCenter,Nashville,TN. 24DepartmentofAnesthesiaandIntensiveCare,MontpellierUniversitySaintEloiHospital,Montpellier,France. 25PhyMedExp,INSERM,CNRS,UniversityofMontpellier,Montpellier,France. 26MelbourneSchoolofHealthSciences,UniversityofMelbourne,Melbourne,VIC,Australia. 27FacultedeMedecinePharmacie,UniversityofPoitiers,Poitiers,France. 28ServicedeNeurophysiologie,CHUdePoitiers,Poitiers,France. 29DepartmentofCriticalCare,MaineMedicalCenterandSchoolofMedicine,TuftsUniversity,Portland,ME. 30SchoolofRehabilitationScience,McMasterUniversity,Hamilton,ON,Canada. 31DepartmentofAnesthesiologyandPainMedicine,HarborviewMedicalCenter,UniversityofWashington,Seattle,WA. 32DivisionofPulmonaryandCriticalCareMedicine,UniversityofChicago,Chicago,IL. 33DepartmentofPhysicalMedicineandRehabilitation,IntermountainHealthcare,SaltLakeCity,UT. 34SchoolofNursingandMidwifery,DeakinUniversity,Geelong,VIC,Australia. 35DepartmentofPsychiatryandBehavioralSciences,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD. 36DivisionofPulmonary,CriticalCareandSleepMedicine,SchoolofMedicine,YaleUniversity,NewHaven,CT. 37DepartmentofAnesthesiologyandCriticalCare,GrenobleAlpesUniversityHospital,Grenoble,France. 38SchoolofNursing,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA. 39DepartmentofSurgery,UniversityofWashington,Seattle,WA. 40DepartmentofCriticalCareandPerioperativeMedicine,SchoolofClinicalSciences,MonashUniversity,Melbourne,VIC,Australia. 41DepartmentofPharmacy,BrighamandWomen’sHospital,Boston,MA. 42FrancesPayneBoltonSchoolofNursing,CaseWesternReserveUniversity,Cleveland,OH. 43DepartmentofAnesthesiaandCriticalCare,McMasterUniversity,Hamilton,ON,Canada. 44WelchMedicalLibrary,JohnsHopkinsUniversity,Baltimore,MD. 45DepartmentofPsychiatryandBehavioralSciences,NewYorkMedicalCollege,Valhalla,NY. 46DepartmentofPhilosophy,UniversityofToronto,Toronto,CA. 47DivisionofAnesthesiology,StanfordUniversityHospital,PaloAlto,CA. 48PatientandFamilyAdvisoryCommittee,JohnsHopkinsHospital,Baltimore,MD. 49DepartmentofMedicine(CriticalCareandGastroenterology),McMasterUniversity,Hamilton,ON,Canada. TheseguidelinesareendorsedbytheAmericanAssociationofCritical-CareNurses,AmericanCollegeofChestPhysicians,AmericanCollegeofClinicalPharmacy,AmericanDeliriumSociety,AustralianCollegeofCriticalCareNurses,CanadianCriticalCareSociety,EasternAssociationfortheSurgeryofTrauma,EuropeanDeliriumAssociation,EuropeanFederationofCriticalCareNursingAssociations,NeurocriticalCareSociety,andSocietyofCriticalCareAnesthesiologists. Supplementaldigitalcontentisavailableforthisarticle.DirectURLcitationsappearintheprintedtextandareprovidedintheHTMLandPDFversionsofthisarticleonthejournal’swebsite(http://journals.lww.com/ccmjournal). Dr.DevlinhasreceivedresearchfundingfromtheNationalInstituteofAging,NationalHeart,LungandBloodInstitute,andAstraZenecaPharmaceuticals,heisontheeditorialboardofCriticalCareMedicine,andheisthepresidentoftheAmericanDeliriumSociety.Dr.SkrobikparticipatesintheATSandtheAmericanCollegeofChestPhysicians(ACCP),andsheisontheeditorialboardforIntensiveCareMedicineandChest.Dr.NeedhamisaprincipalinvestigatoronaNationalInstitutesofHealth(NIH)-funded,multicenteredrandomizedtrial(R01HL132887)evaluatingnutritionandexerciseinacuterespiratoryfailureand,relatedtothistrial,iscurrentlyinreceiptofanunrestrictedresearchgrantanddonatedaminoacidproductfromBaxterHealthcareandanequipmentloanfromReckMedicalDevicestotwooftheparticipatingstudysites,externaltohisinstitution.Dr.Slooterhasdisclosedthatheisinvolvedinthedevelopmentofanelectroencephalogram-baseddeliriummonitor,whereany(future)profitsfromelectroencephalogram-baseddeliriummonitoringwillbeusedforfuturescientificresearchonly.Dr.Pandharipande’sinstitutionreceivedfundingfromHospira(researchgranttopurchasestudydrug[dexmedetomidine]incollaborationwithaNIH-fundedRO1study)anddisclosedthatheisthepastpresidentoftheAmericanDeliriumSociety.Dr.NunnallyparticipatesintheSocietyofCriticalCareAnesthesiologists,InternationalAnesthesiaResearchSociety,andAmericanSocietyofAnesthesiology(ASA).Dr.Rochwergparticipatesasaguidelinemethodologistforotherorganizations(i.e.,AmericanThoracicSociety[ATS]andCanadianBloodService)inadditiontotheSocietyofCriticalCareMedicine.Dr.BalasreceivedfundingfromSelectMedical(primaryinvestigatoronresearchstudyexploringAssess,Prevent,andManagePain,BothSpontaneousAwakeningTrialsandSpontaneousBreathingTrials,Choiceofanalgesiaandsedation,Delirium:Assess,Prevent,andManage,EarlymobilityandExercise,andFamilyengagementandempowermentbundleadoption).Dr.BosmareceivedfundingfromtheCanadianInstitutesofHealthResearch(CIHR)wheresheistheprimaryinvestigatorofanindustrypartneredresearchgrantwithCovidienastheindustrypartneroftheCIHRforastudyinvestigatingproportionalassistventilationversuspressuresupportventilationforweaningfrommechanicalventilation.Dr.BrummelparticipatesintheATS(AgingandGeriatricsWorkingGroupCo-Chair)andArjoHuntleigh(advisoryboardactivities).Dr.Chanquesparticipatesinotherhealthcareprofessionalorganizationactivities.Dr.DenehyparticipatesintheAustralianPhysiotherapyAssociation.Dr.DrouotparticipatesintheFrenchSleepSocietyandtheFrenchInstituteforSleepandVigilance.Mr.JoffeparticipatesoncommitteesforASA.Dr.KhoreceivedfundingfromRestorativeTherapies(Baltimore,MD)(loanedtwosupinecycleergometersforongoingresearch).Dr.Kressreceivedfundingfromadexmedetomidinespeakerprogram,heparticipatesintheATSandACCP,andhehasservedasanexpertwitnessinmedicalmalpractice.Dr.McKinleyparticipatesintheAmericanAssociationofCritical-CareNurses(AACN)(editorialboardofAmericanJournalofCriticalCare)andtheAmericanHeartAssociation(editorialboardofJournalofCardiovascularNursing).Dr.NeufeldparticipatesintheAmericanDeliriumSociety(boardmember).Dr.PisaniparticipatesintheACCP(ChairScientificProgrammingCommitteeandSteeringCommitteeWomen’sHealthNetwork).Dr.PayenreceivedfundingfromBaxterSA(distributorofdexmedetomidineinFrance),andhehasreceivedhonorariumsfromBaxterSA(oralpresentationsofdexmedetomidine).Ms.PunparticipatesasanAACNspeakerattheNationalConference.Dr.Puntilloparticipatesinotherhealthcareprofessionalorganizations(e.g.,AACN).Dr.RobinsonparticipatesintheEasterAssociationfortheSurgeryofTrauma,AmericanCollegeofSurgeons,andAmericanAssociationfortheSurgeryofTrauma.Dr.Shehabireceivedfundingfromanunrestrictedresearchgrant(drugsupply)fromPfizer(Hospira)andOrionPharmatoanongoingmultinationalmulticenterstudy.Mr.SzumitaparticipatesinseveralcommitteesfortheAmericanSocietyofHealth-SystemPharmacists.Ms.PricehasdisclosedthatsheisamedicallibrarianworkingatJohnsHopkinsUniversity,andsheconsultsasaninformationspecialisttotheCochraneUrologyReviewGroup.Dr.FloodparticipatesontheSocietyofObstetricAnesthesiaandPerinatologyresearchcommitteeandtheASAChronicPainCommittee.Theremainingauthorshavedisclosedthattheydonothaveanypotentialconflictsofinterest. TheAmericanCollegeofCriticalCareMedicine(ACCM),whichhonorsindividualsfortheirachievementsandcontributionstomultidisciplinarycriticalcaremedicine,istheconsultativebodyoftheSocietyofCriticalCareMedicine(SCCM)thatpossessesrecognizedexpertiseinthepracticeofcriticalcare.TheCollegehasdevelopedadministrativeguidelinesandclinicalpracticeparametersforthecriticalcarepractitioner.Newguidelinesandpracticeparametersarecontinuallydeveloped,andcurrentonesaresystematicallyreviewedandrevised. Forinformationregardingthisarticle,E-mail:[email protected] CriticalCareMedicine: September2018-Volume46-Issue9-pe825-e873 doi:10.1097/CCM.0000000000003299 Free SDC Metrics Abstract Objective:  Toupdateandexpandthe2013ClinicalPracticeGuidelinesfortheManagementofPain,Agitation,andDeliriuminAdultPatientsintheICU. Design:  Thirty-twointernationalexperts,fourmethodologists,andfourcriticalillnesssurvivorsmetvirtuallyatleastmonthly.Allsectiongroupsgatheredface-to-faceatannualSocietyofCriticalCareMedicinecongresses;virtualconnectionsincludedthoseunabletoattend.Aformalconflictofinterestpolicywasdevelopedaprioriandenforcedthroughouttheprocess.Teleconferencesandelectronicdiscussionsamongsubgroupsandwholepanelwerepartoftheguidelines’development.Ageneralcontentreviewwascompletedface-to-facebyallpanelmembersinJanuary2017. Methods:  Contentexperts,methodologists,andICUsurvivorswererepresentedineachofthefivesectionsoftheguidelines:Pain,Agitation/sedation,Delirium,Immobility(mobilization/rehabilitation),andSleep(disruption).EachsectioncreatedPopulation,Intervention,Comparison,andOutcome,andnonactionable,descriptivequestionsbasedonperceivedclinicalrelevance.Theguidelinegroupthenvotedtheirranking,andpatientsprioritizedtheirimportance.ForeachPopulation,Intervention,Comparison,andOutcomequestion,sectionssearchedthebestavailableevidence,determineditsquality,andformulatedrecommendationsas“strong,”“conditional,”or“good”practicestatementsbasedonGradingofRecommendationsAssessment,DevelopmentandEvaluationprinciples.Inaddition,evidencegapsandclinicalcaveatswereexplicitlyidentified. Results:  ThePain,Agitation/Sedation,Delirium,Immobility(mobilization/rehabilitation),andSleep(disruption)panelissued37recommendations(threestrongand34conditional),twogoodpracticestatements,and32ungraded,nonactionablestatements.Threequestionsfromthepatient-centeredprioritizedquestionlistremainedwithoutrecommendation. Conclusions:  Wefoundsubstantialagreementamongalarge,interdisciplinarycohortofinternationalexpertsregardingevidencesupportingrecommendations,andtheremainingliteraturegapsintheassessment,prevention,andtreatmentofPain,Agitation/sedation,Delirium,Immobility(mobilization/rehabilitation),andSleep(disruption)incriticallyilladults.HighlightingthisevidenceandtheresearchneedswillimprovePain,Agitation/sedation,Delirium,Immobility(mobilization/rehabilitation),andSleep(disruption)managementandprovidethefoundationforimprovedoutcomesandscienceinthisvulnerablepopulation. Clinicalpracticeguidelinesarepublished,oftenbyprofessionalsocieties,becausetheyprovideacurrentandtransparentlyanalyzedreviewofrelevantresearchwiththeaimtoguideclinicalpractice.The2018Pain,Agitation/sedation,Delirium,Immobility(rehabilitation/mobilization),andSleep(disruption)(PADIS)guidelinebuildsonthismissionbyupdatingthe2013Pain,Agitation,andDelirium(PAD)guidelines(1);byaddingtwoinextricablyrelatedclinicalcaretopics—rehabilitation/mobilizationandsleep;byincludingpatientsascollaboratorsandcoauthors;andbyinvitinganinternationalpanelofexpertsfromhigh-incomecountriesasanearlysteptowardincorporatingmorediversepracticesandexpertisefromtheglobalcriticalcarecommunity. Readerswillfindrationalesfor37recommendations(derivedfromactionablePatient,Intervention,Comparison,andOutcome[PICO]questions);twoungradedgoodpracticestatements(derivedfromactionablePICOquestionswhereitisunequivocal,thebenefitsoftheinterventionoutweightherisksbutdirectevidencetosupporttheinterventiondoesnotexist);and32ungradedstatements(derivedfromnonactionable,descriptivequestions)acrossthefiveguidelinesections.Thesupplementaldigitalcontentfiguresandtableslinkedtothisguidelineprovidebackgroundonhowthequestionswereestablished,profilesoftheevidence,theevidence-to-decisiontablesusedtodeveloprecommendations,andvotingresults.Evidencegapsandfutureresearchdirectionsarehighlightedineachsection.Thefivesectionsofthisguidelineareinterrelated,andthus,theguidelineshouldbeconsideredinitsentiretyratherthanasdiscreterecommendations. KnowledgetranslationandimplementationeffectivenessareanimportantseguetoourguidelinedocumentandworktofosteradvancesinclinicalpracticerelatedtoPADISassessment,prevention,andtreatment.APADISguidelineimplementationandintegrationarticleseparatelycreatedtofacilitatethisisavailable(2).ManychallengescharacterizedevelopingeffectivePADIS-relatededucationalandqualityimprovementprograms.Althoughsomehavenotachievedexpectedoutcomes(3,4),manyqualityimprovementeffortsinthisfieldhavebeensuccessful(5–10). METHODS ThepanelfollowedtheGradingofRecommendationsAssessment,DevelopmentandEvaluation(GRADE)workinggroup’smethodologyforclinicalpracticeguidelinedevelopment.Guidelinechairs,withinputfromthemethodologyteam,createdaprotocolbeforebeginningformalworkontheguideline.Chairs,groupheads,andpanelmembers,withinputfromICUsurvivors(11),selectedtopicsthatareimportanttopatientsandpracticingclinicians.Alistofquestionswasdevelopedforeachtopic,andquestionsandoutcomeswereprioritizedthroughanelectronicsurveyfollowingtheGRADEprinciples(12). Oncethelistofquestionswasfinalized,auniversity-basedlibrarianconductedaliteraturereviewoffiveelectronicdatabasesfrom1990toOctober2015basedonprioritytopicsvotedonbythemembersandrevisedbycriticalillnesssurvivors.Thelibrarianfinalizedtherelevantsearchtermswiththegroupsandextractedliteraturebasedontheseprioritizedtopics.ThesepublicationswerethenevaluatedfortheirmethodologicrigorthatdeterminedthehighestqualityofevidenceavailableperoutcomeandperquestioninkeepingwithGRADEguidance.Evidenceevaluationwasperformedbydeterminingitsrelevanceforeachquestion;memberswithafinancialorintellectualconflictofinterestdidnotreviewquestionsrelatedtotheirconflict.Full-textscreeningwasperformedinduplicate.EachgroupusedtheGRADEevidence-to-decisionframeworktoformulatethepreliminaryrecommendations(12).Further,allfivegroups’commentsontheoverallrecommendationsandtheliteratureprovidedtosupportitwerereviewedbythechairandvice-chairafterrecommendationvotingandscreenedforpotentialorperceivedconflict. Subsequently,recommendationswerediscussedinpersonamongthefullpanel.Then,onlymemberswhowerefreeofovertorpotentialconflictofinterestvotedelectronicallyforeachrecommendation.Wedefinedconsensusasgreaterthan80%agreementwithgreaterthan70%responserate.ICUsurvivorsparticipatedineverystepoftheguidelinedevelopment,whichprovidedauniqueperspectiveforthisguideline.WeusedtheGRADEcriteriatoformulategoodpracticestatementswhereappropriate(11).Fornonactionable,descriptivequestions,evidencewassummarizedandungradedstatementswereprovided.AcompletedescriptionofthemethodsisfoundinSupplementalAppendix1(SupplementalDigitalContent1,https://links.lww.com/CCM/D759).Adetaileddescriptionofthemethodologicinnovationsthatcharacterizetheseguidelinesispublishedseparately(13). PAIN Painmanagementiscomplexbecausepainpatternsarehighlyindividual(e.g.,acute,chronic,andacute-on-chronic),itarisesfromdifferentsources(e.g.,somatic,visceral,andneuropathic),andpatientshavesubjectiveperceptionsandhaveexceedinglyvariabletolerability.Aconsistentapproachtopainassessmentandmanagementisparamountgiventheuniquefeaturesofcriticallyilladultsthatincludeimpairedcommunication,alteredmentalstatus,mechanicalventilation,proceduresanduseofinvasivedevices,sleepdisruption,andimmobility/mobilitystatus(14). Criticallyilladultsexperiencemoderate-to-severepainatrest(15)andduringstandardcareprocedures(16).Painisdefinedas“anunpleasantsensoryandemotionalexperienceassociatedwithactualorpotentialtissuedamage,ordescribedintermsofsuchdamage”(17).Painshouldbeconsideredtobe“whatever”theexperiencingpersonsaysitis,existing“whenever”theexperiencingpersonsaysitdoes(18).Althoughthereferencestandardmeasureofpainisapatient’sself-report,theinabilitytocommunicateclearlydoesnotnegateapatient’spainexperienceortheneedforappropriatepainmanagement(19).Fortunately,validatedbehavioralpainscalesprovidealternativemeasuresforpainassessmentinthosepatientsunabletoself-reporttheirpain.Severepainnegativelyaffectspatientstatus(e.g.,cardiacinstability,respiratorycompromise,immunosuppression)incriticallyilladults;implementationofassessment-drivenandstandardizedpainmanagementprotocolsimprovesICUoutcomesandclinicalpractice(5,20).Carefullytitratedanalgesicdosingisimportantwhenbalancingthebenefitsversuspotentialrisksofopioidexposure(21–25).Inthisguidelinesection,weaddressthreeactionablequestionsandtwodescriptivequestionsrelatedtothepainexperienceofcriticallyilladults(seeprioritizedtopiclistinSupplementalTable1[SupplementalDigital2,https://links.lww.com/CCM/D760]andvotingresultsinSupplementalTable2[SupplementalDigitalContent3,https://links.lww.com/CCM/D761]).Theevidencesummariesandevidence-to-decisiontablesusedtodeveloprecommendationsforthepaingroupareavailableinSupplementalTable3(SupplementalDigitalContent4,https://links.lww.com/CCM/D762),andtheforestplotsforallmeta-analysesareavailableinSupplementalFigure1(SupplementalDigitalContent5,https://links.lww.com/CCM/D763). RiskFactors Question:Whatfactorsinfluencepainincriticallyilladultsduringbothrestandduringprocedures? UngradedStatements:Painatrestisinfluencedbybothpsychologic(e.g.,anxietyanddepression)anddemographic(e.g.,youngage,oneormorecomorbidities,andhistoryofsurgery)factors. Painduringaprocedureisinfluencedbypreproceduralpainintensity,thetypeofprocedure,underlyingsurgicalortraumadiagnoses,anddemographicfactors(youngerage,femalesex,andnon-whiteethnicity). Rationale:Painiscommonincriticallyilladultsatrestandduringproceduresincludingregularactivities(e.g.,turning)anddiscreteprocedures(e.g.,arterialcatheterinsertion).Thepriorguidelinesdocumenttheincidence,frequency,severity,andimpactofpain(1):1)adultmedical,surgical,andtraumaICUpatientsroutinelyexperiencepain,bothatrestandduringstandardICUcare;2)proceduralpainiscommoninadultICUpatients;and3)paininadultcardiacsurgerypatientsiscommonandpoorlytreated;womenexperiencemorepainthanmen.Thisguideline’snewdescriptivequestionfocusesonobservationalstudiesthathaveidentifiedfactorsassociatedwithpaininICUpatientsatrestandduringprocedures. DuringRest. Fivestudies(evaluatingfrom74to5,176patientseach)describefactorsassociatedwithpaininmedical,surgical,andtraumaICUpopulations(26–30).Thetimefrompainrecognitiontoanalgesicinitiation,thepainbeingworsethanwhatthepatientexpected,andICUlengthofstay(LOS)aresignificantpredictorsofhigherself-reportedpainintensity(26).TheamountofanalgesicadministeredaftercardiacandabdominalsurgeryintheICUisasignificantpredictoroflaterpainintensity,painaffect(i.e.,emotionalexperience),andpainsensation(i.e.,qualityofpainrelatedtothesensorydimensionofthepainexperience)(27).Among301mechanicallyventilatedpatients,youngerageandpriorsurgerybothpredictedgreaterpainatrest(28).Aftercardiacsurgery,patientswithpreoperativeanxietyordepressionhaveahigherlevelofself-reportedpainintensity(29).Onelargecohortof5,176medicalICUadultsreportedthefollowingbaselinepredictorsofhigherself-reportedpainintensityduringtheICUadmission:youngerage;needforsupporttoconductdailylivingactivities;numberofcomorbiditiessuchascardiacandpulmonarydiseases;depression;anxiety;andanexpectationofafuturepoorqualityoflife(30).Cliniciansshouldmakeanefforttoobtaininformationfromallrelevantsources,includingfamilyandothercaregivers,abouttheirpatient’spre-ICUillnessbackgroundtobetterconsiderthesefactorsinplanstoimprovepatientcomfort. DuringProcedures. Atotalof12studies(evaluatingfrom30to5,957patientseach)haveevaluatedpainlevel,mostlythroughpatientself-reports,during12differentproceduresinvariousICUpopulations(i.e.,medical,surgical,cardiovascular,trauma,andneurologic)(27,28,31–37).Thefollowingproceduresareassociatedwiththegreatestincreasedpainintensity:arterialcatheterinsertion,chesttuberemoval(CTR),wounddrainremoval(16),turning(32)andrepositioning,andtrachealsuctioning(37).(AcompletelistofpainfulprocedurescanbefoundinSupplementalTable4[SupplementalDigitalContent6,https://links.lww.com/CCM/D764].)Patientswithasurgicalhistory/diagnosisortraumahadworseproceduralpain(32),asdidyounger(37),female(33),andnon-whitepatients(34,37);however,inonereportevaluatingsixprocedures(35),noassociationwasfoundbetweenproceduralpainintensityandageexceptduringwoundcareandtrachealsuctioning. Opioidusebeforeorduringaprocedurewasfoundtobeariskfactorforhigherproceduralpaininonerecent,largemultinationalstudy(16),butnotinasmaller,olderstudylimitedtosurgicalICUpatients(27).Thisdivergencemaybeduetoafocusonthedoseratherthanefficacyofopioidtherapy,mistimedopioidadministrations(relativetotheprocedure),andtheinclusionofpatientswithprioropioidexposure.Suchfindingsemphasizetheimportanceofpreproceduralpainassessmentandpreemptiveanalgesia,whenappropriate,forproceduresknowntocausepain.Indeed,severeproceduralpainisassociatedwithsevereadverseevents(e.g.,tachycardia,bradycardia,hypertension,hypotension,desaturation,bradypnea,andventilatordistress)(21)thatmaybepreventedwithappropriatepainassessmentandpreemptiveanalgesia. EvidenceGaps:Futureresearchshouldincludethefollowing:1)anexplorationoftheaffectofsociodemographicvariablessuchasage,gender,andethnicitythatmayaffectpainandresponsetopharmacologicintervention;2)identificationofpharmacokinetic,pharmacogenomic,andgender-associatedfactorsthatinfluenceanalgesicresponses;3)adeterminationofwhatpain-relatedbehaviorspredictself-reportedpain;4)thedevelopmentandstudyofobjectivemeasures(e.g.,pupillaryreflexdilatationresponse)todeterminepainbeforeandduringaplannedprocedureinpatientsunabletoself-reportpain;5)identificationofbiomarkersassociatedwithpain;6)conductofclinicaltrialsofpainmanagementinterventionsduringprocedures;and7)investigationoftherelationshipamongopioideffectiveness,opioidtolerance,opioid-relatedhyperalgesia,andproceduralpain(38). Assessment Question:Whatarethemostreliableandvalidpainassessmentmethodstouseincriticallyilladults? Self-ReportScales. UngradedStatements:Apatient’sself-reportofpainisthereferencestandardforpainassessmentinpatientswhocancommunicatereliably. Amongcriticallyilladultswhoareabletoself-reportpain,the0–10NumericRatingScale(NRS)administeredeitherverballyorvisuallyisavalidandfeasiblepainscale. Rationale:Fourstudiesservedtoanswertheabovequestion(39–42).Onestudyevaluated111medical/surgicalICUpatientsforpaininarandomizedorderusingfivedifferentself-reportscales:1)0–10 cmVisualAnalogScaleHorizontal(VAS-H);2)0–10 cmVisualAnalogScale(VAS)Vertical;3)VerbalDescriptorScale(VDS):nopain,mildpain,moderatepain,severepain,andextremepain);4)0–10NRSOral(NRS-O);and5)0–10NRSVisual(NRS-V)inahorizontalformat(39).TheNRS-Vhadthehighestrateofsuccess(i.e.,responseobtained)(91%);theVAS-Hthelowest(66%).TheNRS-VsuccessratewassignificantlygreaterthantheVDSandVAS(bothp<0.001)andNRS-O(p<0.05).Italsohadthebestsensitivity,negativepredictivevalue,andaccuracy;givenitseaseofuse,itwasmosthighlyfavoredbyICUpatients. The0–10FacesPainThermometer(FPT)(4.25 × 14verticalformat)scale,validatedin105postoperativecardiacsurgeryICUpatients,revealedhigherFPTscoresduringturningandgoodcorrelationwiththeVDSforpainsupportingitsconstructvalidity(43).PatientsevaluatedthefacesandnumbersintheFPTfavorablyandnearlyallrateditaseasytouseandusefulinidentifyingpainintensity.Whencomparedwiththe0–10NRS,theWong-BakerFACESscaleresultedinhigherpainscoressuggestingthatpainscalesdevelopedforchildrenshouldbeevaluatedcautiouslybeforebeingusedinadults(41).Finally,inanotherstudy(42),cardiovascularsurgeryICUpatientsstatedthatthe0–10NRSorVerbalRatingScale(VRS)ofsixdescriptorsscaleisbetterforevaluatingtheirpainthanthe0–100VAS;theyprefertohavetheirpainevaluatedwiththeVRS(vsthe0–10NRS).Insummary,the0–10NRSinavisualformatisthebestself-reportedpainscaletouseincriticallyilladults.AdescriptivepainscaleliketheVDSshouldbeconsideredforICUpatientsunabletouseanumericallyformattedscalesuchasthe0–10NRS. BehavioralAssessmentTools. UngradedStatement:Amongcriticallyilladultsunabletoself-reportpainandinwhombehaviorsareobservable,theBehavioralPainScaleinintubated(BPS)andnonintubated(BPS-NI)patientsandtheCritical-CarePainObservationTool(CPOT)demonstratethegreatestvalidityandreliabilityformonitoringpain. Rationale:Weupdatedthispsychometricanalysisofbehavioralpainassessmenttools,whichwasinitiatedinthe2013guidelines(1)andinasystematicreview(44).Fifty-threearticlespertainedtothedevelopment,validation,andimplementationof12painscalesforuseincriticallyilladultsunabletoself-reportpain.Fouradditionalpainscaleswereincluded:theFACESScale(45),theFacialActionCodingSystem(46),thePainInAdvancedDementia(PAINAD)(47),andtheBehaviorPainAssessmentTool(BPAT)(48).Inthisanalysis,weconsideredapainscalewithapsychometricqualityscoreof15–20tohaveverygoodpsychometricproperties;ascoreof12–14.9goodpsychometricproperties;10–11.9someacceptablepsychometricproperties;and0–9.9veryfewpsychometricpropertiesreportedand/orunacceptableresults(1,49).Alistofstudies(bypainscale)publishedsince2013areincludedinSupplementalTable5(SupplementalDigitalContent7,https://links.lww.com/CCM/D765),andthepsychometricscoresandthequalityofevidencesupportingeachpainscalearedescribedinSupplementalTable6(SupplementalDigitalContent8,https://links.lww.com/CCM/D766). TheCPOTandtheBPSremainthemostrobustscalesforassessingpainincriticallyilladultsunabletoself-report.Eachhasverygoodpsychometricpropertieswithscoresof16.7and15.1,respectively.TheBPS-NIobtainedapsychometricweightedscoreof14.8.AlthoughboththeBPSandtheCPOThavebeenvalidatedacrosslargesamplesofmedical,surgical,andtraumaICUs(50–54),studiesinvolvingbrain-injuredpatientsusingtheBPS(50,51)andCPOT(52–54)aresmall.Inthebrain-injuredpopulation,althoughtheconstructvalidityofbothscalesissupportedwithhigherscoresduringpainfulprocedures(vsrestandnonpainfulprocedures),patientspredominantlyexpressedpain-relatedbehaviorsthatwererelatedtolevelofconsciousness;grimacingandmusclerigiditywerelessfrequentlyobserved(50,52–54).Anadditionalstudy(51),althoughnotevaluatingvalidity,foundthatBPSandBPS-NIwerefeasibleandreliabletouseinthebrain-injuredpopulation.Ofnote,BehavioralPainScaleshavebeenvalidatedinthefollowinglanguages(otherthanFrenchorEnglish):CPOT—Mandarin(55),Korean(56),Spanish(57),andSwedish(58);BPSandBPS-NI—Mandarin(59). TheBPAT,thefirstbehavioralpainassessmenttooltoundergointernationalvalidation,obtainedapsychometricweightedscoreof10.6whentestedinitsoriginalEnglishversionand12otherlanguagesamong3,851criticallyilladultsfrom28countries(48).ThisislessthanreportedforeithertheBPSortheCPOTbecausethefeasibilityandimpactofitsuseonceimplementedinclinicalpracticeremaintobeinvestigated.Bythetimethisimplementationresearchiscomplete,itmaybeofuseincountries/languageswhereneithertheBPSnorCPOThasbeenvalidated(48).Eachoftheotherscalesconsidered(i.e.,theFace,Legs,Activity,Cry,Consolability;theNon-verbalPainAssessmentTool;thePAIN;theBOT;theFACES;theFear-AvoidanceComponentsScale;andthePAINAD)hadlowpsychometricweightedscores(<10). ProxyReporters. UngradedStatement:Whenappropriate,andwhenthepatientisunabletoself-report,familycanbeinvolvedintheirlovedone’spainassessmentprocess. Rationale:Theintensityanddistressof10differentpatientsymptoms,includingpain,wereindependentlyassessedbyICUpatients,nurses,physicians,andfamilymembers(60).Forbothpainintensityandpaindistress,thereportsoffamilyproxyreporterswerefoundtobeclosertoICUpatients’self-reportsthanthatofthepatients’nursesandphysicians.However,theagreementbetweenfamilyandpatientswasonlymoderate.AsecondstudycomparedICUnurseandpatientpainperceptionacrossnineproceduresusinga10-pointscale.Althoughpatientandnursepainscoresfornasogastrictubeinsertionandtrachealaspirationweresimilar,theyweresignificantlyhigheramongnurses(vspatients)forpositionchange,subcutaneousinjection,bloodsugartesting,andbloodpressure(BP)measurement(61).NostatisticalmeasureofagreementbetweennurseandICUpatientscoreswasreported.Finally,comparedwithseriouslyillpatients’self-reports,surrogatescorrectlyidentifiedpainpresence74%ofthetimeandpainseverity53%ofthetime,withatendencytooverestimatepainintensity(62).Therearefamilieswhomaynotwanttobeinvolvedinpainassessmentorsituationswherefamilyinvolvementinpainassessmentisnotappropriate.FamilyinvolvementinpainassessmentshouldnotsubstituteforanICUteam’sroleandcommitmenttosystematicpainassessmentandoptimalanalgesia. PhysiologicMeasures. UngradedStatement:Vitalsigns(VS)(i.e.,heartrate[HR],BP,respiratoryrate[RR],oxygensaturation[Spo2],andend-tidalCO2)arenotvalidindicatorsforpainincriticallyilladultsandshouldonlybeusedascuestoinitiatefurtherassessmentusingappropriateandvalidatedmethodssuchasthepatient’sself-reportofpain(wheneverpossible)orabehavioralscale(i.e.,BPS,BPS-NI,CPOT). Rationale:The2013guidelinesstatethatVSshouldnotbeusedalonetoassesspainincriticallyilladults(1).Fourteenstudies(fournewsincethe2013guidelines)(n=30–755patients)evaluatedthevalidityofusingVSforpainassessmentacrossvariousICUpopulationsandreportedinconsistentresults(31,34,37,63–73).In11of14studies,HRand/orBPwasfoundtoincreasewhenICUpatientswereexposedtoanociceptiveprocedure(e.g.,endotracheal/trachealsuctioning)comparedwitheitherrestoranonnociceptiveprocedure(e.g.,cuffinflation,eyecare)(34,37,63–71).However,theseHRandBPincreases(<20%inallstudies)werenotconsideredtobeclinicallysignificantbytheauthors.Inaddition,VSwerefoundtoincreaseduringbothnociceptiveandnonnociceptiveproceduressuggestingthelackofvalidityoftheseindicators(68,70,72–74).Insomestudies,RRincreasedand/orend-tidalCO2decreasedduringapainfulprocedure(64,65,68),whereasSpo2decreased(65,69).ExceptforassociationsfoundamongtheseVSs(i.e.,HR,RR,andSpo2)andthepaindescribedbycardiacsurgeryICUpatientsthemselves(64)andbycriticallyilladultswithatraumaticbraininjury(TBI)(74),anassociationbetweenVSchangesandpatients’self-reportedpainwasnotobserved(65,67,68,70).Inonequalityimprovementproject(19),changesinVS(e.g.,tachycardia,bradycardia,hypertension,hypotension,desaturation,andbradypnea)duringnursingcare(bathing,massage,sheet-change,repositioning)wereconsideredasseverepain-relatedadverseevents.AlthoughVSchangescanbeconsideredtobepain-relatedadverseevents,theyshouldnotbeusedforpainassessmentincriticallyilladults. EvidenceGaps:Whenevaluatingself-reportedpainintensityscales,furtherresearchcomparingFACESpainscaleswithotherratingscales(e.g.,NRS,VDS,andVAS)inheterogeneousICUpopulationsisrequired.Familymembers’actingasproxyreportersusingbehavioralpainassessmenttools(e.g.,BPS/BPS-NIandCPOT)forICUpatientsunabletoself-reportshouldbeexplored.Behavioralscalesarethealternativemeasurestousewhenthepatientisunabletoself-report(75).ScalerevisionscouldenhancethevalidityoftheiruseinICUpatientswithbraininjuryandotherneurologicallycriticallyillpatients(suchasthosewithneuromusculardiseases);researchontheapplicationoftheBPATinICUpracticeisencouraged.However,situationsexistforwhichbehavioralscalesareimpossibletouse(e.g.,unresponsivepatientswithaRichmondAgitation-SedationScale[RASS]≤−4).Insuchsituations,noalternativemethodsarecurrentlyavailabletoICUclinicians.OthertechnologythatmaybeusefulintheICUpainassessmentprocessshouldbeexplored.TechnologymeasuringHRvariability(e.g.,theAnalgesiaNociceptionIndex)(76,77)orincorporatingsimultaneouslydifferentphysiologicparameters(e.g.,NociceptionLevelIndex)(78)mayberelevant.Pupillaryreflexdilationusingvideopupillometryhasshownpromisingresultsinpainassessmentofcriticallyilladults(79–81),butfutureresearchisnecessarytoinvestigatethebenefits,harms,andfeasibilityofimplementationintheICU. PharmacologicAdjuvantstoOpioidTherapy OpioidsremainamainstayforpainmanagementinmostICUsettings.However,theirsideeffectspreoccupycliniciansbecauseofimportantsafetyconcerns,suchassedation,delirium,respiratorydepression,ileus,andimmunosuppression,maylengthenICULOSandworsenpost-ICUpatientoutcome.A“multi-modalanalgesia”approachhasbeenusedintheperioperativesettingtoreduceopioiduseandtooptimizepostoperativeanalgesiaandrehabilitation(82).Nonopioidanalgesicssuchasacetaminophen,nefopam,ketamine,lidocaine,neuropathicagents,andnonsteroidalanti-inflammatorydrugs(NSAIDs)haveeachbeenevaluatedincriticallyilladultswiththeaimofsparingopioiduseandimprovinganalgesiceffectiveness.Inadditiontoopioids,thesenonopioidanalgesicalternativesmaybecombinedwithregionalanestheticsandnonpharmacologicinterventionsknowntoreducepain(seebelow).Dose,duration,andpharmacologiceffectivenessneedtobeevaluatedwhencombinationstrategiesarebeingevaluated. Acetaminophen. Question:Shouldacetaminophenbeusedasanadjuncttoanopioid(vsanopioidalone)forpainmanagementincriticallyilladults? Recommendation:Wesuggestusingacetaminophenasanadjuncttoanopioidtodecreasepainintensityandopioidconsumptionforpainmanagementincriticallyilladults(conditionalrecommendation,verylowqualityofevidence). Rationale:Twosingle-centered,parallel-grouprandomizedcontrolledtrials(RCTs)evaluatedIVacetaminophen1 gevery6hours(q6h)versusplaceboinadouble-blindfashionin113postcardiacsurgerypatients(83)andinanopendesignin40postabdominalsurgicalICUpatients(84).After24hours,pooledanalysisofthesetwotrialsrevealedadecreaseinpainintensityatrestmeasuredbytheVAS-H(meandifference[MD],–0.5points;95%CI,–0.7to–0.2;moderatequality)andinopioidconsumption(MD,–4.5 mg[morphineequivalents];95%CI,–6.6to–2.5;moderatequality)intheacetaminophengroups.Inthestudydemonstratingthegreatestreductioninopioidconsumption(84),timetoextubation,sedation,andnausearatewereallsignificantlyimprovedintheacetaminophengroup.TheriskforIVacetaminophen-associatedhypotension(adecreaseinthemeanarterialpressure>15 mmHgmayoccurinupto50%ofpatients)mayprecludeitsuseinsomepatients(85).Giventhesefindings,panelmemberssuggestusingacetaminophen(IV,oral,orrectal)todecreasepainintensityandopioidconsumptionwhentreatingpainincriticallyillpatients,particularlyinpatientsathigherriskforopioid-associatedsafetyconcerns(e.g.,criticallyillpatientrecoveringfromabdominalsurgeryandatriskforileusornauseaandvomiting).AlthoughIVacetaminophenwastheinterventionevaluatedinthetworelevantstudies,thepanelfeltthatthisconditionalrecommendationwasgeneralizabletoallacetaminophenadministrationroutes.Althoughnotstudiedinthecriticallyill,theabsorption(i.e.,bioavailability)ofacetaminophenadministeredbytheoralorrectalroutemaybereducedinsomecriticallyillsubgroups(e.g.,thoserequiringvasopressorsupport).TheIVrouteofadministrationmaybepreferableinthesesituations,balancedwiththehypotensionriskdescribedwithIV(butnotenteral)acetaminophenadministration.TheacquisitioncostandavailabilityofIVacetaminophenvarywidelyamongcountriesandwilllikelyinfluencethedecisiontousethisspecificformulationofacetaminophenincriticallyilladults. Nefopam. Question:Shouldnefopambeusedeitherasanadjunctorareplacementforanopioid(vsanopioidalone)forpainmanagementincriticallyilladults? Recommendation:Wesuggestusingnefopam(iffeasible)eitherasanadjunctorreplacementforanopioidtoreduceopioiduseandtheirsafetyconcernsforpainmanagementincriticallyilladults(conditionalrecommendation,verylowqualityofevidence). Rationale:Nefopamisanonopioidanalgesicthatexertsitseffectbyinhibitingdopamine,noradrenaline,andserotoninrecaptureinboththespinalandsupraspinalspaces.A20-mgdosehasananalgesiceffectcomparableto6 mgofIVmorphine(86).Unlikenon–cyclooxygenase(COX)-1selectiveNSAIDs(e.g.,ketorolac),nefopamhasnodetrimentaleffectsonhemostasis,thegastricmucosa,orrenalfunction;unlikeacetaminophen,ithasnodetrimentaleffectsonhepaticfunction,andunlikeopioids,ithasnodetrimentaleffectsonvigilance,ventilatorydrive,andintestinalmotility.However,nefopamusecanbeassociatedwithtachycardia,glaucoma,seizure,anddelirium.Nevertheless,nefopammaybeasafeandeffectivealternativeoradjunctiveanalgesicforICUpatients.AlthoughnotavailableinUnitedStatesandCanada,nefopamisalow-costdrugthatisusedinnearly30countries.Forexample,afteracetaminophen,itisthesecondmostfrequentlyusednonopioidmedicationinmechanicallyventilatedICUpatientsinFrance(87). Athree-armed,double-blind,noninferiorityRCTtestedtheeffectofnefopam,fentanyl,andcombinationnefopam+half-dosefentanyl,administeredbyapatient-controlledanalgesia(PCA)device,in276electivecardiacsurgerypatientsinoneICU(88).Patients’self-reportedpainintensitywasnotsignificantlydifferentamongthethreegroupsdespitesimilarPCAvolumes.Nauseawassignificantlymorefrequentinthefentanylgroupcomparedwithnefopamgroups.Ifavailable,nefopamcouldbeusedtoreducetheopioidconsumptionandopioid-associatedsideeffects,suchasnausea,afteranevaluationoftherisk-to-benefitratioofallavailableanalgesicoptionsandpatientreassessmentforpotentialsideeffects(tachycardia,glaucoma,seizure,anddelirium)(89–92). Ketamine. Question:Shouldketaminebeusedasanadjuncttoanopioid(vsanopioidalone)forpainmanagementincriticallyilladults? Recommendation:Wesuggestusinglow-doseketamine(0.5mg/kgIVPx1followedby1-2μg/kg/mininfusion)asanadjuncttoopioidtherapywhenseekingtoreduceopioidconsumptioninpostsurgicaladultsadmittedtotheICU(conditionalrecommendation,verylowqualityofevidence). Rationale:Ketamine,becauseofitsN-methyl-d-aspartate(NMDA)receptor-blockingpropertiesandpotentialtoreducetheriskforopioidhyperalgesia,hasbeenevaluatedinpostoperativeadultsasastrategytoimprovepainreliefwhilereducingopioidrequirementsintwonon-ICUsystematicreviews(93,94).Inasingle-center,double-blindRCTof93postabdominalsurgeryICUpatients,adjunctiveketamine(0.5mg/kgIVpush,2μg/kg/mininfusion×24hrfollowedby1μg/kg/min×24 hr)wasassociatedwithreducedmorphineconsumption(MD,–22 mg;95%CI,–30to–14;lowquality)butnodifferenceinpatients’self-reportedpainintensity(95).Thepanelnotedthatreducedopioidconsumptionisonlyasurrogateforbetterpatient-centeredoutcomes.Theincidenceofsideeffects(i.e.,nauseadelirium,hallucinations,hypoventilation,pruritus,andsedation)wasnotdifferentbetweentheketamineandopioid-alonegroups.BasedonthisgenerallypositiveICURCT,thepanelmadeaconditionalrecommendationfortheuseoflow-doseketamineasanadjuncttoopioidstooptimizeacutepostoperativepainmanagementincriticallyilladultsoncethebenefitsandharmsofitsusehavebeenconsideredbyclinicians.BecausethissingleavailableICURCThadahighriskofbiasandwasalsolimitedtopostoperativeabdominalsurgerypatients,thepanelalsoconsideredindirectevidencefromRCTsinvolvingnon-ICUpatientsthat,overall,suggestedbenefitwithketamineuse(93,94). NeuropathicPainMedications. Question:Shouldaneuropathicpainmedication(e.g.,gabapentin,carbamazepine,andpregabalin)beusedasanadjuncttoanopioid(vsanopioidalone)forpainmanagementincriticallyilladults? Recommendations:Werecommendusinganeuropathicpainmedication(e.g.,gabapentin,carbamazepine,andpregabalin)withopioidsforneuropathicpainmanagementincriticallyilladults(strongrecommendation,moderatequalityofevidence). Wesuggestusinganeuropathicpainmedication(e.g.,gabapentin,carbamazepine,andpregabalin)withopioidsforpainmanagementinICUadultsaftercardiovascularsurgery(conditionalrecommendation,lowqualityofevidence). Rationale:TwoRCTsinICUpatientswithGuillain-Barrésyndrome(96,97)andtwoRCTsinpostcardiacsurgeryICUpatients(98,99)wereincluded.Eachofthesetrials,althoughdouble-blinded,wassmallandsinglecentered.ThefirstGuillain-Barrésyndrometrialcomparedgabapentin(15 mg/kg/d)withplaceboin18patientsusingacrossoverdesign(96).InthesecondGuillain-Barrésyndrometrial,gabapentin(300 mg/d),carbamazepine(100 mg/d),andplacebowerecomparedin36patientsusingaparalleldesign(97).Pooledanalysisshowedthatneuropathicagentsreducedpainintensitymeasuredbythe0–10NRS(MD,–3.44 cm;95%CI,–3.90to–2.98;highquality).Patientsreceivinggabapentinhadalsosignificantlylowerpainintensitythanpatientsreceivingcarbamazepine(97).Twopostcardiacsurgerytrialscomparedpregabalin(150 mgbeforesurgerythen150 mgdaily)withplaceboin40and60patients,respectively(98,99). Pooledanalysisofthesefourtrialsdemonstratedasignificantdecreaseinopioidconsumptioninthefirst24hoursafterneuropathicagentinitiation(MD,–13.54 mg[morphineequivalent];95%CI,–14.57to–12.5;moderatequality).However,thefourRCTsincludeddiverseopioidsasbaselinetreatment:fentanyl(96,97),oxycodone(98),andtramadol(99),whichmaylimittheapplicabilityofresults.Acrossthetwopostsurgicaltrials,bothtimetoextubation(MD,+0.36 hr;95%CI,–0.7to+1.43;lowquality)andICULOS(MD,–0.04d;95%CI,–0.46to+0.38;lowquality)weresimilarbetweentheneuropathicandnonneuropathicmedicationgroups(99). TheGuillain-Barrésyndromepopulationisconsideredbyneurologiststobeoneofthebestpopulationstoevaluateneuropathicpainmedicationefficacy(amongthelargerpopulationofICUpatientswhomighthaveneuropathicpain).Theexistenceoflimiteddataandpotentialdrawbackstoneuropathicpainmedicationusearedistinctinthemuchlargerpopulationofcardiovascularsurgicalpatients;ourrecommendationfocusesonopiateexposurereductioninpatientswho,inmostcases,donothaveneuropathicpain.Thequalityofevidenceforthepostcardiacsurgeryrecommendationwaslowduetoissuesrelatedtoriskofbiasandimprecision(98).Panelmembersestimatedthatneuropathicagentshadnegligiblecostsandwerewidelyavailablealthoughthepossiblesedativeandcognitiveeffectsoftheseagentscouldprecludetheiruseinsomepatients.Thesedrugsrequiretheabilityforpatientstoswalloworhaveenteralaccess. Lidocaine. Question:ShouldIVlidocainebeusedasanadjuncttoanopioid(vsanopioidalone)forpainmanagementincriticallyilladults? Recommendation:WesuggestnotroutinelyusingIVlidocaineasanadjuncttoopioidtherapyforpainmanagementincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:Onesingle-center,double-blindRCTof100cardiacsurgerypatientsrequiringapostoperativeICUstayfoundthatlidocaine(1.5 mg/kgIVbolus×1over10 minatthetimeofsurgeryfollowedbyanIVinfusionof30µg/kg/minfor48 hr)versusplacebodidnotaffectpatient’sself-reportedpainintensity;postoperativefentanylorsedativeconsumption,timetoextubation;norICUandhospitalLOSwhencomparedwithplacebo(100).Thisstudyhadahighriskofbiasrelatedtoselectionbiasandalackofintention-to-treatanalysis. Evidencefromnon-ICUstudieshelpedsupportthisrecommendation.Ameta-analysisassessingtheimprovementofanalgesiaandopioid-relatedsideeffectsinnon-ICUpostoperativepatientsreportedonlylow-to-moderatequalityevidencethatadjunctivelidocaine,whencomparedwithplacebo,decreasedpostoperativepainintensityscoresafterabdominalsurgery.Itdidnotfindanimprovementwithlidocaineuseforobjectiveoutcomesliketimetofirstspontaneousbowelmovementaftersurgery.Itdidnotevaluatetheimportantsafetyconcernsassociatedwithlidocaineuse(101).AlthoughtheuseofIVlidocaineinfusionsasadjunctivemedicationisdiscouragedforthegeneralICUpopulation,individualpatientsandcertainsurgicalICUcohortsmaybenefitfromthisintervention.Ofnote,theinfluenceofIVlidocaineinfusiondoseanddurationandinterpatientpharmacokineticvariabilityontheriskthatneurologicandcardiactoxicitywilloccurintheICUpopulationremainsunclear.Atthistime,concernsaboutsafetyoutweighthetheoreticalbenefitsofitsuseinthegeneraladultICUpopulation. NSAIDs. Question:ShouldaCOX-1–selectiveNSAIDbeusedasanadjuncttoanopioid(vsanopioidalone)forpainmanagementincriticallyilladults? Recommendation:WesuggestnotroutinelyusingaCOX-1–selectiveNSAIDasanadjuncttoopioidtherapyforpainmanagementincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:Twosingle-centerRCTs,oneincluding120postcardiacsurgeryICUpatientsinfourparallelgroups(adjunctive75 mgdiclofenac,100 mgketoprofen,100 mgindomethacin,orplacebo)(102)andoneincluding43postabdominalsurgeryICUpatientsintwoparallelgroups(adjunctive100 mgketoprofenorplacebo)(103),evaluatedtheroleofCOX-1–selectiveNSAIDsforpostoperativeICUpaincontrol.PooledanalysisdemonstratedthatNSAIDsnonsignificantlyreducedpainintensityatrestat24hoursasmeasuredbythe0–10VASorNRS(MD,–0.35 cm;95%CI,–0.91to+0.21;lowquality).Inonetrial(103),painintensityduringdeepinspiration—althoughsignificantlylowerat6hours(MD,–1.3 cm;95%CI,–2.36to–0.24;moderatequality)—wasnotdifferentat24hours(MD,–0.6 cm;95%CI,–1.44to+0.24;lowquality).Pooledanalysisshowedasignificantreductionofmorphineconsumptionat24hours(MD,–1.61 mg[morphineequivalents];95%CI,–2.42to–0.8;verylowquality).Neitherstudyreportedadifferenceinnausea/vomitingbetweengroups.Norespiratorydepressioneventswerereported(103). NSAID-relatedsideeffectsincludingacutekidneyinjuryandexcessivebleedingwerenotsignificantlydifferentbetweenthethreeNSAIDsandtheplacebogroup.Bothstudieshadahighriskofbias(102,103).Giventheperceivedsmallbeneficialeffectbalancedwithseriouspotentialsafetyconcerns(e.g.,bleedingandkidneyinjury),particularlywhenNSAIDsareadministeredformultipledoses,thepanelmembersrecommendagainstroutineuseofNSAIDsalongwithopioidsfornonproceduralpainmanagementincriticallyilladults.Aswithmostconditionalrecommendations,thepanelfeltthattherearelikelypatients—andperhapsevencohortsofpatients—whomaybenefitfromNSAIDs.NoRCTevaluatingaCOX-2–specificNSAID(e.g.,celecoxib)incriticallyilladultswasidentified;thus,theroleoftheseagentsremainsunclear. EvidenceGaps:Alladjunctivenonopioidanalgesics(whenusedinthecontextofmultimodalanalgesia)requirelargersizedstudiesincriticallyilladultsthataredesignedtoclearlyevaluatetheiropioid-sparingpropertiesandtheirabilitytoreduceopioid-relatedsideeffects(104).Theoutcomesassociatedwithopioidsafetyconcernssuchasileus,durationofmechanicalventilation,immunosuppression,healthcare-associatedinfections,delirium,andbothICUandhospitalLOSmustbeevaluatedcarefully.Therisksofusingnonopioid-adjunctivemedicationsforanalgesiainapopulationatincreasedriskforadversedrugeffectsneedtobebetterdefined.Thisincludesanalysisofliverandrenaltoxicitiessecondarytoacetaminophen(allroutes),hemodynamicinstabilitysecondarytoIVacetaminophen(85),riskofbleedingsecondarytonon-COX-1–selectiveNSAIDs,delirium,andneurotoxicityassociatedwithketamine(105),andhemodynamicalterationswithIVlidocaine(100).Theoptimaldoseandrouteofadministrationforthesenonopioidsincriticallyillpatientsneedtobeinvestigated,andstudiesshouldbeconductedinthecriticallyillmedicalpatientsunabletoself-reportpain.Finally,therolefortheuseofdifferentopioid-adjunctivemedicationsincombinationneedstobeevaluated. SummaryofPharmacologicAdjuvantstoOpioidTherapy. Thepanelgenerallysupportstheutilizationofmultimodalpharmacotherapyasacomponentofananalgesia-firstapproachtospareand/orminimizebothopioidsandsedatives.Amultimodalanalgesiastrategyislikelytoimprovepaincontrol,reduceopioidconsumption,andimprovepatient-centeredoutcomes.Inpatientsforwhomtheriskofthesenonopioid-adjunctivemedicationsfavorstheirexclusion,theseveralnonpharmacologicstrategies(describedbelow)provideanopportunitytominimizeopioidconsumption. Protocolsmandatingsystematicassessmentswithvalidatedpainandsedationscalesconsistentlyreducedtheconsumptionofopioidsandsedatives(3,106–111).Studiesaimingtoevaluateanimprovementinsystematicpainassessmentwithvalidatedscalesevaluatedcohortsinwhomtheuseofnonopioidmultimodalpharmacotherapywassignificantlyhigher(106,110).Dailysedationinterruptioncanalsobeausefulinterventionatreducingopioidconsumption,providedproperassessmentofpainprecedesit(112).Musicandmassage,asrecommendedintheseguidelines,havealsobeenshowntoreduceopioids(113–117).Selectedadjunctiveagentsshouldbebothpatientspecific(e.g.,minimizingacetaminophenusewithliverdysfunctionorhighdosesofgabapentinwithrenaldysfunction)andsymptomspecific(e.g.,useofketamineinsurgicalICUpatientsathighriskofopioidsideeffects)toimprovepainscores,decreaseopioidconsumption,minimizenewadverseeffects,andreducepolypharmacy(SupplementalFig.2[SupplementalDigitalContent9,https://links.lww.com/CCM/D767]summarizesapharmacologicstrategytodecreaseopioidconsumptionintheICU). PharmacologicInterventionstoReduceProceduralPain BedsideproceduresintheICUcanincluderegularactivities(e.g.,turning)anddiscreteprocedures(e.g.,arterialcatheterinsertion).Painshouldbeassessedandappropriatelytreatedbeforeaproceduretopreventmoreintensepainduringtheprocedure.The2013guidelinesrecommendedthatpreemptiveanalgesiaand/ornonpharmacologicinterventions(e.g.,relaxation)beadministeredtoalleviatepaininadultICUpatientsbeforeCTRandsuggesttheseinterventionsbeforeotherprocedures(1). OpioidUseandDose. Questions:Shouldanopioid(vsnoopioid)beusedforcriticallyilladultsundergoingaprocedure? Shouldahigh-doseopioid(vsalow-doseopioid)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:Wesuggestusinganopioid,atthelowesteffectivedose,forproceduralpainmanagementincriticallyilladults(conditionalrecommendation,moderatelevelofevidence). Remarks:Thesameopioids(i.e.,fentanyl,hydromorphone,morphine,andremifentanil)thatarerecommendedinthe2013guidelinestomanagepainshouldalsobeconsideredwhenanopioidisdeemedtobethemostappropriatepharmacologicinterventiontoreduceproceduralpain(1). Rationale:ThreesmallRCTstestedtherelativeeffectivenessofdifferentdosesofopioidsadministeredbeforeturningandCTR.Cardiacsurgerypatientsinahigh-doseremifentanilgroupversusalow-doseremifentanilgrouphadsignificantlylowerCTRpain(118).However,inasecondstudy,whenhigh-doseversuslow-dosemorphinewasadministeredbeforeturningorCTR(whensteady-statemorphineserumconcentrationshadnotbeenreached),nosignificantdifferencesinproceduralpainscoreswereseen(119);however,proceduralpainscoreswerelowinbothgroups.Pooledanalysiscomparinghigh-doseversuslow-doseopioidsforperiproceduralpainmanagementdemonstratedasmallreductioninthe0–10NRSpainscorewithhigh-doseopioiduse(standardmeandifference[SMD],–0.26 cm;95%CI,–0.94to+0.42;lowquality);however,conclusionsarelimitedgiventhedifferingresultsbetweenindividualstudies.Inathirdstudy,medical-surgicalICUpatientswhoreceivedIVfentanylversusplacebobeforeturninghadasignificantlylowerscoreontheBPS(120).Thepotentialforharmwithopioids,inadose-dependentproportion,wasdemonstrated.Twoof20patientsinthehigh-doseremifentanilgrouphad1–3minutesofapnea,requiringbagandmaskventilationfor3minutes(118),whereas10%ofpatientsinanotherstudywhowereadministeredhigh-dosefentanyl(atadoseof1–1.5µg/kg)experiencedrespiratorydepression(120).Giventhisshort-termconsequenceofhigherdoseopioidsincriticallyillpatients,aswellastheeffectivenessofsmalldosesofopioidsinthethreestudiesinmaintaininglowpainlevels,opioidsatthelowesteffectivedosesforproceduralpainarefavored.Timingopioidadministrationsothattheopioid’speakeffectcoincideswiththeprocedureisimportant. LocalAnalgesia/NitrousOxide. Questions:Shouldlocalanalgesia(vsanopioid)beusedforcriticallyilladultsundergoingaprocedure? Shouldnitrousoxide(vsanopioid)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:WesuggestnotusingeitherlocalanalgesiaornitrousoxideforpainmanagementduringCTRincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:OnlyoneRCTtestedtheeffectsofsubcutaneousinfiltrationof20 mLof0.5%bupivacainearoundamediastinalCTRsiteversusinhaled50%nitrousoxideandoxygenaftercardiacsurgery(121).Patientsinthebupivacaine(vs50%nitrousoxideandoxygen)grouphadsignificantlylowerCTRpainscores;however,thequalityofevidencewaslow.Despiteasignalofbenefit,thefeasibilityofsubcutaneousbupivacaineuseintheICUischallenging,giventhatitcanonlybeadministeredbyaqualifiedclinician.Alackofdatatosupporttheuseoflowerrisklocalanestheticslikelidocaine,abletobeadministeredbyawiderrangeofclinicians,alsoinfluencedthepanel’srecommendation. VolatileAnesthetics. Question:Shouldaninhaledvolatileanesthetic(vsnouseofthisagent)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:Werecommendnotusinginhaledvolatileanestheticsforproceduralpainmanagementincriticallyilladults(strongrecommendation,verylowqualityofevidence). Rationale:Isoflurane,avolatileanesthetic,istraditionallyusedforgeneralanesthesia.Ithasarelativelyrapidonsetandrecoveryandhasdemonstratedcardioprotectiveeffectssuchaspreservedmitochondrialoxygenconsumption,troponinrelease,andmyocardialinfarction(122).LittleisknownoftheanalgesiceffectsofisofluraneforperiproceduralpaininICUpatients. NoRCTscomparingisofluranetoacontrolintervention(e.g.,opioidalone)werefound.Onesmalldouble-blindedRCTtestedtherelativeeffectivenessofnitrousoxide50%andoxygencombinedwithisofluraneversusinhalednitrousoxide50%andoxygenaloneforCTRinpatientsafteruncomplicatedcardiacsurgery(123).Nitrousoxide50%andoxygenalongwithisofluraneinhalationweremoreeffectiveforpainrelatedtothefirstoftwochesttubesremoved.However,removalofthesecondchesttubewasmorepainful,regardlessofthegasinhaled.Althoughthestudyshowedapotentialforbenefit,wedonotrecommendthisinterventionbecausethestudyfailedtoconsidertheCTRtimerelativetothegasadministrationtime;theverylowqualityofevidenceavailable(imprecision[asmallsamplesizeandonlyonestudy]andindirectness[onlycardiacsurgerypatients]);theincreasedresourcesneededforuseofgasesintheICU;andinsomecenters,safetyissuesrelatedtotheuseofvolatileanestheticsoutsidetheoperatingroom. NSAIDs. Question:ShouldanNSAIDadministeredIV,orally,and/orrectally(vsanopioid)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:WesuggestusinganNSAIDadministeredIV,orally,orrectallyasanalternativetoopioidsforpainmanagementduringdiscreteandinfrequentproceduresincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:Inarandomizeddouble-blindstudy(124),theeffectsoftwotypesofanalgesicswithdifferentmechanismsofactionweretestedonCTRpain:asingle4-mgdoseofIVmorphine(anopioid)orasingle30-mgdoseofIVketorolac(anon-COX-1–specificNSAID).Proceduralpainintensityscoresdidnotdiffersignificantlyamongthegroups,althoughpainintensitywasmildinbothgroupsandthequalityofevidencewaslimitedbyimprecision(smallnumberofpatients). Question:ShouldanNSAIDtopicalgel(vsnouseofNSAIDgel)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:WesuggestnotusinganNSAIDtopicalgelforproceduralpainmanagementincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:TopicalvaldecoxibisanNSAIDgel.UseofatopicalanalgesicratherthananIVNSAIDoropioidorlocalanestheticinjectioncouldbelessdemandingonavailablenursingresources(125).Onerandomizeddouble-blindstudyinpostcardiacsurgerypatientstestedtheefficacyoftopicalvaldecoxib50-mgplacebogel(vsaparaffingel)appliedtotheskinsurroundingachesttubebeforeCTR(125).PatientswhoreceivedtheNSAIDgelhadlessCTRpainthanthosewhoreceivedtheparaffincontrolgel.However,thepanelmadeaconditionalrecommendationagainsttheuseofNSAIDgelforproceduralpainmanagementgivenconcernsaboutthequalityofthisstudyandthehighacquisitioncostofNSAIDgelproductinsomecountriesthatmaymaketheiruseprohibitive. EvidenceGaps:Futurestudiesarewarrantedtotesttheeffectivenessofvarioustypesanddosesofopioidsinlargersampleofpatientsduringdifferentprocedureswhileattendingtothepatients’preproceduralpain,particularlyinacontextwhereopioidexposuremaybeundesirable.Studiesofproceduralpaininterventionsshouldavoidriskofbiasthroughuseofcontrolgroups,allocationconcealment,andblinding.GeneralizabilityofstudyfindingscanbeimprovedbyincludingheterogeneoussamplesofICUpatientsundergoingthesameprocedureandalsopatientsadmittedtotheICUwithaknownopioidusedisorder.MuchproceduralpainresearchhasusedCTRastheparadigmprocedure,mostlikelybecausetheresearchprotocolcanbestandardizedmoreeasilythanwithotherproceduresandbecauseCTRrepresentsapainfulICUprocedurethatfrequentlyoccursaftercardiacsurgery.ThedegreetowhichdatafromCTRstudiescanbeextrapolatedtootherICUprocedureslikelytobeassociatedwithpainremainsunclear. NonpharmacologicInterventionstoReducePain Cybertherapy/Hypnosis. Questions:Shouldcybertherapy(virtualreality[VR])(vsnouseofcybertherapy)beusedforpainmanagementincriticallyilladults? Shouldhypnosis(vsnouseofhypnosis)beusedforpainmanagementincriticallyilladults? Recommendation:Wesuggestnotofferingcybertherapy(VR)orhypnosisforpainmanagementincriticallyilladults(conditionalrecommendation,verylowqualityofevidence). Rationale:CybertherapyisaVRdistractionpostulatedtoreducepostoperativepainanddistressintheICU.Asetoffivesimulatedenvironmentswasdisplayedtothepatientfor30minutesbeforeandaftersurgery(126).HypnosiswasadministeredbyatrainedICUnurseinalertICUpatientsandwasinducedusingthecenesthesicapproach(i.e.,patientattentionfocusedonanybodysensation)orcarriedoutontheactualsymptom(painoranxiety)(127).Onestudyevaluated67postcardiacsurgeryICUpatientsbeforeandafterthecybertherapyintervention(126).Most(88%)reportedadecreasedlevelofpostoperativepain(MD,–3.75 cmonthe0–10VAS)thatcorrespondedtoachangefrom“severetomoderate”to“moderatetolight”pain.Althoughriskofbiaswasminimal,imprecision(smallsamplesize),failuretouseavalidatedpainintensityscale,andthemethodologiclimitationsinherenttoobservationalstudiesledtoanoverallverylowqualityofevidence.Also,manyfactorsrelatedtoresources(equipment,time,ICUenvironment,andtraining)makethisinterventionpossiblyinfeasibletoimplement.Therefore,thepanelsuggeststhatcliniciansnotusecybertherapyforpainmanagementincriticallyilladults. Hypnosiswasevaluatedwith23burnICUpatientscomparedwith23matchedhistoricalcontrols(127).ThefirstICUhypnosissessionoccurredatamedianof9days(0–20d)afterinjury,andanadequatelevelofhypnosiswasobtained,onaverage,after15minutes.Onthedayafterhypnosis,repeatedpainassessments(upto12)foundthathypnosiswasassociatedwithareductioninthe0–10VAS(MD,–0.5 cm;95%CI,–1.37to+0.37;verylowquality).Opioidconsumptionwasreducedcomparedwithhistoricalcontrols.Withintheinterventiongroup,opioidconsumptionwaslowerinpatientswhoreceivedhypnosisatadmissiontotheICUcomparedwiththosewhodidnot.Theriskofbiaswasjudgedtobeveryseriousduetopoorlyevaluatedoutcomes,variabilityonassessmenttimepoints,cointerventionsbetweengroups,andunclearascertainmentofexposure.Duetohighriskofbiasandtheimprecisionassociatedwiththeobservationaldata,theoverallqualityofevidencewasverylow.Manyfactors(resources,ICUenvironment,extensivetraining,andpatientacceptability)makethisoptionpossiblyunfeasibletoimplement.Therefore,thepanelissuedaconditionalrecommendationagainsttheuseofhypnosisforpainmanagementincriticallyilladults. Massage. Question:Shouldmassage(vsnomassage)beusedforpainmanagementincriticallyilladults? Recommendation:Wesuggestofferingmassageforpainmanagementincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Remarks:Massageinterventionsvariedinsessiontime(10–30 min),frequency(onceorbid),duration(for1–7d),andbodyarea(back,feetandhands,oronlyhands). Rationale:MassageforpostoperativeICUpainmanagementincardiacandabdominalsurgerypatients(n=751and265,respectively)wasinvestigatedinfiveRCTs(65,117,128–130)(SupplementalTable7,SupplementalDigitalContent10,https://links.lww.com/CCM/D768).Thecomparatorarmsweredifferentacrossstudiesandincludedstandardcare(117,129,130),attention(129,130),orshammassage(i.e.,handholding)(65).Pooledanalysisshowedareductioninpainintensityscores(0–10VASorNRSscale)withmassageuseonthefirstdayafteritwasprovided(MD,–0.8 cm;95%CI,–1.18to–0.42;lowquality).RepetitiveadministrationofmassageseemedtoreducepainintensityscoreswithMDsvaryingfrom–0.3to–1.83 cmfromday1today5(afterpatientsweredischargedfromtheICU).Theoverallqualityofevidencewaslowduetoriskofbiasandimprecision.Noadverseeventswerereportedinrelationtotheadministrationofmassageintheincludedstudies.Resourcesvariedacrossstudiesinwhichnursesormassagetherapistsprovidedtheintervention.Minimaltraining(3–6 hr)wasprovidedtonurses.ThepanelfeltthatfeasibilityofusingmassageforICUpainmanagementwoulddependontheinterventiondurationandresourcesneeded,whichcouldaffectcost. Music. Question:Shouldmusictherapy(vsnomusictherapy)beusedforpainmanagementincriticallyilladultstorelievebothproceduralandnonproceduralpain? Recommendation:Wesuggestofferingmusictherapytorelievebothnonproceduralandproceduralpainincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:Amongthestudiesevaluated,musicinterventionsvariedinmusictype(participant’schoicefromapreselectionofmusicorharplivemusic),duration(10–45 min),andpainmanagementpurposes(proceduralornonprocedural)intheevaluatedstudies.ParticipantswereprovidedwithheadsetstolistentomusicexceptinonestudywhereliveharpmusicwasplayedintheICUroom(116).Musicinterventionswereadministeredonceinmoststudiesexceptintwostudiesinwhichparticipantsreceivedthemusicinterventionduringtwoturningprocedures(115),andoncedailyuptoamaximumof3days(117)(SupplementalTable8,SupplementalDigitalContent11,https://links.lww.com/CCM/D769). EffectivenessofmusicwastestedforproceduralpainmanagementinthreeRCTsduringdifferentproceduresincludingCTRin156cardiacsurgeryICUadults(113),C-clampprocedureafterpercutaneouscoronaryinterventionsin66patients(114),andduringtwoturningproceduresinpostoperativeICUpatients(115).Thecomparatorarmsweredifferentacrossstudiesandincludedstandardcareandwhitenoise(113),headsetsattachedtoaCDplayerwithoutmusic(115),orarestperiod(114).Pooledanalysisshowedthatmusictherapyreducedpainintensity(0–10NRS)(MD,–0.52 cm;95%CI,–1.49to+0.45;lowquality). Fornonproceduralpainmanagement,effectivenessofmusicwastestedinfourstudiesincludingthreeRCTswithatotalof434medicalorsurgicalICUpatients(12,116,117,131)andapre/posttestobservationalstudywith87cardiacsurgeryICUpatients(132).Thecomparatorarmsincludedstandardcare(117)orarestperiod(116,131).Pooledanalysisshowedthatmusicreducedpainintensity(0–10NRS)(MD,–0.66 cm;95%CI,–0.89to–0.43;lowquality).Thesereductionsinpainintensityforbothproceduralandnonproceduralpainmanagementwerenotconsideredtobeclinicallysignificant.However,thepotentialforbenefitoutweighedanysignalforharmorresourcerequirements.OnelargeRCTthatfoundthatpersonal-directedmusictherapyreducesanxietyandsedativeuseincriticallyilladultswasnotincludedintheevidenceprofileforthisquestionbecauseitdidnotreportpainassessments(133). Thequalityofevidenceofincludedstudieswasdeemedtobelow(nonproceduralpainmanagement)toverylow(proceduralpainmanagement)duetoriskofbiasandtheinconsistencyinthereportedresultsbetweenstudies.Therewerenoreportedadverseeventsrelatedtomusictherapy.However,nineparticipantsdidnotcompletethemusicinterventionintwostudiesbecausetheydislikedmusicorremovedtheirheadsets(114,131).Thepanelfeltthatmusicisasafeinterventionforpainmanagement,butthepatient’spreferenceshouldbeconsidered.Feasibilitywasraisedasanissuebythepaneldependingontheresourcesneededforitsimplementationincludingprofessionals(e.g.,musicianandmusictherapist)andequipment(e.g.,purchaseofmusicandheadsets).Storageroomandhygienemeasuresmustalsobeconsidered. ColdTherapy. Question:Shouldcoldtherapy(vsnouseofcoldtherapy)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:Wesuggestofferingcoldtherapyforproceduralpainmanagementincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Remarks:Coldicepackswereappliedfor10minutes,andwrappedindressinggauze,ontheareaaroundthechesttubebeforeitsremoval. Rationale:ColdtherapyforperiproceduralpainmanagementduringCTRwasinvestigatedintwoRCTs(n=130total)inpostcardiacsurgeryICUpatients(134,135).Inonestudy,theeffectsofcoldtherapywerecomparedwithusualcare(i.e.,oralacetaminophenevery6hr)(n=40pergroup)(134),whereasintheother,aplacebotapwaterpack(n=25pergroup)wasusedasthecomparator(135).Althoughapooledanalysisofstudiesdemonstratedanonsignificantreductioninpainintensity(0–10NRS)withcoldtherapy(MD,–1.91 cm;95%CI,–5.34to+1.52;lowquality),thepanelconsideredthatareductionofthismagnitudeontheNRSscalewasclinicallyimportantandconsistentwithmeaningfulacutepainreductions(1.3–2.4 cm)asdefinedinonestudyof700postsurgicalpatients(136). AlthoughonlyCTRwasinvestigatedinahomogeneousgroupofpostcardiacsurgerypatients,thepanelfeltthatthisrecommendationwasgeneralizabletootherproceduresandforuseinothercriticallyillpopulations.Nomentionofpossibleundesirableeffectsrelatedtotheuseofcoldtherapyappearedintheincludedliterature;however,thepanelagreedthatthesearelikelytobetrivial(unlesstheclinicianforgetstoremovethecoldpackafterCTR).AdequateroomintheICUfreezerandawrittenprotocolforuseofthisinterventionwillberequired.Simple,inexpensive,andwidelyavailableinterventionslikecoldtherapycanbeusedfrequentlyinresource-poorareaswheremedicationsmaynotbeavailable. RelaxationTechniques. Question:Shouldrelaxationtechniques(vsnouseofrelaxationtechniques)beusedforcriticallyilladultsundergoingaprocedure? Recommendation:Wesuggestofferingrelaxationtechniquesforproceduralpainmanagementincriticallyilladults(conditionalrecommendation,verylowqualityofevidence). Remarks:Therelaxationtechniqueusedineachstudydiffered. Rationale:RelaxationtechniquesrelatedtobreathingweretestedforproceduralpainmanagementandtimedwithopioidadministrationduringCTRintwodifferentmatchedcontrolstudiesevaluatingatotalof88postcardiacsurgeryICUpatients(137,138).Inonestudy(137)(inwhichtherapidlyadministeredrelaxationtechniqueconsistedofinstructingthepatienttoinhaleandholdtheirbreathforamoment;tobreatheoutandgolimpasaragdoll;andthentostartyawning),thechesttube(s)wereremovedattheendoftheyawn.Inthesecondstudy(138),patientsweretaughtbreathingexercisesthatincludedinhalingslowlythroughthenoseandexhalingslowlythroughpursedlips.Patientswereencouragedtocompletetheseexerciseseitherwiththeireyesclosedortofocusonanobjectintheroom.Breathingexerciseswereinitiated5minutesbeforeCTRandcontinuedduringchesttubedressing,sutures,andtuberemoval. Pooledanalysisshowedameanreductioninpainintensity(0–10VAS)15–30minutesafterCTR(MD,–2.5 cm;95%CI,–4.18to–0.82;verylowquality).Areductionofthismagnitudeisclinicallyimportant(136).However,thequalityofevidencewasdeemedtobeverylowduetotheimprecision(smallsamplesizes)andtheriskofbias.Althoughabreathing-focusedrelaxationtechniquewasevaluatedinarelativelyhomogeneousgroupofpatientsduringonlyonetypeofpainfulprocedure,thepanelfeltthatthisrecommendationwasgeneralizabletootherpainfulproceduresandothercriticallyillpopulations.Possibleundesirableeffectsrelatedtorelaxationwerenotmentionedintheincludedstudies,andthepanelfeltthatthesewereunlikelytooccur.Thepanelagreedthatminimalresourcesandtrainingwereneededtoprovidethisinterventionsafelyandefficiently.Therefore,relaxationusingbreathingtechniquesappearsfeasibletoimplementandacceptabletostakeholders.Writteninformationcouldalsobeprovidedtopatientstohelpfamiliarizethemwithrelaxationtechniques. EvidenceGaps:Theeffectsofnonpharmacologicinterventionsincriticallyilladultsunabletoself-reportremainunknown.Theroleofafamilymemberinthedeliveryofsomeinterventions(e.g.,relaxation,massage,andmusic)couldbeexplored.Whethermusic’scoanalgesiceffectdependsonpatient’smusicalpreferencesshouldbeconsidered.InterventionstoreduceproceduralpainshouldbeevaluatedduringproceduresotherthanCTR.Implementationstudiesdocumentingthefeasibilityandassociatedcostsrelatedtotheuseoftheseinterventionsarealsoneeded.Studiestodeterminetheeffectofrelaxationtechniquesonotheroutcomessuchassleeparealsorequired. Protocol-BasedPainAssessmentandManagement Question:Shouldaprotocol-based(analgesia/analgosedation)painassessmentandmanagementprogrambeusedinthecareofcriticallyilladultswhencomparedwithusualcare? GoodPracticeStatement:ManagementofpainforadultICUpatientsshouldbeguidedbyroutinepainassessmentandpainshouldbetreatedbeforeasedativeagentisconsidered. Recommendation:Wesuggestusinganassessment-driven,protocol-based,stepwiseapproachforpainandsedationmanagementincriticallyilladults(conditionalrecommendation,moderatequalityofevidence). Remarks:Forthisrecommendation,analgosedationisdefinedaseitheranalgesia-firstsedation(i.e.,ananalgesic[usuallyanopioid]isusedbeforeasedativetoreachthesedativegoal)oranalgesia-basedsedation(i.e.,ananalgesic[usuallyanopioid]isusedinsteadofasedativetoreachthesedativegoal).Theimplementationofthisrecommendationinfersthatinstitutionsshouldhaveanassessment-drivenprotocolthatmandatesregularpainandsedationassessmentusingvalidatedtools,providesclearguidanceonmedicationchoiceanddosing,andmakestreatingpainapriorityoverprovidingsedatives. Rationale:Thefiveoutcomesdeemedcriticaltotherecommendationincludepainintensity,medicationexposure(analgesics/sedatives),adverseevents,durationofmechanicalventilation,andICULOS(5,106–110,127,139–156)(SupplementalTable9,SupplementalDigitalContent12,https://links.lww.com/CCM/D770).Pooledanalysissuggeststhataprotocol-based(analgesia/analgosedation)painandsedationassessmentmanagementprogramcomparedwithusualcaredoesnotaffecttheincidenceofnosocomialinfection,constipation,hypotension,bradycardia,oropioidexposure,butdoesreducesedativerequirements(SMD,–0.57;95%CI,–0.84to–0.31;lowquality),durationofmechanicalventilation(MD,–1.26d;95%CI,–1.8to–0.73;moderatequality),ICULOS(MD,–2.27d;95%CI,–2.96to–1.58;moderatequality),andpainintensity(0–10VASorNRS)(MD,–0.35 cm;95%CI,–0.22to–0.49;lowquality).Panelmembersissuedaconditionalrecommendationbecausethebenefitsofaprotocol-basedapproachwerenotobservedacrossallcriticaloutcomes. EvidenceGaps:Tobeabletogeneratestrongrecommendationsfortheuseofaprotocol-basedanalgesia/analgosedationprogram,futurerandomizedstudiesmustbecompletedthataddressthefollowingquestions:1)whatistheoptimalopioid,orotheranalgesic,touseintheprotocol?2)whatICUsettingorpatientpopulationismostappropriatefortheuseofsuchaprotocol?3)whatarethepotentialbenefitsofsuchprotocolsbasedontheirabilitytoreducepainoravoidtheuseofpotentiallyharmfuleffectsofsedatives?and4)whatarethepotentialsafetyconcernsassociatedwithsuchprotocols(e.g.,opioidwithdrawal,posthospitalopioidusedisorder)? AGITATION/SEDATION Sedativesarefrequentlyadministeredtocriticallyillpatientstorelieveanxiety,reducethestressofbeingmechanicallyventilated,andpreventagitation-relatedharm(1).Thesemedicationsmaypredisposepatientstoincreasedmorbidity(157,158).Thehealthcareprovidermustdeterminethespecificindicationfortheuseofsedatives.Ifasedativeisneeded,thepatient’scurrentsedationstatusshouldbeassessedandthenfrequentlyreassessedusingvalidandreliablescales(158–161).Incriticallyillpatients,unpredictablepharmacokineticsandpharmacodynamicssecondarytodruginteractions,organdysfunction,inconsistentabsorptionandproteinbinding,hemodynamicinstability,anddrugaccumulationcanleadtoadverseevents(1,162,163). The2013guidelines(1)suggestedtargetinglightlevelsofsedationorusingdailyawakeningtrials(112,164–166),andminimizingbenzodiazepines(167)toimproveshort-termoutcomes(e.g.,durationofmechanicalventilationandICULOS).Inaddition,sedationdeliveryparadigmsandthespecificsedativemedicationusedcanhaveanimportantimpactonpost-ICUoutcomesincluding90-daymortalityphysicalfunctioning,neurocognitive,andpsychologicoutcomes.Theseissueshavebeenevaluatedinthepresentguidelinesthroughthreeactionableandthreedescriptivequestions.(AprioritizedtopiclistisinSupplementalTable10[SupplementalDigitalContent13,https://links.lww.com/CCM/D771],andvotingresultsappearinSupplementalTable11[SupplementalDigitalContent14,https://links.lww.com/CCM/D772].)Theevidencesummariesandevidence-to-decisiontablesusedtodeveloprecommendationsfortheagitation(sedation)groupareavailableinSupplementalTable12(SupplementalDigitalContent15,https://links.lww.com/CCM/D773),andtheforestplotsforallcompletedmeta-analysesareavailableinSupplementalFigure3(SupplementalDigitalContent16,https://links.lww.com/CCM/D774). LightSedation Question:Doeslightsedation(vsdeepsedation),regardlessofthesedativeagent(s)used,significantlyaffectoutcomesincriticallyill,mechanicallyventilatedadults? Recommendation:Wesuggestusinglightsedation(vsdeepsedation)incriticallyill,mechanicallyventilatedadults(conditionalrecommendation,lowqualityofevidence). Rationale:The2013PADguidelinesmadeanungradedstatementthatmaintainingalightlevelofsedationwillshortentimetoextubationandreduceICULOS(1).AlthoughthepriorguidelinedefinedlightsedationasaRASSscalescoreofgreaterthanorequalto–2andeyeopeningofatleast10minutes(112),thislevelofsedationisprobablydeeperthanrequiredformanagementofmechanicallyventilatedadultsinanICU.Nouniversallyaccepteddefinitionoflightsedationexists.Toaddressthisquestion,weevaluatedstudiesinwhichlightversusdeepsedationweredefinedapriori,measured,andexplicitlyreportedwithobjectivescalesdescribingwhetherpatientsmettheseclearlight,versusdeep,sedationtargetssystematicallyoverthetimespentintheICUandatleastq6h.Surrogatemeasures(e.g.,sedativeplasmalevels)orsubjectiveclinicalassessmentsofwakefulnesswerenotconsideredaspartofthedefinitionoflevelofsedation.Studiesdescribingadailyspontaneousawakeningtrial(SAT)werenotdeemedindicativeofalightsedationapproachbecausetheyreportedlighteningofsedationatasinglepointintime,ratherthanovertheentireday.Forstudiesthatusedscales,suchastheRASS(159),aRASSscoreof–2to+1range(oritsequivalentusingotherscales)wasconsideredaslightsedationintheevaluatedstudies. EightRCTssatisfiedourresearchcriteria(156,168–174).Weevaluatedtheeffectoflightversusdeepsedationonoutcomesthatwereconsideredcriticalbythesedationgroupandpatientrepresentatives:90-daymortality,timetoextubation,delirium,tracheostomy,cognitiveandphysicalfunctionaldecline,depression,andposttraumaticstressdisorder(PTSD).TheoutcomesevaluatedweremostlymeasuredafterICUdischargeandaredifferentfromtheshort-termoutcomesassessedinthe2013guidelineungradeddescriptivequestion.Lightsedationwasnotassociatedwith90-daymortality(RR,1.01;95%CI,0.80–1.27;moderatequality)(168,169),butitwasassociatedwithashortertimetoextubation(MD,–0.77d;95%CI,–2.04to–0.50;lowquality)(168–170)andareducedtracheostomyrate(RR,0.57;95%CI,0.41–0.80;lowquality)(170,171).Lightsedationwasnotassociatedwithareductionintheincidenceofdelirium(RR,0.96;95%CI,0.80–1.16;lowquality)(168,172),PTSD(RR,0.67;95%CI,0.12–3.79;lowquality)(156,174),depression(RR,0.76;95%CI,0.10–5.58;verylowquality)(156,170),orself-extubation(RR,1.29;95%CI,0.58–2.88;lowquality)(168–170,173).NoRCTsevaluatedtheimpactoflightversusdeepsedationoncognitiveorphysicalfunctioning. Theoverallqualityofthebodyofevidencewaslow.Boththemagnitudeofreductionintimetoextubationandtracheostomyratewereconsideredsmall;themagnitudeofharmassociatedwithself-extubationwasuncertain.WeinitiallyevaluatedthedatafromRCTsandthenreviewedobservationalstudiesrelatedtooutcomeswheretheRCTdatawereoflowquality.Observationaltrialssuggestedbenefitsinreducedriskofdeathat90daysandtimetoextubation,butnotindeliriumoutcomes(166,175,176).Onerecentcohortstudynotconsideredintheguidelineevidencedemonstratesthatsedationintensity(sumofnegativeRASSmeasurementsbynumberofassessments)independently,inanescalatingdose-dependentrelationship,predictsincreasedriskofdeath,delirium,anddelayedtimetoextubation(177).Theamountofsedationpreferredbypatientsislikelyvariable;somepatientsorfamiliesmaypreferdeepersedation,butthispreferencemaynotbeconsideredappropriatebycliniciansgiventheadverseoutcomesassociatedwithdeepsedation.Uncertaintyaboutthecost-effectivenessoflightsedationwasconsidered.Lightsedationwasconsideredlikelyacceptabletocliniciansandpatientsandfeasibletoimplement. EvidenceGaps:Despitethewideuseofvalidatedsedationscales,noconsensusonthedefinitionoflight,moderate,anddeepsedationisavailable.Furtherexplorationoftheconceptofwakefulnessandlightsedationisrequired.TherelationshipbetweenchanginglevelsofsedationandtheirdurationoverthecourseoftheICUstayandclinicaloutcomesisalsounknown.Theeffectofdepthofsedationonpost-ICU,patient-centeredoutcomessuchas90-dayall-causemortalityandcognitivefunction,physicalrecovery,PTSD,anxiety,anddepressivesymptomshasnotbeenwellevaluatedinRCTs.Thereisalsoadearthofinformationregardingtheinteractionamongsedativechoice,sedationdepth,andthepatient-specificfactorsthataffectthisrelationship.Finally,asoutlinedelsewhereintheseguidelines,therelationshipbetweenlevelofsedationandtheabilitytoevaluate,pain,delirium,andsleephasnotbeenfullyelucidated. DailySedativeInterruption/Nurse-ProtocolizedSedation Question:Incriticallyill,intubatedadults,isthereadifferencebetweendailysedativeinterruption(DSI)protocolsandnursing-protocolized(NP)-targetedsedationintheabilitytoachieveandmaintainalightlevelofsedation? UngradedStatement:Incriticallyill,intubatedadults,DSIprotocolsandNP-targetedsedationcanachieveandmaintainalightlevelofsedation. Remarks:ADSIoraSATisdefinedasaperiodoftime,eachday,duringwhichapatient’ssedativemedicationisdiscontinuedandpatientscanwakeupandachievearousaland/oralertness,definedbyobjectiveactionssuchasopeningeyesinresponsetoavoice,followingsimplecommands,and/orhavingaSedation-AgitationScale(SAS)scoreof4–7oraRASSscoreof–1to+1.NP-targetedsedationisdefinedasanestablishedsedationprotocolimplementedbynursesatthebedsidetodeterminesedativechoicesandtotitratethesemedicationstoachieveprescription-targetedsedationscores. Rationale:Fiverandomized,prospective,unblindedtrialscomparedDSIprotocolsandNP-targetedsedationtousualcare(178–182)(SupplementalTable13,SupplementalDigitalContent17,https://links.lww.com/CCM/D775).SomestudiescomparedDSIto“usualcare,”definedasanNPprotocol.Moststudiesdidnotspecificallytargetorassesshoweffectivelyeithertechniqueachievedlightlevelofsedation;rather,theyevaluatedthedifferencesintheoverallsedationscoresamongpatientsbeingmanagedwithDSIorNP-targetedsedation.Acrossthefivestudies,atotalof739patientswererandomized(DSI,n=373;NP,n=366).Benzodiazepineswerecommonlyprescribedforsedationinbothgroups,oftenpairedwithopioidsforanalgesia.TwostudiesreportednodifferenceinlevelofsedationachievedbetweenDSIandNP-targetedsedation(178,179).Theremainingstudiesappearcontradictory;onenotedhigherRASSwithDSIversusNP-targetedsedation(180),anothernotedlowermedianSASscoreswithDSIversusNP-targetedsedation,butnodifferenceinthepercentageoftimespentinthetargetedlightsedationrange(181).AthirdstudyreportedlightersedationwithDSIthanwithNP-targetedsedation(182). Asoutlinedintheseguidelines,cliniciansshouldtargetalightratherthandeeplevelofsedationintheirintubated,criticallyilladultpatientsunlessdeepersedationisclinicallyindicated.OurliteraturereviewsuggeststhatbothDSIprotocolsandNP-targetedsedationaresafeandnodifferencesexistbetweentheminachievingandmaintainingalightlevelofsedation.Thereare,however,someimportantcaveats:first,moststudiesevaluatingDSIsandNPhavedonesointhecontextofsedationwithbenzodiazepines,whicharenolongerrecommendedforsedationincriticallyillpatients;second,DSIprotocolsmaybeassociatedwithincreasingnursingworkload(179);andthird,abriefDSIshouldnotbeusedtojustifytheuseofdeepsedationfortherestofthedaywhenitisnotindicated.Becauselightlevelsofsedationareassociatedwithimprovedoutcomesandareneededtofacilitateotherinterventionssuchasspontaneousbreathingtrialsandearlymobilization,healthcareprovidersshouldstrivetoachievelightlevelsofsedationinthemajorityofpatientsthemajorityofthetime.Lightsedation,assessedusingavalidatedsedationscale,canbeachievedeitherusingaNPorthroughDSIprotocols(wherelightsedationistargeted,whereassedativesareinfusing). EvidenceGaps:Variabilityinnursingsedationassessmentfrequencyanditsreporting,andmodalityofsedativeadministration(infusionvsbolus)differamonginstitutions.Themostfrequentsedativechoice(benzodiazepines)describedinthestudiesmaynotreflectcurrentpractice.Patientandfamilypreferencesandeducationastodepthofsedationwithina“lightsedation”rangeshouldalsobeconsidered.Nonetheless,futureresearchshouldfocusontheeffectofsedationlevelonpatient-centeredoutcomes. ChoiceofSedative Criticallyilladultsmayrequiresedationtoreduceanxietyandstressandtofacilitateinvasiveproceduresandmechanicalventilation.Sedationindication,goal,clinicalpharmacology,andacquisitioncostareimportantdeterminantsinchoosingasedativeagent.The2013PADguidelinessuggest(inaconditionalrecommendation)thatnonbenzodiazepinesedatives(eitherpropofolordexmedetomidine)arepreferabletobenzodiazepinesedatives(eithermidazolamorlorazepam)incriticallyill,mechanicallyventilatedadultsbecauseofimprovedshort-termoutcomessuchasICULOS,durationofmechanicalventilation,anddelirium(1).Forthecurrentguidelines,weconsideredbothshort-termandlong-termoutcomesascriticalforevaluation.Theseincludedtimetoextubation,timetolightsedation,anddelirium,andlong-termoutcomessuchas90-daymortality,cognitiveandphysicalfunctioning,institutionalization,andpsychologicdysfunction. ElectivecardiacsurgicalpatientsaredifferentfromcriticallyillmedicalandsurgicalpatientswhoseadmissionprofileisseldomelectiveandwhoseICUstayandmechanicalventilationdurationarelonger.Wethereforeseparatedstudiesdescribingmechanicallyventilated,routinecardiacsurgicalpatientsandcriticallyill,mechanicallyventilatedmedicalandsurgicalpatients.Pharmacogenomicfactorsthatmayinfluencetheresponseofsedativesandothermedicationsinthecriticallyillwerereviewed(163). CardiacSurgery Question:Shouldpropofol,whencomparedwithabenzodiazepine,beusedforsedationinmechanicallyventilatedadultsaftercardiacsurgery? Recommendation:Wesuggestusingpropofoloverabenzodiazepineforsedationinmechanicallyventilatedadultsaftercardiacsurgery(conditionalrecommendation,lowqualityofevidence). Rationale:WeidentifiedeightRCTs:sevenofwhichcomparedinfusionsofbothsedativeagents(183–189)andoneRCTcomparedpropofolinfusionstomidazolamboluses(190).Incardiacsurgicalpatients,weconsideredashortenedtimetolightsedationofatleast30minutesandtimetoextubationofatleast1hourtobeclinicallysignificant.TwosmallRCTs(n=70)reportedshortertimetolightsedationwithpropofolwhencomparedwithbenzodiazepines(MD,–52 min;95%CI,–77to–26;lowquality)(185,186).SevenRCTs(n=409),includingonestudyusingonlybenzodiazepinebolusesreportedshortertimetoextubationwithpropofolversusabenzodiazepine(MD,–1.4 hr;95%CI,–2.2to–0.6;lowquality)(183–189).WewereunabletofindRCTscomparingpropofolandbenzodiazepineeffectsonothercriticaloutcomesinthecardiacsurgicalpopulation.Overall,thepaneljudgedthatthedesirableconsequencesofusingpropofolprobablyoutweightheundesirableconsequences,andthusissuedaconditionalrecommendationfavoringpropofoloverabenzodiazepine. MedicalandSurgicalPatientsNotUndergoingCardiacSurgery Questions:Shouldpropofol,whencomparedwithabenzodiazepine,beusedforsedationincriticallyill,mechanicallyventilatedadults? Shoulddexmedetomidine,whencomparedwithabenzodiazepine,beusedforsedationincriticallyill,mechanicallyventilatedadults? Shoulddexmedetomidine,whencomparedwithpropofol,beusedforsedationincriticallyill,mechanicallyventilatedadults? Recommendation:Wesuggestusingeitherpropofolordexmedetomidineoverbenzodiazepinesforsedationincriticallyill,mechanicallyventilatedadults(conditionalrecommendation,lowqualityofevidence). Rationale:Weevaluatedtheeffectofpropofolversusbenzodiazepine,dexmedetomidineversusbenzodiazepine,andpropofolversusdexmedetomidineinthreeseparateanalysesfortheoutcomesdeemedcritical.Inmoststudies,benzodiazepineswereadministeredascontinuousinfusionsandnotintermittentboluses.Wecombinedstudiesusingmidazolamandlorazepam.Incriticallyill,mechanicallyventilatedpatients,ashortenedtimetolightsedationofatleast4hoursandtimetoextubationofatleast8–12hours(onenursingshift)weredeemedclinicallysignificant. PropofolVersusBenzodiazepines. Seventrials(n=357)(191–197)reportedshortertimetolightsedationwithpropofolwhencomparedwithabenzodiazepine(MD,–7.2 hr;95%CI,–8.9to–5.5;lowquality).Ninetrials(n=423)(191,196–202)reportedshortertimetoextubationwithpropofolcomparedwithabenzodiazepine(MD,–11.6 hr;95%CI,–15.6to–7.6;lowquality).OnlyoneRCTassesseddeliriumandfoundnodifference(196).Nodatawereavailableforothercriticaloutcomes.Althoughpropofolwasassociatedwithahigherriskofself-extubation(RR,2.2;95%CI,0.30–26.45;lowquality),reliableconclusionsforthisoutcomecannotbemadegiventhewideCI.Additionally,itwasnotcleariftheself-extubationscausedanyharm(e.g.,needforreintubation).Althoughthiswasanimportantconsiderationforthephysiciansonthesedationgrouppanel,ICUpatientsmightfeelotherwise.Overall,thepaneljudgedthatthedesirableconsequencesofusingpropofolprobablyoutweighstheundesirableconsequences,andthusissuedaconditionalrecommendationfavoringpropofoloverabenzodiazepineinfusion. DexmedetomidineVersusBenzodiazepines. FiveRCTs(n=1,052)assesseddurationofmechanicalventilation(167,172,202–204);threestudies(n=969)evaluatedICULOS(167,172,203);andfourRCTs(n=1,007)evaluateddeliriumprevalence(167,172,203,205).Thestudywiththelowestriskofbias(n=366),SafetyandEfficacyofDexmedetomidineComparedWithMidazolam(SEDCOM),hadthegreatestbenefitforthetimetoextubation(MD,–1.90d;95%CI,–2.32to–1.48)anddelirium(RR,0.71;95%CI,0.61–0.83)withdexmedetomidinecomparedwithabenzodiazepineinfusion,andinfluencedhowtheevidencewasgradedwhendevelopingthisrecommendation(167). AlthoughthestudybyXuetal(205)alsoshowedreduceddeliriumwithdexmedetomidineuse,andtheDexmedetomidineVersusMidazolamforContinuousSedationintheICU(MIDEX)study(203)demonstratedashorterdurationofmechanicalventilationwithdexmedetomidineoverabenzodiazepineinfusion,pooledanalysisofallevaluatedstudiesdidnotshowasignificantbenefitofdexmedetomidinecomparedwithabenzodiazepineinfusionfordurationofmechanicalventilationextubation(MD,–0.71d;95%CI,–1.87to0.45;lowquality),ICULOS(MD,–0.23d;95%CI,–0.57to0.11;lowquality),andtheriskfordelirium(RR,0.81;95%CI,0.60–1.08;lowquality).Ofnote,theMIDEXstudy(203),inwhichdeliriumwasassessedonlyonce48hoursaftersedationdiscontinuation,showednoimprovementsindeliriumprevalencewithdexmedetomidine. TheSEDCOM(167)andMaximizingtheEfficacyofSedationandReducingNeurologicalDysfunction(MENDS)(172)studiesbothdemonstratedagreaterincidenceofbradycardiainthedexmedetomidinegroup;neitherstudyfoundinterventionwasrequiredforthebradycardia.Overall,thepaneljudgedthatthedesirableconsequencesofusingdexmedetomidineprobablyoutweighanyundesirableconsequencesandthusissuedaconditionalrecommendationfavoringdexmedetomidineoverabenzodiazepine. PropofolVersusDexmedetomidine. ThreeRCTs(n=850)assessedtimetoextubationandshowednodifferenceinthisoutcome(202,203,206).Nodatawereavailableforothercriticaloutcomes.AsingleRCT,thePropofolVersusDexmedetomidineforContinuousSedationintheICU(PRODEX)study,showedadecreasedincidenceofdeliriumwithdexmedetomidineatthesingletimepointof48hoursaftersedationcessation(203).Patientswereabletocommunicatemoreeffectivelyifsedatedwithdexmedetomidinewhencomparedwithpropofol(203).Nodifferenceswerereportedinbradycardiaorhypotensionbetweenpatientssedatedwithpropofolanddexmedetomidine(203). Overall,therewaslowqualityevidencefortheoutcomesassessed,withamoderatebenefitnoted(reducedtimetolightsedationandextubation)whenbothpropofolanddexmedetomidinewerecomparedwithbenzodiazepines.Noimportantdifferencesinoutcomeswerenotedbetweenpropofolanddexmedetomidine.Asreportedinthesestudies,associatedharmwitheitherpropofolordexmedetomidinewasdeemedtobeminimalandnotclinicallysignificant.Thecost-effectivenessofthesesedativeregimenswasuncertainasbothpropofolanddexmedetomidineacquisitioncostsarenowlowerthanwhentheywereinitiallystudied.Additionally,thecostofacquisitionoftheseagentsvarieswidelyintheworld,makingitdifficulttogeneralizecost-effectiveness.Nevertheless,incorporatingbothpropofolanddexmedetomidineintopracticewaslikelyacceptableandfeasible.Recognizingthatdexmedetomidineshouldnotbeusedwhendeepsedation(withorwithoutneuromuscularblockade)isrequired,panelmembersjudgedthatthedesirableandundesirableconsequencesofusingpropofol(vsdexmedetomidine)werebalanced;therefore,theyissuedaconditionalrecommendationtouseeitheragentsforsedationofcriticallyilladults.Implementationwilllikelydependontheavailabilityofthedruganditsassociatedcostatindividualinstitutions. EvidenceGaps:Larger,well-conductedstudiesassessingthecriticaloutcomeswedefinedneedtobeundertaken.Fasterextubationandincreasedhospitalsurvival,thoughthebuildingblocksoflong-termoutcomes,nolongersufficeasthesoledescriptorsofpatient-centeredoutcomes.Improvementsinmanyaspectsofsurvivorship,includingreturntoformerqualityoflife,independentfunction,andemployment,aremeaningful(207).FurtherstudiesevaluatingthevalueofpatientcommunicationwithfamilymembersduringandafterICUcareandtheperceptionsofpatientswhileoneachofthesesedativesarealsoneeded;ofnote,ourpatientpanelmembersdescribedverydifferentsubjectiveexperienceswhenreceivingsedativesthatcouldnotbetranslatedintoguidelinerecommendationcontent.Pharmacokineticandpharmacodynamicconsiderationsshouldbeincorporatedinbothsedativechoiceanddeliverymethods(162,163).Forexample,therisksandbenefitsofanintermittentbenzodiazepineadministrationstrategyafterestablishinganalgesianeedtobestudiedagainstuseofcontinuoussedativeinfusions.Benzodiazepinemedicationsstillformthemainstayoftherapyinresource-poorareas;risksandbenefitsneedtobestudiedinthecontextoftheircost.Additionally,theroleofsedativemedicationsinthecontextofananalgesia-firstapproachortosupplementanalgosedationneedstobebetterstudied.Theroleofbenzodiazepinesversuspropofolordexmedetomidineinpatientswhoarehemodynamicallyunstable,needdeepsedation,areatriskfordelirium,orhavesignsofalcoholwithdrawalneedstobestudied.Withincreasedpropofoluse,strategiestodetectpropofol-relatedinfusionsyndromeearlierarerequiredandlarge-scaleregistrystudiestocharacterizeitsprevalenceandrisksshouldbeundertaken.Theroleofnonpharmacologicstrategiestoreduceagitation,anxiety,anddistressintermsofsedativechoiceandrequirementsisuncertain,andthus,norecommendationscouldbemadeinthisregard. ObjectiveSedationMonitoring Question:Areobjectivesedationmonitoringtools(electroencephalogram-basedtoolsortoolssuchasHRvariability,actigraphy,andevokedpotentials)usefulinmanagingsedationincriticallyill,intubatedadults? UngradedStatements:Bispectralindex(BIS)monitoringappearsbestsuitedforsedativetitrationduringdeepsedationorneuromuscularblockade,thoughobservationaldatasuggestpotentialbenefitwithlightersedationaswell. SedationthatismonitoredwithBIScomparedwithsubjectivescalesmayimprovesedativetitrationwhenasedativescalecannotbeused. Rationale:TheliteratureforICU-basedstudiesofobjectivemonitoringtoolsforsedationconsistsprimarilyofreportsforelectroencephalogram-basedtools(particularlytheBIS).FewICU-basedstudiesevaluatedoutcomebenefits(208–210).ThemethodsusedtoevaluatetheaccuracyofBISintheICUareoutlinedinSupplementalTable14(SupplementalDigitalContent18,https://links.lww.com/CCM/D776),andthecharacteristicsofthe32studiesincludedaresummarizedinSupplementalTable15(SupplementalDigitalContent19,https://links.lww.com/CCM/D777)(161,208–239). Severalcommonchallengesinresearchdesignforthesestudieshavebeenidentified.Therelationshipbetweenelectroencephalogramdataandsubjectivesedationdatawasoftenassumedtobeconstantandlinear,butthisisaninaccurateperception.Becausesedationgetsdeeperandpatientsbecomeunresponsive,subjectivesedationscalesreachaminimumvalue(SAS1orRASS–5),whereasobjectiveelectroencephalogram-basedtoolscancontinuetodeclineuntilanisoelectricelectroencephalogramisobtained(SupplementalFig.4,SupplementalDigitalContent20,https://links.lww.com/CCM/D778)(211).Attheotherextreme,withincreasingagitation,objectivetoolsreachamaximum(i.e.,aBIS100),whereassubjectivescalescontinuetodescribeincreasinglevelsofagitation(SupplementalFig.5,SupplementalDigitalContent21,https://links.lww.com/CCM/D779)(211).Inaddition,objectivemonitorssuchasBISallowmeasurementwithoutstimulatingthepatient,whereassubjectivesedationscalesrequireassessingthepatientresponsetovoice,physical,andevennoxiousstimuli.ThisstimulationchangesthepreexistingstateofthepatientandincreasestheBISvalue;dependingonthetimingoftheBISmeasurements(i.e.,before,during,orafterstimulation),agreementbetweenthetwoassessmenttechniqueswillbeaffected. The32ICU-basedstudiesthatcomparedBISandsubjectivesedationscaleassessmentwerescoredbasedontheirapproachtotimingofBISmeasurementrelativetothestimulationfromsubjectiveassessment(0–4points),typeofstimulation(0–2points),adjustmentfordeepsedation(0–2points),andwhetherelectroencephalogramsignalqualityandsoftwareversionweredefined(0–2points)(161,208–239).Studieswithlesspotentialconfounding(4pointsonthetimingissue)trendedtobetteragreementbetweenBISandsubjectivescales(p=0.09),whereasthestudiesthatdidnotaccountfortheeffectofsubjectivestimulation(scoring0ontiming)hadtheworstagreementbetweenBISandsubjectivescales(seetheredellipseinSupplementalFig.6,SupplementalDigitalContent22,https://links.lww.com/CCM/D780). ThreestudiesevaluatedtheeffectofusingtheBIStoassesssedationcomparedwithusingasubjectivetool(209–211).Theseshowedreductionsintotalsedativeuseandfasterwakeningtimesdespitesimilarclinicalsedation(Ramsay4)(208),areductioninprocedure-relatedadverseevents(Ramsey2–3)(209),andreducedmidazolamandfentanyldoses,lessagitation,lessneedfortracheostomy,andshorterICULOS(210). EvidenceGaps:ResearchmethodologytoevaluateICUsedationmonitorshasnotbeenstandardized,resultinginwidevariabilityinstudydesignasnotedabove.Definingbestcomponentsandapproacheswillimprovestudyquality.Withimprovedresearchrigor,validcomparisonsbetweenthevariousobjectivesedationmonitoringtoolsandbetweenobjectiveandsubjectivesedationscalesmaybepossible.Additionalresearchisneededtodefinethebestapproachtodealingwithissuessuchasdepthofsedation(particularlyinanerawhenmorepatientsarelightlysedated),stimulationduringsedationassessment,andhowdifferentpatientpathology(neurologicvsnonneurologicdiagnoses)mayaffectobjectivetoolreliability.Finally,moreoutcomestudiesareneededtoconfirmwhetherthesetoolsimprovepatientoutcomesorreducehealthcareresourceconsumptioncomparedwithsubjectivescales. PhysicalRestraints Question:Whataretheprevalencerates,rationale,andoutcomes(harmandbenefit)associatedwithphysicalrestraintuseinintubatedornonintubatedcriticallyilladults? UngradedStatements:Physicalrestraintsarefrequentlyusedforcriticallyilladultsalthoughprevalenceratesvarygreatlybycountry. Criticalcareprovidersreportusingrestraintstopreventself-extubationandmedicaldeviceremoval,avoidfalls,andtoprotectstafffromcombativepatientsdespitealackofstudiesdemonstratingefficacyandthesafetyconcernsassociatedwithphysicalrestraints(e.g.,unplannedextubationsandgreateragitation). Rationale:Inanerafocusedonimprovingpatient-centeredcare,theeffectphysicalrestraintshaveonthecareandoutcomesofcriticallyilladultsremainscontroversial.Physicalrestraintsaredefinedas“anymanualmethod,physical,ormechanicaldevice,material,orequipmentthatimmobilizesorreducestheabilityofapatienttomovehisorherarms,legs,body,orheadfreely”(240).Thisquestionspecificallyfocusesonphysicalrestraintsattachedtotheankle,wrist,oruppertorso.Physicalrestraintusevarieswidelyfrom0%insomeEuropeancountriestomorethan75%inNorthAmerica(SupplementalTable16,SupplementalDigitalContent23,https://links.lww.com/CCM/D781)(168,241–261).Thetypeandlocation(e.g.,wrist,ankle,uppertorso)ofphysicalrestraintssimilarlyvary,withresource-richcountriesreportingusingcommerciallyavailablerestraints(242,245–247,249,252,255,260,262–268). HealthcareprovidershavehistoricallyjustifiedtheuseofphysicalrestraintsintheICUformanyreasonsincludingtoenhancepatientsafety(242,249,252,262,263);preventself-extubation,tubedislodgement,and/ormedicaldeviceremoval(242,246,249,255,262,263,265,266,269);controlpatientbehavior(249,262,265,266,269);protectstafffromcombativepatients(263);andpreventfalls(242,263,266).Lesscommonlycitedreasonsincludethefollowing:preservingposture/positioningofthepatient(249,266);staffingshortagesorlackofsupervisionduringbreakcoverage(249,263,265);andcompliancewithpatient,familymember,orothermedicalstaffsuggestions(265). Todate,noRCThasexploredthesafetyandefficacyofphysicalrestraintuseincriticallyilladults.Thefewdescriptivestudiesexploringphysicalrestraintuseandoutcomesofthecriticallyillparadoxicallyreporthigherratesoftheeventsthattheiruseisintendedtoprevent.Theseeventsincludemoreunplannedextubationsandfrequentreintubations(245,247,267,268);greaterunintentionaldeviceremoval(268);longerICULOS(245);increasedagitation;higherbenzodiazepine,opioid,andantipsychoticmedicationuse(244,268);andincreasedriskfordeliriumordisorientation(257,259,268,270,271). Certainmodifiableandnonmodifiablefactorsappeartoincreasecriticallyilladults’riskforphysicalrestraintuse.Thesefactorsincludethefollowing:olderage(250,264);non-comalevelofarousal;neurologicorpsychiatricconditionsincludingdelirium(257,258,261,268);sedativetype/strategy(169,242,261,272);mechanicalventilationuse(242,261,263);useofinvasivedevices(246,250);nurse-to-patientratioandperceivedworkload(242,268,271);andtimeofday(249).Interestingly,patientsparticipatinginanearlymobilityprogram(273)whoreceivedearlypharmacologictreatmentofdelirium(272)andpatientswhohadahistoryofalcoholusewerelessrestrained(268). Patients’perceptionsofbeingphysicallyrestrainedduringanICUstayvarybutoftenprovokestrongemotionalresponsesthatpersistaftertheICUstay(169,269).Giventheprevalence,unintendedconsequences,andpatients’perceptionsofphysicalrestraintuse,criticalcareprovidersshouldcloselyweightherisksandbenefitsofthispracticeintheadultICUsettingbeforeinitiatingormaintainingphysicalrestraintuse.Althoughcertaincountriesreporta“restraint-free”ICUenvironment,itmaybepossiblethattheiruseofbedsidesittersand/orpharmacologicrestraintsisincreased. EvidenceGaps:Whethereffortstoreducephysicalrestraintusewillhavetheunintendedconsequenceofincreasingpatients’exposuretopotentiallyharmfulsedativeandantipsychoticmedicationsremainunclear.Theeffectnursestaffingpatterns,staffeducation,andpatient/familyadvocacyhaveontheincidenceofphysicalrestraintuseintheICUhasalsoyettobedetermined.ParticularlyrelevanttotheICUsetting,thenecessityandethicsofphysicalrestraintsduringend-of-lifecareneedfurtherexploration.Finally,thetrueeffectphysicalrestraintsplayonoutcomesrelevanttopatientsshouldbeexploredinRCTs. DELIRIUM Deliriumiscommonincriticallyilladults.ThedeliriumencounteredintheICUandothersettingsareassumedtobeequivalentpathophysiologicstates.Deliriumisaclinicaldiagnosis;moststudiesdetectdeliriumusingscreeningtoolssuchastheConfusionAssessmentMethodfortheICU(CAM-ICU)ortheIntensiveCareDeliriumScreeningChecklist(ICDSC)(274,275).Deliriumcanbedisturbingforaffectedpatientsandrelativesandisassociatedwithworseoutcome,andmuchhigherICUandhospitalLOSandcosts(276).Manyresearchgapsexistinthisarea(277).Inthisguideline,weaddresssixactionablequestionsandfivedescriptivequestions(seeprioritizedtopiclistinSupplementalTable17[SupplementalDigitalContent24,https://links.lww.com/CCM/D782]andvotingresultsinSupplementalTable18[SupplementalDigitalContent25,https://links.lww.com/CCM/D783]).Theevidencesummariesandevidence-to-decisiontablesusedtodeveloprecommendationsforthedeliriumgroupareavailableinSupplementalTable19(SupplementalDigitalContent26,https://links.lww.com/CCM/D784),andtheforestplotsforallmeta-analysesareavailableinSupplementalFigure7(SupplementalDigitalContent27,https://links.lww.com/CCM/D785). RiskFactors Question:Whichpredisposingandprecipitatingriskfactorsareassociatedwithdeliriumoccurrence(i.e.,incidence,prevalence,ordailytransition),deliriumduration,orseverityincriticallyilladults? UngradedStatement:Forthefollowingriskfactors,strongevidenceindicatesthattheseareassociatedwithdeliriumincriticallyilladults:“modifiable”—benzodiazepineuseandbloodtransfusions,and“nonmodifiable”—greaterage,dementia,priorcoma,pre-ICUemergencysurgeryortrauma,andincreasingAcutePhysiologyandChronicHealthEvaluation(APACHE)andASAscores. Rationale:Sixty-eightstudiespublishedfrom2000toNovember2015thatevaluatedcriticallyilladultsnotundergoingcardiacsurgeryfordeliriumthatusedeithermultivariableanalysisorrandomizationwereusedtoevaluatevariablesaspotentialriskfactors(SupplementalTable20,SupplementalDigitalContent28,https://links.lww.com/CCM/D786).Riskofbiasoftheretrievedarticleswasscored(cohortstudiesusingtheScottishIntercollegiateGuidelinesNetworkqualitychecklist[s]andcontrolledtrialsusingCochranemethods),andstudieswereclassifiedashigh,acceptable,orlowquality(SupplementalTable21,SupplementalDigitalContent29,https://links.lww.com/CCM/D787).Eachvariablewasevaluatedusingthreecriteria:1)thenumberofstudiesinvestigatingit;2)thequalityoftheseinvestigations,and3)whereconsistencyexistedacrossthestudies(i.e.,thedirectionofassociationwasconsistentfor≥50%ofstudies).Strengthsofassociationwerenotsummarizedbecauseoftheheterogeneitybetweenstudies.Thefollowing,nonvalidated,criteriawereusedtodefinewhethertherewasstrong,moderate,orinconclusiveevidencethatariskfactorwasassociatedwithincreaseddelirium:strong—morethanorequaltotwohigh-qualityarticlesandassociationconsistency;moderate—onehigh-qualityarticleandmorethanorequaltooneacceptablequalityarticlewithassociationconsistency;andinconclusive—inconsistentfindingsandnofulfilmentofcriteriaforstrongevidenceandformoderateevidence(278).Theevaluationofpredisposingandprecipitatingriskfactorswascombinedbecausethesewerestudiedinmostinvestigationssimultaneously. Benzodiazepineuseandbloodtransfusionadministrationaretheonlytwomodifiablefactorswithstrongevidenceforanassociationwithdeliriumdetectedbyscreeningtools(SupplementalTable22,SupplementalDigitalContent30,https://links.lww.com/CCM/D788).Thenonmodifiableriskfactorswithstrongevidenceforanassociationwithdeliriumincludeincreasingage,dementia,priorcoma,pre-ICUemergencysurgeryortrauma,andincreasingAPACHEandASAscores.Sex,opioiduse,andmechanicalventilationeachhavebeenstronglyshownnottoaltertheriskofdeliriumoccurrence.Moderateevidenceexistsshowingthefollowingincreasetheriskfordelirium:historyofhypertension;admissionbecauseofaneurologicdisease;trauma;andtheuseofpsychoactivemedication(e.g.,antipsychotics,anticonvulsants).Ahistoryofrespiratorydisease,medicaladmission,nicotineuse,dialysisorcontinuousvenovenoushemofiltration,andalowerGlasgowComaScalescorehaveeachbeenmoderatelyshownnottoincreasetheriskfordelirium.Seethe“Sedationsection”forareviewonhowsedativechoicemayaffectdeliriumandthe“Sleepsection”regardingtherelationshipbetweensleepanddelirium.Forallotherpotentialdelirium-associatedriskfactors,evidencecurrentlyremainsinconclusive. Prediction Question:Candeliriumbepredictedincriticallyilladults? UngradedStatement:PredictivemodelsthatincludedeliriumriskfactorsatboththetimeofICUadmissionandinthefirst24hoursofICUadmissionhavebeenvalidatedandshowntobecapableofpredictingdeliriumincriticallyilladults. Rationale:WeidentifiedfourstudiesthatusedmodelingtopredictICUdelirium(279–282),threeofwhichwereconsideredtobepsychometricallystrong(SupplementalTable23,SupplementalDigitalContent31,https://links.lww.com/CCM/D789)(280–282).Ofthese,twostudiesaimedtopredictICUdeliriumwithin24hoursafterICUadmissionusingthePREdictionofDELIRiuminICupatients(PRE-DELIRIC)model(280,281).Inamultinationalstudy,10predictors(age,APACHE-IIscore,admissiongroup,urgentadmission,infection,coma,sedation,morphineuse,urealevel,andmetabolicacidosis)permittedamodelwithanareaunderthereceiveroperatingcharacteristic(AUROC)curveof0.77(95%CI,0.74–0.79)(281).Inanotherhigh-quality,multinationalstudy(282),amodelwasbuilttopredictdeliriumwithpatientcharacteristicsavailableatICUadmission.ThisEarly(E)-PRE-DELIRICmodelincludesninepredictors(age,historyofcognitiveimpairment,historyofalcoholabuse,bloodureanitrogen,admissioncategory,urgentadmission,meanarterialBP,useofcorticosteroids,andrespiratoryfailure)andwasfoundtohaveanAUROCof0.76(95%CI,0.73–0.77).BecauseboththePRE-DELIRICandtheE-PRE-DELIRICmodelshadsimilarpredictivevalue,themodelofchoicecanbebasedonavailabilityofpredictors(SupplementalTable24,SupplementalDigitalContent32,https://links.lww.com/CCM/D790).BothmodelswerebasedonscreeningwiththeCAM-ICUonly. EvidenceGaps:Futureetiologicstudiesondeliriumshouldfocusonpresumedriskfactorsforwhichthereiscurrentlyinconclusiveevidenceandwheremodifiabilityislikely.Theeffectofareductioninknowndeliriumriskfactorsincludingcomorbiddiseases,sepsis,nicotineandalcoholabuse,andtheuseofopioidsandsystemicsteroidsondeliriumburdenandpatientoutcomeisunknown.Confoundingisakeyissueinthesestudies.Futurestudiesondeliriumriskfactorsshouldthereforemakeadequateadjustmentsbasedonpreviouslyconsideredriskfactors(278). Assessment Question:Shouldweassessfordeliriumusingavalidtool(comparedwithnotperformingthisassessmentwithavalidtool)incriticallyilladults? GoodPracticeStatement:Criticallyilladultsshouldberegularlyassessedfordeliriumusingavalidtool. Remarks:Thepreviousguidelinesprovidedpsychometricappraisalsofpain,sedation,anddeliriumscreeningtools(1).Areevaluationofthepsychometricsforavailabledeliriumscreeningtoolswasnotconductedaspartoftheseguidelines.Thisquestion’sfocusistheeffectofusinganydeliriumassessmenttool(vsnoassessmenttool)inclinicalpractice. Rationale:Moststudiesevaluatingdeliriumassessmentcombinetheassessmentinterventionwithoneormoremanagementstrategies(8,110,283),precludingtheabilitytoevaluateoutcomesrelatedtothemonitoringitself.Threestudiesspecificallyevaluateddeliriumassessmenteffects(284–286)andvariedsignificantlyindesignandchoiceofevaluatedoutcomes.Two(284,285)foundnorelationshipbetweendeliriumassessmentandICULOSordurationofmechanicalventilation.Threestudiesevaluatedtimetodeliriumdiagnosisandtreatment.OnestudycomparedscreeningusingtheCAM-ICUversusclinicalassessment(285)andreportednodifferenceintimetodiagnosisortreatmentwithantipsychotics.TheCAM-ICUarmhadmoreantipsychoticmedicationdays,butthetotaldoseofantipsychoticmedicationadministeredwassimilarinthetwoarms.Thelargestofthefourstudies(286)comparedassessmenttoolimplementationandhaloperidoluse,aproxyinthatstudyfordeliriumincidenceandduration.Morepatientsinthepostimplementationperiodweretreatedwithhaloperidol,butatlowerdosesandforlesstimethanpatientsinthepreimplementationgroup.Inacrossoverstudy,Readeetal(287)comparedaperiodofCAM-ICUassessmenttoaperiodofunstructurednursingassessmentsusingaformwithadeliriumdefinition.TheCAM-ICUarmhadasignificantlylowerproportionofnursingshiftswithdeliriumandashorterdurationofdeliriumwhencomparedwiththeperiodofunstructuredassessments.Systemicdeliriumdetectioncanspuriouslyraisereporteddeliriumprevalence,makingitchallengingtocapturethetrueimpactofdeliriumreductioninterventioneffortsonthisoutcome.Implementationstrategiesdiffered,andeachstudy’ssignificantdesignlimitationsledtolowandverylowqualityofevidenceevaluations.ThesestudiesaresummarizedinSupplementalTable25(SupplementalDigitalContent33,https://links.lww.com/CCM/D791).Althoughnoneofthestudiesreportedpatientharm,thisqualitylevelandtheheterogeneityinstudydesignandresultsprecludearecommendation.Thisevidencecannotestablishwhetherdeliriumscreeningaloneisbeneficial. Insteadofagradedrecommendation,weissueanungradedGoodPracticeStatementgiventhatthepotentialbenefitsofdeliriummonitoringfaroutweighanypotentialdownsides.Summarizingtheliteratureandevaluatingthequalityofevidencewasnotfeasibleduetocomplexityofstudies.Theprimarypotentialbenefitofdeliriummonitoringisearlyrecognitionthatmayhastenclinicalassessmentandintervention.Earlydetectionmayleadtopromptidentificationandcorrection(whenpossible)ofetiology,assuranceofpatientsexperiencingdistressingsymptoms,treatment(pharmacologicornonpharmacologic),andtreatmenteffectivenessassessments.MultiplestudiesinbothICUandnon-ICUsettingshavefoundthatwithoutvalidatedscreeningtools,bedsidenursesandphysiciansfailtorecognizedelirium(285,287–294). Whataretheconsequencesofmissingdeliriuminadditiontopossibleearlierdetectionofunderlyingdeliriumcauses?DeliriumisadistressingexperienceforICUpatients,theirfamilies,andforICUstaff(295–298).Althoughnotproven,suchdistressmightbemitigatedbydiscussionsbetweenstaffandpatients/familiesaboutdelirium.Regulardeliriummonitoringmayprovideafoundationforthosediscussions(299).QualitativestudiesofICUexperiencesconsistentlyhighlightthatdeliriouspatientsfeelgreatertrusttoward,andencouragementfrom,familymembersversusstaff(295,300).Theearlydetectionandidentificationofdeliriummightbenefitpatientsbyfosteringreassurancewhenfrighteningsymptomsoccur. DeliriumscreeningusingtheCAM-ICUortheICDSCisquick(2–5 min)(284,286).Arecentsystematicreviewhasupdatedthepsychometricpropertiesofdeliriumscreeningtoolsforcriticallyilladults(301).Thesensitivityandspecificityofdeliriumscreeningtoolswhencomparedwithclinicalassessment,andtheirreproducibilityandreliabilitywhenscreeningtoolsaresubstitutedforaclinicaldiagnosisvarybetweenICUpopulations(e.g.,cardiacsurgeryICUorneurologicallyinjuredpatients)(51,302,303).Arecentpublication(304)describesanewvalidatedtool(theICU-7)todocumentdeliriumseverityandsuggeststhatseverityisassociatedwithworseoutcome.Almostalltheclinicaltrialsinvestigatingstrategiestopreventand/ortreatdeliriumarebasedondeliriumassessmenttools.Thegeneralizabilityofanydelirium-focusedstudyreliesontheseinstrumentsinclinicalpractice.Becausethecharacteristicsofthetools(andtheirconfounders)arebetterdescribed,theresultsoftheseinvestigationswillhelpguidefutureclinicaltrials. Thedisadvantagesofdeliriumscreeningshouldbeconsidered.Afalse-positivescreening,althoughrarewitheithertheCAM-ICUortheICDSC,mayresultinunnecessarypharmacologicornonpharmacologictreatment.ICUantipsychoticuseisoftenassociatedwithitscontinuationandprolongedadministrationafterICUandhospitaldischarge(305–307).Deliriumscreeningmaybeburdensomefornursingstaff(287).Inthecontextofthecriterianeededtogenerateabestpracticestatement,wefeltthatthebenefitsofwidespreaddeliriumassessmentwiththeCAM-ICUortheICDSCfaroutweighanypotentialdisadvantages. EvidenceGaps:Thecurrentbodyofevidenceinsupportofpainandagitationassessments,whichhasbeenstudiedlongerthandelirium,mayprovidesomeguidanceforfutureresearchindeliriummonitoring(19,106,110,308–310).Somestudies(18,310)suggestthattheabilityofassessmenttoolstoimprovepatientoutcomesmaybeassociatedwiththeintensityofthetrainingstrategyusedandthequalityimprovementinitiativesdeployed.Arecentobservationalstudy(311)foundanassociationbetweenhighdeliriummonitoringadherence(i.e.,assessmentson≥50%oftheICUdays)andimprovedpatientoutcomes(i.e.,lowerin-hospitalmortality,shorterICULOS,andshortertimeonmechanicalventilation).Futurestudiesshouldincludevariouscriticalcarepopulationssuchaspatientswithprimaryneurologicdiagnoses.Thelackofhigh-qualitytrialsinvestigatingtheeffectofdeliriumassessmentunderscoresthegapsinunderstandingtherelationshipamongdeliriumassessmentandpatient-centeredoutcomes,treatmentdecisions,patientandfamilysatisfaction,andstaffsatisfaction. LevelofArousalandAssessment Question:Doesthelevelofarousalinfluencedeliriumassessmentswithavalidatedscreeningtool? UngradedStatement:Levelofarousalmayinfluencedeliriumassessmentswithavalidatedscreeningtool. Rationale:FourobservationalcohortstudieshaveexamineddeliriumassessmentsatdifferentlevelsofwakefulnessandsedationasassessedbytheCAM-ICU,ICDSC,andRASS(312–315).BecausemanypatientswithRASSof–3weredeemedinthesestudiestobe“unabletoassess,”dataarelimitedtoanevaluationoftheinfluenceofaRASSrangefrom0to–2ondeliriumpositivity.Thesedatadonotallowfordiscriminationbetweendeliriumthatispotentiallysedationinducedcomparedwiththatrelatedtootherpathologicalterations(withorwithoutsedation). Atotalof12,699deliriumassessments(97%involvingtheCAM-ICU)wereevaluatedinpatientswithaRASSbetween0and–2.Thelikelihoodofapositivedeliriumassessmentwassignificantlygreater(77%vs23%;p<0.0001)whenpatientshadaRASS–2(vsaRASSof–1to0),whichcouldsuggestthatlevelofarousalinfluencesdeliriumassessments.However,becausedeliriumcanpresentwithadecreasedarousallevel,noinferencescanbemadefromthesedata(SupplementalTable26,SupplementalDigitalContent34,https://links.lww.com/CCM/D792).ApartfromthestudybyPateletal(312)inwhich12%ofpatientsinwhomdeliriumwaspresentduringsedativeinfusionresolvedwithin2hoursofstoppinginfusion,nootherstudyinformsthequestionofwhetherapositivedeliriumassessmentasaresultofconcomitantsedationaffectspatientoutcomeorwhethersedationmerelyrepresentsaconfoundingissueforpatientassessment.Giventhatstudiestodatehaveshownthatdeliriumisassociatedwithworseoutcomes,evenwhenadepressedlevelofarousalispresent,cliniciansshouldnotcurrentlydiscounttheclinicalsignificanceofdeliriuminthissetting(316–318). EvidenceGaps:Theeffectsoflevelofarousalondeliriumareinneedoffurtherstudy.Thisincludestheimpactofdeliriumatdifferentlevelsofarousalondeliriumassessments(withorwithoutconcomitantsedativeexposure)onimportantoutcomessuchashospitaldispositionandlong-termcognitiveimpairment. Outcomes Delirium. Questions:Whataretheshort-andlong-termoutcomesofdeliriumincriticallyilladultsandarethesecausallyrelated? UngradedStatements:Positivedeliriumscreeningincriticallyilladultsisstronglyassociatedwithcognitiveimpairmentat3and12monthsafterICUdischarge(316–319)andmaybeassociatedwithalongerhospitalstay(257,279,316,320–327). DeliriumincriticallyilladultshasconsistentlybeenshownNOTtobeassociatedwithPTSD(328–333)orpost-ICUdistress(316,333–336). DeliriumincriticallyilladultshasNOTbeenconsistentlyshowntobeassociatedwithICULOS(257,258,272,279,318,320–326,334,337–352),dischargedispositiontoaplaceotherthanhome(257,342,344,353,354),depression(330,356),functionality/dependence(330,334,350,353,354,357–360),ormortality(316,357). Rationale:Despitethefactthat48studiesenrolling19,658patientsdescribepotentialoutcomesassociatedwithICUdelirium,thecomplexrelationshiplinkingdeliriumtotheseoutcomeshasyettobefullydefined(257,258,279,316–326,330–332,334–354,356–358,360–365)(SupplementalTable27,SupplementalDigitalContent35,https://links.lww.com/CCM/D793).Weemphasizethattheseassociationsdonotimplycausalityandthattheyhighlightareasforfuturestudiesparticularlythoseinvolvingcognition.AnothersignificantgapinICUdeliriumoutcomesdataincludesthepsychologictollthatdeliriumexertsinrealtimeonpatients,families,andcaregivers. RapidlyReversibleDelirium. Question:Whataretheshort-andlong-termoutcomesofrapidlyreversibledelirium? UngradedStatement:Rapidlyreversibledeliriumisassociatedwithoutcomesthataresimilartopatientswhoneverexperiencedelirium. Rationale:Oneprospectiveobservationalstudywithblindedevaluationsenrolled102patients(312)andfoundthatoutcomes(ICUandhospitalLOS,dischargedisposition,and1-yrmortality)weresimilarbetweenthe12patientswhodevelopedrapidlyreversible,sedation-relateddeliriumandthe10patientswhoneverexperienceddelirium.Mostpatients(n=80)whohadeitherdeliriumornotalwaysrapidlyreversibledeliriumhadworseoutcomesthanthepatientswithrapidlyreversible,sedation-relateddelirium,orwhoneverdevelopeddelirium.Thesepreliminarydatasuggestthatforasmallgroupofpatientswithrapidlyreversibledelirium,deliriumisnotassociatedwiththespecificallymeasuredadverseclinicaloutcomes.DeliriumassessmentsshouldbeperformedbothbeforeandafteraDSI(SAT)toidentifythesesubtypesofdelirium. PharmacologicPreventionandTreatment Prevention. Question:Shouldapharmacologicagent(vsnouseofthisagent)beusedto“prevent”deliriuminallcriticallyilladults? Recommendation:Wesuggestnotusinghaloperidol,anatypicalantipsychotic,dexmedetomidine,aβ-Hydroxyβ-methylglutaryl-CoenzymeA(HMG-CoA)reductaseinhibitor(i.e.,statin),orketaminetopreventdeliriuminallcriticallyilladults(conditionalrecommendation,verylowtolowqualityofevidence). Rationale:Theoutcomesdeemedcriticaltothisrecommendationincludeddeliriumincidenceandduration,durationofmechanicalventilation,lengthofICUstay,andmortality.Single,randomizedstudiesofadultswhowereadmittedtotheICUforpostoperativecarewerereviewedforhaloperidol(366);theatypicalantipsychotic,risperidone(367);anddexmedetomidine(368).Eachstudyreportedasignificantreductionindeliriumincidencefavoringthepharmacologicagent:scheduledIVhaloperidol(n=457)afternoncardiacsurgery(RR,0.66;95%CI,0.45–0.97;lowquality)(366);asingledoseofrisperidone(n=126)followingelectivecardiacsurgery(RR,0.35;95%CI,0.16–0.77;lowquality)(366);andscheduled,low-dosedexmedetomidine(n=700)afternoncardiacsurgery(oddsratio[OR],0.35;95%CI,0.22–0.54;lowquality)(368).Onerecentlypublished,double-blind,placebo-controlledRCTof1,789delirium-freecriticallyilladults,notincludedintheevidenceprofile,foundthatadministrationoflow-doseIVhaloperidolintheICUuntildeliriumdevelopeddidnothelppreventdeliriumoraffect90-daysurvival(369).Anothersuggestedthatnocturnaladministrationoflow-dosedexmedetomidineincriticallyilladultswithAPACHE-IIscoresof22(sd,±7.8)wasassociatedwithasignificantlygreaterproportionofpatientswhoremaineddeliriumfree(80%vs54%;p=0.008)duringtheirICUstay(370). Despitetheconsistentreductionindeliriumincidenceineachstudy,nonereportedastatisticallysignificantand/orclinicallymeaningfuldifferenceforanyoftheotheroutcomesthatthegroupdeemedcritical.Therandomizedtrialsinformingthisquestionincludedsurgicaladultshavingaseverityofillnesslessthanhalf,onaverage,ofthe(predominantlymedical)ICUpatientsrepresentedinthesetrials(366–368).Giventhestrongassociationbetweenseverityofillnessanddeliriumoccurrence(365),dataderivedfromsurgicalpatientswithalowseverityofillnessmustbeinterpretedwithcaution. ManyacutecriticallyillpatientshavedeliriumatICUadmissionandthusdeliriumpreventionstrategiesmaynotapplytothisproportionoftheICUpopulation.Giventhisevidencegapandthelackofgeneralizabilityfromeachstudypopulationtothebroadercriticallyilladultpopulation,thecurrentrecommendationreflectsthepanel’sconcernthatthepotentialrisksandcostsofexposingalargeproportionofthecriticallyilladultpopulationtooneormoremedicationsaimedatpreventingdeliriumwilloutweighanybenefit. Threecohortstudiessuggestthatwhenstatinuseisstoppedduringcriticalillness,deliriumoccurrenceincreases(371–373).However,onerecentrandomizedstudyofdelirium-freecardiacsurgerypatientsadmittedtotheICU(notincludedintheevidenceprofileforthisquestion)foundthattheuseofpreoperativeatorvastatindidnotaffectincidentdelirium(374).TheroleofanNMDAreceptorantagonistfortheprimarypreventionofdeliriumpreventionincriticallyilladultswasbeingprospectivelyevaluatedinarandomizedtrialatthetimeofguidelinedevelopment.OnerecentlargeRCTfoundthatasinglesubanestheticdoseofketamine,administeredperioperatively,didnotdecreasedeliriuminolderadultsaftermajorsurgery,someofwhorequiredadmissiontotheICU(375). SubsyndromalDeliriumTreatment. Question:Shouldapharmacologicagent(vsnouseofthisagent)beusedto“treatsubsyndromaldelirium”inallcriticallyilladultswithsubsyndromaldelirium? Recommendation:Wesuggestnotusinghaloperidoloranatypicalantipsychotictotreatsubsyndromaldeliriumincriticallyilladults(conditionalrecommendations,verylowtolowqualityofevidence). Rationale:Subsyndromaldeliriumispartofanoutcome-predictingspectrumofdeliriumsymptoms,ispresentwhentheICDSCscoreis1–3outof8andoccursinabout30%ofcriticallyilladults(342).Acriticallyillpatientwhodevelopssubsyndromaldelirium,comparedwithonewhodevelopsneitherdelirium(ICDSC,≥4)norsubsyndromaldelirium,ismorelikelytodieintheICU,spendmoretimehospitalized,andtobedischargedtoalong-termcarefacilityratherthanhome(342).DurationofsubsyndromaldeliriumwhenevaluatedusingtheCAM-ICUisanindependentpredictorofincreasedoddsofinstitutionalization(376).Theoutcomesdeemedcriticaltothisrecommendationincludeddeliriumincidence,duration,andseverity;durationofmechanicalventilation;ICULOS;andmortality.BothRCTsusedtheICDSCtoidentifypatientswithsubsyndromalandfull-syndromedelirium(ICDSC,≥4).ScheduledIVhaloperidol1 mgq6h,whencomparedwithplaceboin60mechanicallyventilatedadults,wasnotassociatedwithachangeindeliriumincidence,duration,ortimetofirstepisodeofdelirium;daysofmechanicalventilation;orICULOSincriticallyillmedicalandsurgicalpatients(377).Risperidone(0.5 mgevery8 hr),whencomparedwithplaceboin101cardiacsurgerypatients,wasassociatedwithareducedlikelihoodforatransitionfromsubsyndromaltofull-syndromedelirium(RR,0.41;95%CI,0.02–0.86)(378). Despitethisreductionindeliriumincidence,neitherstatisticallysignificantand/orclinicallymeaningfuldifferenceswerenotedforanyoftheotheroutcomesdeemedcriticalbythegroup.Giventheseevidencegaps,questionableclinicalbenefit,andthepotentiallackofapplicabilityofdatafromthestudybyHakimetal(378)totheentiremedicalandsurgicalcriticallyillpopulationhavingagreaterseverityofillnessanddifferentriskfactorsfordelirium,thecurrentrecommendationreflectsthepanel’sconcernabouttherisksofexposingupto35%ofallcriticallyilladultstoantipsychotictherapy(379).Theroleofdexmedetomidine,aHMG-CoAreductaseinhibitor(i.e.,astatin),oranNMDAantagonist(e.g.,ketamine)asatreatmentforsubsyndromaldeliriumhasnotbeenevaluatedinarandomizedtrial. DeliriumTreatment. Question:Shouldapharmacologicagent(vsnouseofthisagent)beusedtotreatdeliriuminallcriticallyilladultswithdelirium? Antipsychotic/statin. Recommendation:Wesuggestnotroutinelyusinghaloperidol,anatypicalantipsychotic,oraHMG-CoAreductaseinhibitor(i.e.,astatin)totreatdelirium(conditionalrecommendation,lowqualityofevidence). Rationale:Theoutcomesdeemedmostcriticaltothisquestionincludeddeliriumduration,durationofmechanicalventilation,ICULOS,andmortality.AtotalofsixRCTswereidentified:haloperidol(n=2)(380,381),atypicalantipsychotics(quetiapine)(n=1)(382),ziprasidone(n=1)(380),olanzapine(n=1)(383),andastatin(i.e.,rosuvastatin)(n=1)(384).Arecentrandomizedtrialofcriticallyilladults,notincludedintheevidenceprofile,foundthathigh-dosesimvastatindoesnotreducedaysspentwithdeliriumandcoma(385).NoevidencewasfoundtoinformarecommendationregardingtheuseofanNMDAantagonist(e.g.,ketamine)fordeliriumtreatment. Thisevidencesuggeststhattheuseofthetypicalantipsychotic,haloperidol;anatypicalantipsychotic(e.g.,quetiapine,ziprasidone);orastatinwasnotassociatedwithashorterdurationofdelirium,areduceddurationofmechanicalventilationorICULOS,ordecreasedmortality.Althoughtherandomizedtrialsinformingthisquestionwereconductedinbothmedicalandsurgicalpatientswhowerecriticallyill,eachusedopen-labelantipsychoticrescuemedicationforagitationorhallucinations(368,380–384,386).Administrationofsuchopen-labelmedicationtotheplacebogroupinthesestudiesmaybiastheresultsoftheseinvestigationstowardthenullhypothesis.Theundesirableeffectsofhaloperidolandatypicalantipsychoticsremainuncertain,giventhesmallsamplesizesoftheavailablestudies. Althoughthisrecommendationdiscouragesthe“routine”useofantipsychoticagentsinthetreatmentofdelirium,patientswhoexperiencesignificantdistresssecondarytosymptomsofadeliriumsuchasanxiety,fearfulness,hallucinations,ordelusions,orwhoareagitatedandmaybephysicallyharmfultothemselvesorothers,maybenefitfromshort-termuseofhaloperidoloranatypicalantipsychoticuntilthesedistressingsymptomsresolvebasedonthepanel’sclinicalexperience.PatientswhostartwithanantipsychoticfordeliriumintheICUoftenremainonthesemedicationsunnecessarilyafterdischarge(305–307).Continuedexposuretoantipsychoticmedicationcanresultinsignificantmorbidityandfinancialcost.Panelmembersjudgedthattheundesirableconsequencesofusingeitherhaloperidoloranatypicalantipsychoticfaroutweighedthepotentialbenefitsformostcriticallyadultswithdeliriumandthusissuedaconditionalrecommendationagainsttheirroutineuse. Dexmedetomidine. Recommendation:Wesuggestusingdexmedetomidinefordeliriuminmechanicallyventilatedadultswhereagitationisprecludingweaning/extubation(conditionalrecommendation,lowqualityofevidence). Rationale:ThesingleRCTusedtoevaluatetheroleofdexmedetomidineasatreatmentforagitationprecludingventilatorliberationinpatientswithdeliriumscreened21,500intubatedpatientsfrom15ICUstoenrollthe71studypatientsandwasterminatedearlybecausethefundingamount(fromthemanufacturerofdexmedetomidine)hadbeenusedup(386).Althoughdexmedetomidine(vsplacebo)wasassociatedwithasmall,butstatisticallysignificantincreaseinventilator-freehoursinthefirst7daysafterstudyrandomization(MD,17.3 hr;95%CI,4.0–33.2;verylowquality),itsusedidnotaffecteitherICUorhospitalLOS,orpatient’sdispositionlocationathospitaldischarge.Patientsdidnotcommonlyreceiveopioids;someoftheagitationmayhavebeenpainrelated;andthenumberofpatientsenrolledwithacutealcoholwithdrawalwasnotreported. PanelmembersjudgedthatthedesirableconsequencesofusingdexmedetomidineformechanicallyventilatedICUpatientswithagitationprecludingweaning/extubationoutweighedthepotentialundesirableconsequencesassociatedwithitsuse;therefore,theyissuedaconditionalrecommendationsupportingitsuseinthenarrowpopulationofcriticallyilladults.Theroleofdexmedetomidineinpatientswithdeliriumwithoutagitationorwhohaveagitationthatisnotprecludingventilatorliberationremainsunclear.Recommendationsregardingchoiceofsedationinmechanicallyventilatedcriticallyilladultsinthecontextofdeliriumcanbefoundinrecommendationsaboutsedativechoice. EvidenceGaps:Studiesevaluatingpharmacologicpreventionstrategiesneedtoevaluatepatientswithoutdelirium,enrollseverelyillmedicalpatients,identifypatientsubgroupswherethedeliriumpreventionbenefitsaregreatest,andevaluateclinicallymeaningfuloutcomes.Toimprovethemethodologyofsuchsubsyndromaltreatmenttrials,ourunderstandingofthesignificance,characteristics,andmeasurementofsubsyndromaldeliriumneedstoexpand.Inaddition,futurestudiesshouldtargetspecificsymptoms(e.g.,anxiety)insteadofsubsyndromaldeliriumasawhole.Deliriumtreatmentstudiesshouldfocusonmorehomogeneoushigh-riskICUpopulationsgiventhatthecauseofdelirium(andthusresponsetotherapy)maybedifferent.Symptomaticdistress(e.g.,agitation)andlong-termcognitiveandfunctionaloutcomeshouldbeevaluated.Medicationsshowninsmallstudiestoreducedeliriumsymptoms(e.g.,valproicacid)shouldberigorouslyevaluated.Finally,systeminnovationsareneededtoensurethatpatientsdonotremainindefinitelyonmedicationssuchasantipsychoticsaftersymptomaticinitiationduringanICUepisodeofdelirium. NonpharmacologicPreventionandTreatment SingleComponent. Question:Shouldasingle-component,nonpharmacologicstrategynotsolelyfocusedonsleepimprovementorearlymobilization(vsnosuchstrategy)beusedtoreducedeliriumincriticallyilladults? Recommendation:Wesuggestnotusingbrightlighttherapytoreducedeliriumincriticallyilladults(conditionalrecommendation,moderatequalityofevidence). Rationale:ICUdeliriumstudiesofnonpharmacologicinterventionsfocusedoneitheronemodifiableriskfactorwithasingleinterventionorseveralmodifiableriskfactorswithmulticomponentinterventions(SupplementalTable28,SupplementalDigitalContent36,https://links.lww.com/CCM/D794).Forthepurposesoftheseguidelines,onequestionaddressedsingleinterventionstudiesandonequestionaddressedmulticomponentinterventionstudies.Deliriumincidence,prevalence,anddurationwereconsideredthemostimportantoutcomesacrossbothquestions.ICULOS,hospitalLOS,andhospitalmortalitywerealsoconsideredtobecriticaloutcomesforthesequestions.Brightlighttherapy,familyparticipationincare,andapsychoeducationalprogramweretheonlysingle-componentinterventionsthathavebeenstudiedintheICU. Threestudiesexaminedtheeffectsoflighttherapy,whichdidnotdemonstratebeneficialeffectoneitherdeliriumincidenceorICULOS(387–389).Onebefore-afterstudyevaluatedtheeffectoffamilyparticipationincare(390).Panelmembersjudgedthattheundesirableconsequencesofusingbrightlighttherapyoutweighedthepotentialdesirableeffectsassociatedwithitsuseandthusissuedaconditionalrecommendationagainstitsuse. Multicomponent. Question:Shouldamulticomponent,nonpharmacologicstrategy(vsnosuchstrategy)beusedtoreducedeliriumincriticallyilladults? Recommendation:Wesuggestusingamulticomponent,nonpharmacologicinterventionthatisfocusedon(butnotlimitedto)reducingmodifiableriskfactorsfordelirium,improvingcognition,andoptimizingsleep,mobility,hearing,andvisionincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Remarks:Thesemulticomponentinterventionsinclude(butarenotlimitedto)strategiestoreduceorshortendelirium(e.g.,reorientation,cognitivestimulation,useofclocks);improvesleep(e.g.,minimizinglightandnoise);improvewakefulness(i.e.,reducedsedation);reduceimmobility(e.g.,earlyrehabilitation/mobilization);andreducehearingand/orvisualimpairment(e.g.,enableuseofdevicessuchashearingaidsoreyeglasses). Rationale:Themulticomponentinterventionstudiesevaluatedabundleofinterventions.Manyexamplesofmulticomponentbundles(8,283,391–396)haveshownimprovedoutcomesincriticallyilladults(SupplementalTable29,SupplementalDigitalContent37,https://links.lww.com/CCM/D795).Pilotstudiessuggestedthatcombiningcognitiveandphysicaltherapyearlyduringcriticalillnessisfeasibleandsafe(391)andusingnonpharmacologicmulticomponentinterventionsinICUpatientsisfeasible(392).Studiesofmulticomponentinterventions,manyofwhichwerenotrandomized,focusoncognitiveimpairment(e.g.,reorientation,cognitivestimulation,music,useofclocks);sedation/sleepdisruption(e.g.,reducingsedation,minimizinglightandnoise);immobility(earlyrehabilitation/mobilization);andhearingandvisualimpairment(e.g.,useofhearingaidsandglasses).Overall,theuseofsuchstrategiesreduceddeliriumsignificantly(fivestudies,n=1,318;OR,0.59;95%CI,0.39–0.88)(392–396).Further,ICUdurationofdelirium(16vs20 hr)(395),ICULOS(387),andhospitalmortalityalldecreased(393). Anothermulti-interventionapproach,theawakeningandbreathingcoordination,deliriummonitoring/management,andearlyexercise/mobility(ABCDE)bundle,wassignificantlyassociatedwithlessdelirium(n=296;49%vs62%;OR,0.55;95%CI,0.33–0.93)(7)whenevaluatedinabefore-afterstudyatonehospital.WhenarevisedandexpandedABCDEFbundle(whichincludesafocuson“F,”Familyengagement)wasevaluatedinalarger,multicenter,before-after,cohortstudy,andwheredeliriumwasalsoassessedusingtheCAM-ICU,anadjustedanalysisshowedthatimprovementsinbundlecomplianceweresignificantlyassociatedwithreducedmortalityandmoreICUdayswithoutcomaordelirium(9).Adverseeffectswerenotreportedinthesenonpharmacologicinterventionstudies.Sixoftheeightstudies’smallinterventionswereheterogeneous,andthestudieswithpositivefindingswereobservational.Panelmembersjudgedthatdesirableconsequencesofusinganyofthesemulticomponentinterventionstoreducedeliriumoutweighedanypotentialundesirableconsequencesandthusissuedaconditionalrecommendationsupportingtheiruse. EvidenceGaps:Overall,thecertaintyofevidencesupportingsingle-componentandmulticomponentinterventionsislow.Becausedeliriumalmostalwayshasamultifactorialetiology,multicomponentinterventionsareplausiblymorepromisingthansingleinterventions.However,amajorgapinunderstandingtheavailabledataisuncertaintyastowhichinterventionsresultintheeffect.Theroleoffamiliesinreducingpatientstressandfacilitatingnonpharmacologicdeliriumpreventionandmanagementinterventionsrequiresfurtherresearch.Theexperienceofpatientswithdeliriumhasnotbeenqualitativelyevaluated.Somearticlesdescribethesameinterventionsdifferently(2);consistentdefinitionsshouldbeestablished. IMMOBILITY(REHABILITATION/MOBILIZATION) Survivorsofcriticalillnessfrequentlyexperiencemanylong-termsequelae,includingICU-acquiredmuscleweakness(ICUAW).ICUAWcanbepresentin25–50%ofcriticallyillpatients(397)andisassociatedwithimpairmentsinpatients’long-termsurvival,physicalfunctioning,andqualityoflife(398–400).OneimportantriskfactorforICUAWisbedrest(398,401).Thesafety,feasibility,andbenefitsofrehabilitationandmobilizationdeliveredintheICUsettinghavebeenevaluatedaspotentialmeanstomitigateICUAWandimpairedphysicalfunctioning. Ashighlightedinthe2013guidelines(1),rehabilitation/mobilizationmaybebeneficialaspartofdeliriummanagementstrategies.Furthermore,importantassociationsexistbetweenanalgesicandsedationpracticesandpainandsedationstatuswithpatients’participationinrehabilitation/mobilizationintheICU(402).Giventhegrowingliteratureinthisfieldandtheinterplayofrehabilitation/mobilizationwithpain,agitation,anddelirium,thistopicwasintroducedasanewpartofthepresentguideline.Oneactionablequestionandthreedescriptivequestionswereaddressed(seeprioritizedtopiclistinSupplementalTable30[SupplementalDigitalContent38,https://links.lww.com/CCM/D796]andvotingresultsinSupplementalTable31[SupplementalDigitalContent39,https://links.lww.com/CCM/D797])(403).Aglossaryofrehabilitation/mobilizationinterventionsandoutcomesrelevanttothistopiccanbefoundinSupplementalTable32(SupplementalDigitalContent40,https://links.lww.com/CCM/D798).Theevidencesummariesandevidence-to-decisiontablesusedtodeveloprecommendationsfortheimmobility(rehabilitation/mobilization)groupareavailableinSupplementalTable33(SupplementalDigitalContent41,https://links.lww.com/CCM/D799),andtheforestplotsforallmeta-analysesareavailableinSupplementalFigure8(SupplementalDigitalContent42,https://links.lww.com/CCM/D800). EfficacyandBenefit Question:Forcriticallyilladults,isreceivingrehabilitationormobilization(performedeitherin-bedorout-of-bed)beneficialinimprovingpatient,family,orhealthsystemoutcomescomparedwithusualcare,adifferentrehabilitation/mobilizationintervention,placebo,orshamintervention? Recommendation:Wesuggestperformingrehabilitationormobilizationincriticallyilladults(conditionalrecommendation,lowqualityevidence). Remarks:Rehabilitationisa“setofinterventionsdesignedtooptimizefunctioningandreducedisabilityinindividualswithahealthcondition”(404).Mobilizationisatypeofinterventionwithinrehabilitationthatfacilitatesthemovementofpatientsandexpendsenergywithagoalofimprovingpatientoutcomes(405).Thisrecommendationsupportsperformingrehabilitation/mobilizationinterventionsoverusualcareoroversimilarinterventionswithareducedduration,reducedfrequency,orlateronset.Theimplementationofthisrecommendationwillbeinfluencedbyfeasibility-relatedissues,particularlyrelatedtovariabilityintheavailabilityofappropriatestaffingandresourcestoperformrehabilitation/mobilizationinterventionsacrossICUs. Rationale:Awidevarietyofcriticallyillpatientpopulationswerestudied(seestudyeligibilitycriteriainSupplementalTable34[SupplementalDigitalContent43,https://links.lww.com/CCM/D801]).Studiesevaluateddifferenttypesofinterventionsanddifferenttimingsforinitiatingtheintervention,whichpreventusfrommakingmorespecificrecommendationsintheseareas.Comparatorsfortheinterventionsincludedusualcarerehabilitationormobilization;rehabilitationormobilizationinterventionswithreduceddurationorfrequency;oralongertimetoinitiationcomparedwiththeinterventiongroup.Asdescribedbelow,fiveoutcomeswereevaluatedforthisquestion.Threeadditionaloutcomes(cognitivefunction,mentalhealth,andtimingofreturntoworkandrelatedeconomicoutcomes)couldnotbeevaluatedduetoinadequatedata. Weidentifiedatotalof16RCTs(391,406–420)(SupplementalTable25,SupplementalDigitalContent33,https://links.lww.com/CCM/D791)thatmetoureligibilitycriteriaandreportedonfivecriticaloutcomes.ThepooledestimatesfromsixRCTs(304patients)showedthatrehabilitation/mobilizationimprovedmusclestrengthatICUdischarge(MDinMedicalResearchCouncilsumscore[range,0–60]:6.24points[95%CI,1.67–10.82;lowqualityevidence])(408–410,414,415,420).Durationofmechanicalventilation(11RCTs,1,128patients)wasreducedby1.31days(95%CI,–2.44to–0.19;lowqualityevidence)(406–409,411,413–416).Forhealth-relatedqualityoflifemeasuredusingthe36-ItemShortFormHealthSurveyinstrumentwithin2monthsofdischargeinfourRCTs(303patients),amoderate-sizedimprovement(SMD,0.64[95%CI,–0.05to1.34])notreachingstatisticalsignificancewasobserved,withanoverallratingoflowqualityofevidence(412,416–418).Fortheremainingtwocriticaloutcomes,across13RCTs(1,421patients),therewasnoeffectonhospitalmortality(moderatequalityofevidence)(391,407,408,410–418,420).Physicalfunctionwasevaluatedviathe“TimedUpandGo”testinthreeRCTs(209patients)andthePhysicalFunctioninICUTestinthreeRCTs(209patients),withnosignificanteffectofrehabilitation/mobilization(moderatequalityofevidence)(391,411,414,416,420).Theincidenceofadverseeventsforpatientswasverylowbasedonfivetrialsandeightobservationalstudies(moderatequalityofevidence). Rehabilitation/mobilizationwasassessedasfeasible,acceptabletokeystakeholders,andlikelytobecost-effectivebasedonpreliminarydata.Inaddition,indirectevidence(421),alongwithadiscussionwithpanelmembers(includinganICUpatientrepresentative),suggeststhatpatientswillprobablyvaluethebenefitsofrehabilitation/mobilization.Givenasmallbenefitofrehabilitation/mobilizationinterventions(performedeitherin-bedorout-of-bed)andthelowoverallqualityofevidence,panelmembersagreedthatthedesirableconsequencesforpatientsprobablyoutweightheundesirableconsequences,andissuedaconditionalrecommendationfavoringrehabilitation/mobilizationinterventions. SafetyandRisk Question:Forcriticallyilladults,isreceivingrehabilitation/mobilization(performedeitherin-bedorout-of-bed)commonlyassociatedwithpatient-relatedsafetyeventsorharm? UngradedStatement:Serioussafetyeventsorharmsdonotoccurcommonlyduringphysicalrehabilitationormobilization. Rationale:Datafrom10observationalandnineRCTs(SupplementalTable35,SupplementalDigitalContent44,https://links.lww.com/CCM/D802)werereviewedtoanswerthisquestion.Serioussafetyeventsorharmsweredefinedasachangeinphysiologicstatusoraninjurythatrequiredanintervention.Theseeventswererare,withonly15reportedduringgreaterthan12,200sessionsacross13studies(283,391,416–418,422–429).Anincidenceratefortheseeventscouldnotbecalculatedbecauseinformationaboutthenumberofpatientsatriskand/orthenumberofrehabilitation/mobilizationsessionsperpatientwasnotconsistentlyorclearlyreportedinmanystudies. Themajorityofsafetyeventsorharmswasrespiratoryrelated,withfourdesaturationsthatrequiredanincreaseinFio2(423,429)andthreeunplannedextubations(285).Threemusculoskeletal-relatedeventsoccurred:onefall(427),oneAchillestendonrupture(418),andonepolyarthralgiaexacerbation(416).Twocardiovascular-relatedeventsoccurred:onehypertensiveurgency(391)andonesyncopalepisode(416).Overall,patientharmrelatedtorehabilitation/mobilizationisrare;thisconclusionissupportedbyarecentmeta-analysis(430). IndicatorsforInitiation Question:Forcriticallyilladults,whataspectsofpatientclinicalstatusareindicatorsforthesafeinitiationofrehabilitation/mobilization(performedeitherin-bedorout-of-bed)? UngradedStatements:Majorindicatorsforsafelyinitiatingrehabilitation/mobilizationincludestabilityincardiovascular,respiratory,andneurologicstatus. Vasoactiveinfusionsormechanicalventilationarenotbarrierstoinitiatingrehabilitation/mobilization,assumingpatientsareotherwisestablewiththeuseofthesetherapies. Rationale:Safeinitiationofphysicalrehabilitationormobilizationwasevaluatedin17(283,391,407,408,413,416–418,424–426,429,431–435)studiesthatenrolled2,774patientsandreportedcardiovascular,respiratory,orneurologiccriteria(SupplementalTable36,SupplementalDigitalContent45,https://links.lww.com/CCM/D803).Datafromthesestudiesweresummarized,andexpertopinionwasusedtodeterminesuggestedrangesforcardiovascular,respiratory,neurologic,andotherrelevantcriteriawithinwhichrehabilitation/mobilizationcanbesafelyinitiated(Table1).Althoughtheseparameterswerebasedonclinicalresearchwithclinicalapplicationinterpretedviaexpertopinion,theyshouldnotbeasubstituteforclinicaljudgment.Allthresholdsshouldbeinterpretedormodified,asneeded,inthecontextofindividualpatients’clinicalsymptoms,expectedvalues,recenttrends,andanyclinician-prescribedgoalsortargets.TABLE1.:SummaryofSafetyCriteriaforStartingandStoppingPhysicalRehabilitationorMobilizationPerformedEitherIn-BedorOut-of-BedIndicatorsforStopping Question:Foradultcriticallyillpatients,whataspectsofpatientclinicalstatusareindicatorsthatrehabilitation/mobilization(performedeitherin-bedorout-of-bed)shouldbestopped? UngradedStatements:Majorindicatorsforstoppingrehabilitation/mobilizationincludedevelopmentofnewcardiovascular,respiratory,orneurologicinstability. Otherevents,suchasafallormedicaldeviceremoval/malfunction,andpatientdistressarealsoindicationsforstopping. Rationale:Indicatorsforstoppingrehabilitation/mobilizationwerereportedin14studies(283,391,407,408,413,416,418,424,425,429,431–434)thatenrolled2,617patients(SupplementalTable37,SupplementalDigitalContent46,https://links.lww.com/CCM/D804).Specificstoppingcriteriaforcardiovascular,respiratory,orneurologicinstabilitywereidentified.Datafromthesestudiesweresummarized,andexpertopinionwasusedtodeterminesuggestedcardiovascular,respiratory,neurologic,andotherrelevantcriteriaforstoppingrehabilitation/mobilization(Table1).Althoughtheseparameterswerebasedonclinicalresearchwithclinicalapplicationinterpretedviaexpertopinion,theyshouldnotbeasubstituteforclinicaljudgment. EvidenceGaps:ThefieldofICU-basedrehabilitation/mobilizationisatanearlystagewitharapidlyevolvingbodyofevidence.Manyresearchquestionsremainoutstanding.Importantdirectionsforfutureresearchincludeunderstandingdifferencesinpatientoutcomesaccordingtothetypeofinterventionandthetiming,frequency,duration,andintensityofinterventions.Themodeofinterventiondelivery,includingtheexpertise/trainingofpersonneldeliveringinterventions,needsadditionalinvestigation.Theinfluenceofpatientconditions(e.g.,pre-ICUfunctionalstatus,deliriumandsedationstatus,musclewasting,andnerveandmuscledysfunction)onpatientoutcomesafterrehabilitation/mobilizationinterventionsshouldbeexamined.Thesefactorsmayhelptoidentifypotentialsubgroupsofcriticallyillpatientswhomaygainthegreatestbenefitfromrehabilitation/mobilizationinterventions.Aswell,methodstoassessthepatientexperienceduringrehabilitation/mobilization,particularlyinnonverbalcriticallyillpatients,arewarranted.Standardizedreportingofinterventiondetails(e.g.,timing,frequency,duration,andintensity),potentialsafetyevents,andbothshort-termandlong-termoutcomeswillfacilitatecomparisonsbetweenstudiesandsettings.Finally,futureresearchshouldcontinuetoevaluatethemeasurementpropertiesofshort-termandlong-termoutcomemeasurestodeterminethemosteffectiveandefficientapproachestoevaluatingtheeffectsofrehabilitation/mobilization. SLEEPDISRUPTION Poorsleepisacommoncomplaintandasourceofdistressformanycriticallyillpatients(436,437).Sleepdisruptioninthecriticallyillcanbesevereandischaracterizedbysleepfragmentation,abnormalcircadianrhythms,increasedlightsleep(stageN1+N2),anddecreasedslow-wave(stageN3)andrapideyemovement(REM)sleep(438–440).Theinterplayofmedications,criticalillness,delirium,cerebralperfusion,andsleepiscomplex,butisimportant,andisanincreasingfocusofresearch.Aglossaryofthesleep-relatedtermsusedinthissectioncanbefoundinSupplementalTable38(SupplementalDigitalContent47,https://links.lww.com/CCM/D805),andanoverviewofnormalsleepanditsarchitectureascharacterizedbypolysomnographycanbefoundinSupplementalTable39(SupplementalDigitalContent48,https://links.lww.com/CCM/D806). Inadditiontoemotionaldistress,sleepdisruptionhasalsobeenhypothesizedtocontributetoICUdelirium(441–443),prolongeddurationofmechanicalventilation(444),derangedimmunefunction(445,446),andneurocognitivedysfunction.Giventhatsleepisapotentiallymodifiableriskfactorinfluencingrecoveryincriticallyilladults,thistopichasbeenintroducedinthepresentguidelineandisaddressedinfouractionableandsixdescriptivequestions(seeprioritizedtopiclistinSupplementalTable40[SupplementalDigitalContent49,https://links.lww.com/CCM/D807]andvotingresultsinSupplementalTable41[SupplementalDigitalContent50,https://links.lww.com/CCM/D808]).Theevidencesummariesandevidence-to-decisiontablesusedtodeveloprecommendationsforthedisruptedsleepgroupareavailableinSupplementalTable42(SupplementalDigitalContent51,https://links.lww.com/CCM/D809),andtheforestplotsforallmeta-analysescompletedareavailableinSupplementalFigure9(SupplementalDigitalContent52,https://links.lww.com/CCM/D810). Characterization CriticallyIllVersusHealthy. Question:Howdoessleepincriticallyilladultsdifferfromnormalsleepinhealthyadults? UngradedStatements:Totalsleeptime(TST)andsleepefficiencyareoftennormal. Sleepfragmentation,theproportionoftimespentinlightsleep(stagesN1+N2),andtimespentsleepingduringtheday(vsnight)arehigher. Theproportionoftimespentindeepsleep(stageN3sleepandREM)islower. Subjectivesleepqualityisreduced. Rationale:SmallstudiessuggestthatTSTandsleepefficiencyarenormalduringcriticalillnessalthoughconsiderableinterpatientvariabilityexists(443,447).Duringcriticalillness,theproportionoftimespentinlightsleep(stagesN1+N2)isincreasedandthetimespentindeepsleep(stagesN3+REMsleep)isdecreased(438,440,448–450).Sleepfragmentation(i.e.,numberofarousalsandawakeningsperhour)ishigherincriticallyilladultsthanhealthysubjects(449,451,452).AmonghealthyadultsexposedtotheICUenvironment,daytimesleepwasfoundtoincreaseeachdayspentintheICUsettingandrepresentonethirdoftotalsleep(453).Incriticallyilladults,theproportionoftotalsleepduringthedaytimesleephasbeenshowntobeashighas57%(444,454).Subjectivesleepqualityisseverelyalteredduringcriticalillness;patientsassesstheirsleepqualityintheICUasbeingconsiderablyworsethantheirsleepathome(449,455,456). DeliriumVersusNoDelirium. Question:Issleepdifferentincriticallyilladultsifdelirium(vsnodelirium)ispresent? UngradedStatements:ThepresenceofdeliriummaynotaffectTST,sleepefficiency,orsleepfragmentation. Theinfluenceofdeliriumontheproportionoftimespentinlight(N1+N2)versusdeeper(N3)sleepisunknown. REMsleepislowerifdeliriumispresent. Deliriumisassociatedwithgreatercircadiansleep-cycledisruptionandincreaseddaytimesleep. Whetherdeliriumaffectsreportedsubjectivesleepqualityremainsunclear. Rationale:DeliriumhasnotbeenevaluatedinmostICUpolysomnographysleepstudies.Fourstudieshaveevaluatedsleepwithpolysomnographyincriticallyilladultswithdeliriumthatwasevaluatedwithavalidatedscreeningtool(443,447,457).Twoofthestudiesexcludedpatientsreceivingsedation(443,447).TSTandsleepefficiencyaresimilarbetweendeliriousandnondeliriouspatients(443,447).Onesmallstudyofnoninvasiveventilation(NIV)patientsfoundthatsleepfragmentationissimilarregardlessofdeliriumstatus(443).Theinfluenceofdeliriumontheproportionoftimespentinlightsleep(N1+N2)(vsdeeperN3sleep)wasnotreportedinanyofthestudies.TheamountofREMsleepwassignificantlylowerinpatientswithdelirium(443).DayswithdeliriumweregreaterinthosepatientshavingaverylowamountofREMsleepsuggestingthatanassociationbetweenREMsleepquantityanddeliriumexists(442).Onestudyfoundthatdeliriumisassociatedwithagreatercircadiansleep-cycledisruptionasevidencedbydaytimesleepbecomingagreaterproportionofTST(443).Higherreportedsubjectivesleepqualitywasassociatedwithlowerdeliriumincidenceinoneobservationalstudy(312),andinoneRCT,earplugusereduceddeliriumandimprovedsubjectivesleepquality(458).Inapre-postsleepqualityimprovementstudy,patientsratedtheirsleepbeforeandduringthemulticomponentsleepprotocolsimilarlyalthoughsignificantlyfewerpatientshadcoma/deliriumduringtheintervention(459).Subjectivesleepqualityreportingbydeliriouspatientsmightbeunreliable. MechanicalVentilationVersusNoMechanicalVentilation. Question:Issleepdifferentincriticallyilladultswhoaremechanicallyventilated(vsnotmechanicallyventilated)? UngradedStatements:Theuseofmechanicalventilationincriticallyilladultsmayworsensleepfragmentation,architecture,andcircadianrhythm(daytimesleep)comparedwithnormalsleep,buttheseeffectsareoftenvariableandhavenotyetbeenfullyinvestigated. Theuseofmechanicalventilation(vsperiodswithoutmechanicalventilation)inpatientswithrespiratoryfailuremayimprovesleepefficiencyandreducefragmentation,butdataarelimited. Rationale:Ventilationandsleepsharecomplexandreciprocalrelationships.Duringsleep,oxygenconsumptionandCO2productiondecrease,leadingtoaphysiologicreductionofventilationcomparedwithwakefulness.Excessivepressuresupport,ventilatorasynchronies,orventilatoralarmsmighttriggerarousalsandsleepinterruptions.Forthepurposeofthisquestion,“ventilated”referredtopatientsmechanicallyventilated(bothinvasivelyandnoninvasively)and“nonventilated”aspatientswhowerebreathingwithoutanyrespiratoryassistance(i.e.,nopressuresupport,patientsmaybereceivingcontinuouspositiveairwaypressure).Onlystudiesthatincorporatedpolysomnographyassessmentwereevaluated. Althoughthreepolysomnographystudiescompareddistinctventilatedandnonventilatedgroups(451,454,461),twostudiesevaluatedthesamepatientsbeforeandafterventilatoryassistance(451,454).Duringventilation,sleepdurationhasbeenreportedtobelowerthannormal(241,443,448,453,454,462–464),normal(438,465),orhigherthannormal(466,467).Arousalindicesarelowerduringventilation(460),andsleepfragmentationislowerwithNIVthanwithoutventilation(243,443,448,453,454,462–464). Sleepfragmentationishigherduringmechanicalventilation(vsnoventilation)(449)andNIV(vsnoventilation)(454).TheproportionoftimespentinstageN3sleepisdecreasedinventilatedcriticallyilladults(0–27%)(438,439,448,449,453,462,464,467–473),asistheproportionoftimespentinREMstagesleepreduced(0–14%)(241,438,440,443,448,450,451,453,454,462,464–473).Sleepfragmentationindexduringmechanicalventilationrangesfrom18to35arousalsandawakeningsperhourofsleep(241,438,440,443,448,450,451,453,454,462,464–474).Respiratory-relatedarousalshavebeensuspectedtobeamajorfactorinvolvedinsleepfragmentationincriticallyilladults,reportedinonestudyascausing19%(11–30)ofarousalandawakeningsfromsleep(241,438,440,448,450,451,453,454,460,462,464–474).Amongventilatedcriticallyilladults,studiesconsistentlyshowthatamongventilatedpatients,theproportionoftimespentindaytimesleeprangesfrom36%to57%andisgreaterthanitisfornonventilatedpatients(438,440,443,450,453,454,470). Comparingmechanicalventilation(vsnomechanicalventilation)incriticallyilladults,threestudieshaveshowngreaterTSTduringmechanicalventilation(241,436,438),whereasonestudyshowednodifference(461).Inpatientswithatracheostomy,median(interquartilerange)sleepefficiencyishigherduringventilation(61%[38–74])thanwithoutventilatorysupport(44%[9–63])(451).Twostudieshaveshownthatsleepfragmentationissignificantlylowerduringmechanicalventilation(vsnoventilation)(472,473),whereasonestudyshowednodifference(451).Twostudiesshowednosignificantdifferenceinsleepstages,whereasonestudyshowedimprovedsleeparchitecturewithlesslight,sleep(stageN1),andmoredeepsleep(stages3andREMsleep)duringperiodswithNIVthanwithout(454). EvidenceGaps:Large,additionalstudiesarerequiredtodefinetheinfluenceofcriticalillness,delirium,andmechanicalventilationonsleepquality.Asystematicassessmentofdeliriumshouldbedoneinparallelwithpolysomnographyrecording(472).Amongstudies,considerablevariabilityhasbeenreportedregardingallsleepparameters.Thesediscordancesmightbeduetoseveralfactorssuchastotalrecordingtime,qualityoftherecordings,experienceofthescorer(awarenessofatypicalsleep),thecriteriausedtoanalyzesleep(i.e.,RechtschaffenetKalesvsDrouot-Watsonrules)(457,475,476),diseaseseverity,LOSonthedayofpolysomnographyevaluation,bothsedativetypeanddepthofsedation,andwhetherdeliriumispresent.Harmonizationinscoringrulesandrecordingpractices(e.g.,systematicrecordingofnoiselevelsandmentalstatus)andstudyinghomogeneousgroupsofpatientsmighthelptoassesstheprevalenceofsleepalterationsincriticallyillpatients.Detaileddataonpotentialsleepdisruptersareimportantwhenevaluatingsleepfragmentation.Theeffectofsleepdisruptiononclinicallyrelevantshort-andlong-termoutcomesinlargehomogeneouspatientgroupsremainsuncertain.Finally,reliabletoolstoassesscircadianrhythmdisruptionhaveyettobeidentified. PrevalenceofUnusual/DissociatedSleep Question:Whatistheprevalenceofunusualordissociativesleeppatternsincriticallyilladults? UngradedStatement:Theprevalenceofunusualordissociatedsleeppatternsishighlyvariableanddependsonpatientcharacteristics. Rationale:Atypicalsleep,characterizedbyδwaveswithoutanycyclicorganizationandbytheabsenceofKcomplexesandsleepspindlesthatareconsideredthedefiningelectroencephalogramfeaturesofstageN2sleep,wasfirstreportedinsedatedpatients(438).Pathologicwakefulnessisoftenassociatedwithatypicalsleepandischaracterizedbyanonreactiveslowedelectroencephalogramandbydissociationbetweenelectroencephalogramrhythmsandbehavioralwakefulness.Duringatypicalsleep,notincludedinconventionalRechtschaffenandKaleselectroencephalogramscoringrules,theelectroencephalogramcandisplayδorθwaves(evocativeofsleep)inbehaviorallyawakepatientsorα-βwaves(evocativeofwakefulness)inacomatosepatient(457,476). Elevenstudieshavereportedtheprevalenceoftheabnormalsleepelectroencephalogrampatternsthatmeetthecriteriaforatypicalsleep(438,440,443,450,457,464,476–481).InconsciousnonsedatedorlightlysedatedICUpatients,theabnormalsleepelectroencephalogrampatternprevalencerangesfrom23%to31%(440,443,450,457,480).Whencriteriaareusedtoexcludepatientswithknownfactorsfortheseabnormalelectroencephalogrampatterns(e.g.,receivingsedative/opioids,havingdeliriumcomaorsepsis,orwithahistoryofepilepsy),theprevalenceofatypicalsleepbecomesnonexistent(0%)(464).Insedatedpatients,theprevalenceofatleastonedissociatedelectroencephalogrampattern(dissociatedwakeorsleep)rangesfrom60%to97%(438,476,481),andtheprevalenceofisolatedunusualsleepelectroencephalogrampatternsrangesfrom50%to70%(475,481).Variabilityinthepresencetothosefactors(i.e.,sedation,sepsis,anddelirium)knowntoinfluenceabnormalsleepelectroencephalogrampatternslikelyaccountsforthevariabilityinprevalenceamongstudies(438,440,457,476). EvidenceGaps:Sleeprecordingsincriticallyilladultsshouldbecarefullyexaminedtoidentifynewunusualordissociativesleeppatternsusingpublishedapproachesandspecificcriteria(457,476).Theclinicalcharacteristicsofpatientswiththeseunusualpatterns,andtheirassociatedmechanismsandoutcomesbothduringandlongaftertheICUstay,shouldbeinvestigated. RiskFactors BeforeICUAdmission. Question:WhatriskfactorsthatexistbeforetheonsetofcriticalillnessaffectsleepqualityincriticallyilladultsintheICU? UngradedStatement:Patientswhoreportpoor-qualitysleepand/oruseofapharmacologicsleepaidathomearemorelikelytoreportpoor-qualitysleepintheICU. Rationale:ThefollowingfactorsexistingbeforetheonsetofcriticalillnesshavebeenexaminedtodetermineiftheyaffectsleepqualityinICU:femalegender,olderage,reportedpoorqualityofsleepathome,regularuseofsleepaidmedicationathome,andspecificpremorbidmedicalconditions(e.g.,hypertension,diabetes,cancer,andthyroiddisease)(SupplementalTable43,SupplementalDigitalContent53,https://links.lww.com/CCM/D811).Ofthese,only“reportedpoorqualitysleepathome”(459,482,483)and“regularuseofapharmacologicsleepaidathome”(450,482)havebeenconsistentlyreportedinmorethanonestudyasbeingassociatedwithperceivedlowerqualityofsleepintheICU. DuringICUAdmission. Question:WhichICU-acquiredriskfactorsaffectsleepqualityincriticallyilladults? UngradedStatement:Pain,environmentalstimuli,healthcare-relatedinterruptions,psychologicfactors,respiratoryfactors,andmedicationseachaffectsleepqualityintheICU. Rationale:Patient-perceivedfactorsthatcontributetopatient-perceivedpoorsleepamongcriticallyilladultshavebeenreportedaccordingtoeithertheirseverity(degreetowhichtheydisruptedsleep)orincidence(frequencywithwhichtheywerereported)in12observationalstudies(455,456,460,482,484–492)(SupplementalTable44,SupplementalDigitalContent54,https://links.lww.com/CCM/D812).Thefactorsmostfrequentlycitedbypatientsasdisruptivetosleepwerenoise,painanddiscomfort,immobility/restrictedmovement,nursingcareinterventions,andworry/anxiety/fear(449,455,456,482,484–490,492,493).Fourstudies(449,456,482,492)usedthe“SleepintheIntensiveCareUnit(ICU)Questionnaire”(455)toassesstheseverityofdisruptioncausedbysevenextrinsic(environmental)factors(rankedonascaleof1–10with1beingnodisruptionand10significantdisruption).Thetopthreereportedextrinsicfactorsdisruptingsleepwerenoise,lighting,andnursinginterventions(e.g.,baths).Allsevenfactors,includingthetopthree,ranked5orlessonthe10-pointsleepdisruptivenessscale(455,482,484).WhenICUpatientswereaskedtorank35intrinsicandextrinsicfactorsona0–4scale(basedonhowdisruptiveeachfactorwastosleep),thetopintrinsicfactorswerepain,inabilitytogetcomfortable,thebed,andproceduresbeingperformedonthepatient(456,485–490,492,493).Acompletelistofpatient-identifiedfactorsissummarizedinTable2.TABLE2.:ListofFactorsThatPatientsReportasDisruptivetoSleepInadditiontoaskingpatientstoidentifyfactorstheyperceiveasdisruptive,otherstudieshavemeasuredsleepobjectivelyusingpolysomnographyoractigraphyandattemptedtocorrelateriskfactorswithvariousmeasuresofsleep.Factorsthathavebeenshowntocorrelatewithsleepdisruptioninunivariateanalysesincludeillnessseverity(494),delirium(442,443),hypoxemiaandalkalosis(494),receivingabenzodiazepine(442)orpropofol(464),patient-ventilatorasynchrony(454),spontaneous(vsmechanicallysupported)breathing(452),andaspontaneousmodeofventilation(vsacontrolledmode)(472,495).Noisehasbeenfoundtocorrelatetemporallywitharousalsbutappearstoberesponsibleforonly10–17%ofallarousals(449,455,482,484).Onlyonestudyincludedmultivariableanalysisandfoundthatpresenceofanendotrachealtube(i.e.,receivingmechanicalventilation)seemedtoconferimprovedsleepquality(460).Thesleepofindividualpatientsmaybeaffecteddifferentlybyvariousriskfactors(e.g.,somepatientsmaybemorebotheredbynoisethanotherpatients)andthemeaningorrelevancetopatients(e.g.,somepatientsarecomfortedbyhearingthenursenearby,whereasothersarebotheredbyit),andthepatient’sintrinsicdisposition(e.g.,susceptibilitytofeelworried,afraid,oruncomfortableundersimilarcircumstances). EvidenceGaps:Studiesusingquestionnairesandinterviews,whilepatient-centered,aresubjecttorecallbiasandexcludepatientswhoarenotabletoself-reportduetosedation,delirium,dementia,oracutebraininjury.Furthermore,patientsmayhavesleepthatisseverelyfragmentedwithmicroarousals,butthepatientsmaynotbeabletoidentifythedisruptivefactorsbecausetheywerenotfullyawakenedfromsleep.Studiesusingpolysomnographyarelimitedtothosethatcanbeanalyzedbystandardcriteriaandexcludehighlyabnormalelectroencephalogramsorthosewithpoor-qualityelectroencephalogramsignals.Studiescorrelatingvariousfactorswithimpairedsleeponpolysomnographydonotprovecausation,onlyassociation,andwerelargelyweakassociationsinunivariateanalysis. Outcomes Question:Dosleepandcircadianrhythmalterations“during”anICUadmissionaffectoutcomesduringand/oraftertheICUstayincriticallyilladults? UngradedStatements:Althoughanassociationbetweensleepqualityanddeliriumoccurrenceexistsincriticallyilladults,acause-effectrelationshiphasnotbeenestablished. Anassociationbetweensleepqualityanddurationofmechanicalventilation,lengthofICUstay,andICUmortalityincriticallyilladultsremainsunclear. TheeffectsofsleepqualityandcircadianrhythmalterationsonoutcomesincriticallyillpatientsafterICUdischargeareunknown. Rationale:Ahandfulofstudieshelpanswerthesequestions(SupplementalTable45,SupplementalDigitalContent55,https://links.lww.com/CCM/D813).PoorsleepqualityisoftenassumedtobeapotentiallymodifiableriskfactorforICUdelirium;severalstudieshaveevaluatedthisrelationship.Criticallyilladultswhoareseverelysleepdeprivedare30%morelikelytohavementalstatuschanges(441).Subsequentpolysomnographystudiesfurthersupportedthisassociation(442,451).CriticallyilladultswithsevereREMdeprivation(442,451)andcircadiansleep-cycledisruption(asevidencedbyagreaterproportionofdaytimesleep)aremorelikelytoexperiencedelirium(451).Poorsleepqualityhasalsobeenfoundtobeanindependentriskfactor(496)forpostcardiacsurgeryICUdelirium.Additionally,before-and-afterobservationalstudiesofmultidisciplinarybundlesthatincludesleepenhancementprotocolshavebeenshowntodecreasedeliriumprevalence(312,454),althoughinonlyonestudydidsleepefficiencyimprovewiththeintervention(312).Althoughanassociationbetweensleepqualityanddeliriumoccurrenceexists,itremainsunknownifpoorsleepisacausefordelirium. Useofamulticomponentdeliriumpreventionprotocolthatincorporatedanonpharmacologicsleepenhancementprotocolwasassociatedwithshorterdeliriumdurationandgreaterventilator-freedays(497).Therelationshipofsleeptotheseoutcomesremainsunclearassleepwasnotmeasuredinthestudy.Patientswithabnormalsleep(increaseddaytimesleep;reducedREM)weremorelikelytofailNIVandrequireintubationandmechanicalventilation(443).Inasmallstudyofpatientswithmoderate/severeTBI,betterorimprovingrest-activitycycleconsolidation(≥80%daytimeactivity)wasassociatedwithshorterICUandhospitalstays(498).AmongpatientswhereabnormalsleepwasfelttobeacauseoflateNIVfailure,ICUstayswerelongerandbothICUandhospitalmortalityratesweregreater(443).Onequalityimprovementstudyshowednodifferenceinmortalitywithitsusedespitedelirium’sbeingreduced(459).ThepresenceoforganizedsleeppatternsinpatientswitharecentTBIispredictiveofimprovedsurvival(479).AlthoughanumberofstudieshavefoundthatsleepremainsdisturbedafterICUdischarge,nostudieswerefoundintheliteratureevaluatingtheeffectofsleepintheICUonoutcomesafterICUdischarge. EvidenceGaps:Availablestudiescannotfullyelucidatetherelationshipbetweensleepalterationsinthecriticallyillandimportantoutcomessuchasdeliriumoccurrence,durationofmechanicalventilation,ICULOS,andmortalityareinadequatetoconfirmwhetheranassociationexistsbetweenthesleepalterationsseeninthecriticallyilladultsandimportantoutcomessuchasdeliriumoccurrence,durationofmechanicalventilation,ICULOS,andmortality.Poorsleepmayadverselyaffecttheimmunesystem,glycemiccontrol,andthepsychologicwell-beingofotherwisehealthyindividuals,sounderstandingifthereareclinicaleffectsontheseandotheroutcomesincriticallyilladultsisofgreatimportance.StudiesthatpairtheseoutcomeswithreliablemeasurementofsleepattheICUbedside,whilecontrollingforthemultipleotherfactorsthatareassociatedwiththeseoutcomes,areneeded.Additionally,studiesareneededtodeterminetheeffectsofICUsleepqualityonpost-ICUoutcomes. Monitoring Question:Shouldphysiologicmonitoringberoutinelyusedclinicallytoevaluatesleepincriticallyilladults? Recommendation:Wesuggestnotroutinelyusingphysiologicsleepmonitoringclinicallyincriticallyilladults(conditionalrecommendation,verylowqualityofevidence). Remarks:Physiologicmonitoringreferstotheuseofactigraphy,bispectralanalysis(BIS),electroencephalography,andpolysomnographytodetermineifapatientisasleeporawake.Itspecificallydoes“not”includemonitoringofpatients’perceivedsleepbyeithervalidatedassessment(e.g.,theRichardsCampbellSleepQuestionnaire)orinformalsubjectivebedsideassessment. Rationale:Noneofthefivecriticaloutcomeschosenforthisquestion(i.e.,deliriumoccurrence,durationofmechanicalventilation,ICULOS,ICUmortality,andpatientsatisfaction)havebeenstudied.Observationalstudieshaveevaluatedtheroleofphysiologicsleepmonitoringonotheroutcomes(SupplementalTable46,SupplementalDigitalContent56,https://links.lww.com/CCM/D814).Physiologicmonitoringidentifiedsleep-disorderedbreathinginpatientswithacutecoronarysyndromes(499,500),buttheimpactofthisevaluationwasnotdetermined.Whenmotoractivity(asmeasuredbyactigraphy)wascomparedwithnurses’sleepandsedationassessmentsinasmallseriesofmechanicallyventilatedadults(501),limbmovementswerefoundtocorrelatewiththemeasuredneurologicindices.Theuseofpolysomnography-derivedelectroencephalogramrecordingsofpatientswithnontraumatic(479)andtraumatic(480)encephalopathyconcludedthatthepresenceofrecognizedelementsofsleepwasassociatedwithafavorableprognosis.Finally,threesmallstudiesfoundthatpolysomnographycanbeusedtooptimizethemethodofmechanicalventilatorysupportinICUpatientsinacuterespiratoryfailure(443,502,503).Despitethesepotentialrolesforpolysomnography,itsroutineuseintheICUisnotfeasible. Thepanelarrivedatthisrecommendationbasedonthelackofhigh-qualityevidencecombinedwiththehighcostoftheresourcesnecessarytoimplementmostoftherelevanttechnologies.Physiologicmonitoringandinterpretationhavesignificantlimitationsasdescribedabove.Further,nostudiesinvestigatedsleepmonitoringinanunselectedICUpopulation,thuscallingintoquestionthegeneralizabilityoftheavailabledata. Althoughroutinephysiologicsleepmonitoringisnotrecommended,weemphasizethatclinicians“should”routinelyinquireaboutpatients’sleeportrytomonitoriteitherbyusingoneofthevalidatedassessmenttoolssuchastheRichardsCampbellSleepQuestionnaireorbyinformalbedsideassessment.TheRichard-CampbellSleepQuestionnairehasbeenshowntobeavalidandreliabletoolincriticallyilladultstoevaluateapatient’sperceptionoftheirownsleepiftheyarebothalertandoriented(504). Poorsleepisconsideredtobeoneofthemostcommonstressesexperiencedbycriticallyillpatients(435,437).Askingaboutpatients’sleepmayservetovalidatepatients’andtheirfamilies’concernsandisanecessaryfirststeptoapproachinganintervention.Nurse-observedsleep(439,448,505,506)overestimatedTSTwhencomparedwithpolysomnographyevaluation.Whennurseandpatientperceptionsofsleeparecompared,thenursemaysometimesoverestimatepatients’perceptionofsleepquality(485,492,505,507). EvidenceGaps:Howbesttomeasuresleepincriticallyillpatientscontinuestobedebated(476,508).RoutinemonitoringofanybrainactivityintheICUremainschallenging.Theproblemofmonitoringsleepisfurthercomplicatedbythefactthattheelectricalactivityofthebrainalone(i.e.,electroencephalogram)isinsufficienttodeterminesleepstages,circadianactivity,andsleep-disorderedbreathing.Asimplified,generalizablesystemformonitoringsleepintheICUthatisresistanttothechangingphysiologyofthecriticallyillpatientandwillstanduptoregularuseintheICUsettingwouldenhanceourunderstandingoftherelationshipbetweensleepandICUoutcomes.Incontrasttohealthyindividuals,criticallyillpatientshavevariationinvigilancestatesandelectroencephalogrampatternsnotonlyduetonaturalsleep/wakestatesbutalsofromsedatingmedicationsanddelirium.Whethersedative-inducedsleepprovidesthesamerestorativebenefitsasnaturalsleepisunknown.Largestudiesareneededtodeterminethebestmethodofsleepmeasurementandclassificationandtomeasurehowtheindividualfactors(sleep,sedation,illness-inducedencephalopathy)oracombinationthereofaffectpatientoutcomes,includingpatientsatisfaction.Theexpenseandtime-consumingnatureofpolysomnographyhavemaderesearchofsleepmeasurementandsleepoutcomesdifficult.Othermeasurementtechniquessuchaslimitedelectroencephalogramandprocessedelectroencephalogramdevicesmayprovidevaluabledata,butstudiescomparingthemtopolysomnographyareneededtovalidatethesemethods. NonpharmacologicInterventionstoImproveSleep AdescriptionoftheventilationmodesevaluatedinthissectionquestionandthemethodsusedtoidentifystudiesandsummarizedatacanbefoundinSupplementalTable47(SupplementalDigitalContent57,https://links.lww.com/CCM/D815). VentilatorMode. Question:Shouldassist-controlventilationbeusedatnight(vspressuresupportventilation)toimprovesleepincriticallyilladults? Recommendation:Wesuggestusingassist-controlventilationatnight(vspressuresupportventilation)forimprovingsleepincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:Manyoftheoutcomesdeemedcriticalorimportantbythepanelforthisquestionwerenotevaluatedorreported.Pooledestimatesofthreestudies(n=61)(469,472,473)foundthatassist-controlventilation(vspressuresupportventilation)wasassociatedwithanincreaseinsleepefficiency(MD,18.33%;95%CI,7.89–28.76;moderatequality).Althoughpooledestimatesoftwostudies(472,473)(n=41)foundthatassist-controlventilation(vspressuresupportventilation)wasnotassociatedwithadifferenceinthepercentageofTSTspentinstage1(MD,0.31%;95%CI,–5.17to5.79;lowquality)orstage2(MD,5.29%;95%CI,–4.38to14.97;verylowquality)sleep,itwasassociatedwithmoretimespentinREMsleep(MD,2.79%;95%CI,0.53–5.05;lowquality).Althoughthequalitywasdeemedtobelow,giventhepotentialbenefitsofthisintervention,itslowriskandthefactthatallventilatorshaveassist-controlmodecapability,aconditionalrecommendationforusingassist-controlmodeventilationatnighttoimprovesleepwasmade.Forthosepatientswhoremaindyssynchronousdespitealleffortstooptimizeventilatorsettingsonassist-controlmode,however,clinicianswillhavetomakeacase-by-casedecisionwhethertoreturnthepatienttopressuresupportventilationorconsidersedation,consideringthedeleteriouseffectsofpropofolandbenzodiazepinesonsleepqualityandsynchrony. Question:Shouldanadaptivemodeofventilationbeusedatnight(vspressuresupportventilation)toimprovesleepincriticallyilladults? Recommendation:Wemakenorecommendationregardingtheuseofanadaptivemodeofventilationatnight(vspressuresupportventilation)forimprovingsleepincriticallyilladults(norecommendation,verylowqualityofevidence). Rationale:Fivesmallrandomizedcontrolledcrossovertrialscomparedanadaptivemodeofventilationversusapressuresupportmodeinprimarilymedicalcriticallyilladults,evaluatingoutcomesthepaneldeemedimportantbutnoneweredeemedcritical.Theadaptivemodesstudiedwereasfollows:automaticallyadjustedpressuresupport(473),proportionalassistventilation(462),proportionalassistventilationwithload-adjustablegainfactors(468,471),andneutrallyadjustedventilatorassist(465).FeasibilitymayalsobeaconcernbecausesomeICUsmightnothaveventilatorsorstafftrainedtodeliveranadaptiveventilationmode.Basedontheseissues,andthereluctancetoissuearecommendationbasedonthissmall,single-centerstudyduetofeasibility/availabilityconcernsinothercenters,wewerenotabletomakearecommendationregardingtheuseofadaptiveventilationatnight. NIV-DedicatedVentilator. Question:AmongcriticallyilladultsrequiringNIV,shouldanNIV-dedicatedventilator(vsastandardICUventilatorwithNIVcapacity)beusedtoimprovesleep? Recommendation:WesuggestusingeitheranNIV-dedicatedventilatororastandardICUventilatorforcriticallyilladultsrequiringNIVtoimprovesleep(conditionalrecommendation,verylowqualityofevidence). Rationale:Onlyonesmallrandomizedtrialwasavailabletoanswerthisquestion,anditdidnotevaluatemostofthedefinedoutcomes(454).NosignificantdifferencesappearedbetweenuseofanNIV-dedicatedventilatorandastandardICUventilatorwithrespecttosleepefficiency;percentoftimespentinstage1,stage2,stage3/4,orREMsleep;orsleepfragmentationindex.ComparedwithperiodsoffNIV,sleepduringNIVresultedinincreasedREMandstage3/4sleepwithareductioninsleepfragmentationindex.Basedontheabove,patientswithacutehypercapnicrespiratoryfailurehaveimprovedsleepqualityduringNIVcomparedwithwithoutNIV,butwerecommendthateithertypeofventilator,dependentonfeasibilityandconvenience,isacceptabletouseforICUpatientsrequiringNIV. EvidenceGaps:Studiescomparingsleepbetweenassistedbreathingandcontrolledbreathingintheassist-controlandadaptivemodesandtheadaptivemodeandassist-controlventilationmodeshavenotbeenpublished.Studiesusedpolysomnographytomeasuresleeponvariousmodes,butnoneofthesestudiesevaluatedpatients’perceptionoftheirsleep. Aromatherapy/Acupressure/Music Question:Shouldaromatherapy,acupressure,ormusicbeusedatnight(vsnotusingit)toimprovesleepincriticallyilladults? Recommendation:Wesuggestnotusingaromatherapy,acupressure,ormusicatnighttoimprovesleepincriticallyilladults(conditionalrecommendation,lowqualityofevidence[aromatherapyandacupressure];verylowqualityofevidence[music]). Rationale:Twosmall,unblindedRCTs(509,510)evaluatedtheuseofaromatherapyforimprovingsleepinconsciousandcommunicativeICUpatients.Noadverseeffectswerereported,butapooledanalysisdemonstratednoeffectwithitsuse(vsnouse)inpatient-reportedsleepquality(MD,0.02points;95%CI,–0.36to0.41;lowquality)andtheoverallqualityofevidencewaslow.Althoughalow-costinterventionthatisgenerallyconsideredsafe,thelackofprovenbenefitforsleepinadditiontosomeconcernaboutusingpotentialrespiratoryirritantsinanICUpopulationledthepaneltomakeaconditionalrecommendationagainstaromatherapyintheICU. OnesmallRCT(n=85)(511)evaluatedtheuseofacupressureinICUpatientshavingalowseverityofillness.Researcherswhoattendedanacupressuretrainingcourseappliedpressurefor3minutestoeachofsixacupointsbetween7:00pmand10:00pmandfoundthatacupressure(vsnouseofacupressure)wasassociatedwithanincreaseddurationofsleepwhenevaluatedbyactigraphy(MD,0.5 hr;95%CI,0.09–0.91;lowquality)orthenurse(MD,1.1 hr;95%CI,0.39–1.81;lowquality)andlessdaytimesleepinessontheStanfordSleepinessScale(MD,0.4points;95%CI,0.66–0.14;lowquality).Giventhehighriskofbiasforthesingleincludedstudy,thesmallnumberofpatientsenrolled,thecostofhavingatrainedclinicianprovideacupressure,andthelackofavailabilityofthismodalityatmanycenters,wedecidedtosuggestagainsttheuseofacupressuretoimprovesleepincriticallyilladults.Forthoseinstitutionswithtrainedpersonnelandexpertise,however,itmaybeareasonableintervention,especiallyifrequestedbypatients. OnesmallRCT(n=28)(512)evaluatedtheeffectofplayingmusiconthepiano(foursedatingpieceslasting45 min)onsleepoutcomes(duringfirst2 hrofnight)incriticallyilladults.Themusichadasmalleffectonimprovingsleepquality(asevaluatedbytheVerranandSnyder-HalpernSleepScale)(MD,48points;95%CI,34.5–130.5;verylowquality)andsleepefficiency(asevaluatedbypolysomnography)(MD,2.3%;95%CI,27.3–32.0;verylowquality).Giventhelowqualityofevidence(noblinding,ambientnoisenotcontrolled)andtheresourcesneededtoinstitutethisintervention,thepanelmadeaconditionalrecommendationagainsttheuseofmusictoimprovesleepincriticallyilladults.Musicmayplayaroleinreducingpain(seepainsection)andanxietyintheICU(133).Ifpatients(ortheirfamilies)requestit,itshouldbeconsidered. NoiseandLightReduction Question:Shouldnoiseandlightreductionstrategies(vsnotusingthesestrategies)beusedatnighttoimprovesleepincriticallyilladults? Recommendation:Wesuggestusingnoiseandlightreductionstrategiestoimprovesleepincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:TwoRCTs(458,513)andtwoobservationalstudies(514,515)evaluatedstrategiestoreduceICUnoiseandlightatnightthroughtheuseofearplugswithorwithouttheuseofeyeshades.Useofearplugsandeyeshades(vscontrol)onthefirstpostoperativeICUnightaftercardiacsurgerymaintainedsleepqualityatthepreoperativelevel(513).Applicationofearplugs(vsnoearplugs)tononsedated,criticallyilladultsimprovedpatient-reportedsleepqualityandreduceddelirium(458).PooledanalysisfromthetwoICUobservationalstudies(n=164)foundthatapplicationofearplugs(vsnoearplugs)wasassociatedwithagreaterproportionofachievinggreaterthan4hoursofsleep(RR,1.2;95%CI,0.64–2.24;lowquality)(513,515).Theoverallqualityofevidencewaslowduetoalackofblinding,apopulationofpatientsnotseverelyill,andtherefusalofsomepatientstokeeptheearplugsinserted.Earplugs,withorwithouteyeshades,representalow-costinterventionthatcanbeappliedinallICUstoimprovesleepqualityandreducedelirium.Ingeneralpatients,particularlythosewhocannotinitiatesleep,shouldbeaskediftheywantthisinterventionandearplugsshouldalwaysberemovedinthemorning. EvidenceGaps:NonpharmacologicstrategiesfocusedonimprovingsleepintheICUneedtobeevaluatedinlargerandomizedtrials,includeICUpatientswithhigherseverityofillness,andrigorouslyevaluatetheeffectoftheseinterventionsonsleepquality.ThegroupofpatientsintheICUwhomaygainthemostbenefitfromtheseinterventionsneedstobeelucidated. PharmacologicInterventionstoImproveSleep GiventhechallengesofpromotingnaturallyoccurringsleepintheICU,patientsandtheirfamilymembersmayaskforsleep-enhancingmedication.Althoughtheirrequestshouldalwaysbeconsidered,thispressureandoureffortstoprovidecompassionatecaresometimesleadtotheadministrationofmedicationsthatarepoorlytestedforsafetyandefficacyinICUpatientsandthatmayincreasetheriskforpolypharmacyanddeliriumratherthanactuallypromotesleep.Pharmacologicinterventionswereconsideredbydrugtype/classandwerereviewedbythepanelsolelyfortheireffectonsleeppromotion. Question:Shouldasleep-promotingmedication(i.e.,melatonin,dexmedetomidine,orpropofol)(vsnouseofamedication)beusedtoimprovesleepincriticallyilladults? Melatonin. Recommendation:Wemakenorecommendationregardingtheuseofmelatonintoimprovesleepincriticallyilladults(norecommendation,verylowqualityofevidence). Rationale:Threesmall,placebo-controlled,randomizedtrials(n=60)evaluatingthenight-timeadministrationofmelatoninwerereviewed.Thefirstfoundthattheadministrationof10 mgofmelatoninatnight(vsplacebo)to12patientsintheICUhavingchronicrespiratoryfailurewasassociatedwithnonsignificantimprovementsinbothsleepqualityandquantity(asevaluatedbyBIS)(516).AsecondRCTthatevaluatednight-timemelatonin3 mg(orplacebo)in16patientsinasimilarpopulationandevaluatedsleepusingactigraphyarrivedatasimilarconclusion(517).AthirdRCTthatcomparedmelatonin3 mg(orplacebo)to32patientswhoalsowereadmittedtotheICUwithchronicrespiratoryfailureasthefirsttwostudiesfoundnodiscernibledifferenceinthedurationof“observednocturnalsleep”bybedsidenurseassessment(518).ThelimitationsofevaluatingsleepintheICUusingBIS,actigraphy,orsubjectivenursingscalesratherthanpolysomnographyarehighlightedpreviouslyintheguidelines. ThemanufactureofmelatoninintheUnitedStatesisnotFoodandDrugAdministrationregulated;concernsastothequalityandconsistencyoftheproduct(519)havepreventedmanyhospitalsfromaddingittotheirformulary.Melatoninis,however,associatedwithrelativelyfewadverseeffects(e.g.,mildsedationandheadache)andinexpensive.Thepaneldecidedonnorecommendationduetotheperceivedbalancebetweendesirableandundesirableoutcomesandthelackofhigh-qualityevidence. Ramelteon,anFDA-approvedmelatoninreceptoragonist,wasevaluatedinasinglestudy(notincludedinthisanalysis)topreventdeliriumintheelderly(520).Asmallnumberofpatientsinthatstudywerecriticallyill;however,therewasnodemonstrableimprovementinsubjectivesleepquality.Similartomelatonin,fewadverseeventsarereportedwiththemedication,butsleeppromotionwasnotprovenandthecostishigherthanthatofmelatonin.Onerecentsingle-center,double-blind,placebo-controlledRCT,alsonotincludedinthisanalysis,foundthattheadministrationof8 mgoframelteonat20:00hourseachdaytocriticallyilladultswithoutdeliriumwasassociatedwithsignificantreductionindeliriumoccurrence(521). Dexmedetomidine. Recommendation:Wemakenorecommendationregardingtheuseofdexmedetomidineatnighttoimprovesleep(norecommendation,lowqualityofevidence). Rationale:Tworandomizedtrials(n=74)evaluatedtheeffectsofdexmedetomidineincriticallyill,mechanicallyventilatedadultsrequiringsedation(470)andincriticallyill,nonmechanicallyventilatedpatientsnotrequiringacontinuousinfusionofasedativemedication(521).Bothstudiesdemonstratedthatdexmedetomidineincreasedstage2sleep(MD,47.85%min;95%CI,24.05–71.64;moderatequality)anddecreasedinstage1sleep(MD,–30.37%;95%CI,–50.01to–10.73;moderatequality),eachofwhichthepanelconsideredfavorableoutcomes(470,521).Neitherstudy,however,demonstratedadecreaseinsleepfragmentationoranincreaseindeepsleeporREMsleepthatarethoughttobethemostrestorativesleepstagesandthuspotentiallymostimportanttorecovery.Athird,observationaltrial,notincludedinthisanalysis,corroboratedthesefindingswithregardtosleeparchitectureandnotedpreservedday-nightcyclingwhendexmedetomidinewasadministeredovernightinmechanicallyventilatedICUpatients(522).Onerecentlypublisheddouble-blind,placebo-controlledRCTof100delirium-freecriticallyilladultsreceivingsedatives,andnotincludedintheevidenceprofile,foundthattheadministrationoflow-dosedexmedetomidinedidnotchangeLeedsSleepEvaluationQuestionnairescoresbetweenthedexmedetomidineandplacebogroups(370). Considerationwasgiventoaconditionalrecommendationinfavorofusingdexmedetomidineatnightforthesolepurposeofsleeppromotion;however,clinicalconcernsincludeitshighcost,hemodynamicsideeffects,andgeneralizabilityoftheexistingstudies.Ifasedativeinfusionisindicatedforahemodynamicallystable,criticallyilladultovernight,dexmedetomidinemaybeareasonableoptionbecauseofitspotentialtoimprovesleeparchitecture(523).Seethesedationsectionforamorein-depthevaluationofsedativechoiceincriticallyilladults. Propofol. Recommendation:Wesuggestnotusingpropofoltoimprovesleepincriticallyilladults(conditionalrecommendation,lowqualityofevidence). Rationale:TwoRCTscomparedpropofolwithbenzodiazepines(454,524),andonecomparedpropofolwithplacebo(525).Nodemonstrableimprovementinsleepoccurredwithpropofolcomparedwithplacebo.Further,propofolwasassociatedwithREMsuppression,hemodynamicsideeffects,andrespiratorydepressionsometimesnecessitatingmechanicalventilation.Althoughwerecommendagainstusingpropofolforthesolepurposeofimprovingsleepinthecriticallyill,thisrecommendationdoesnotintendtoaddressitsuseinpatientsrequiringproceduralorcontinuoussedation. Othermedicationsadministeredwiththeintenttoimprovesleepinthecriticallyillincludetricyclicantidepressants,atypicalantipsychotics,andhypnoticssuchasbenzodiazepinesandbenzodiazepine-receptoragonists.Currently,thereisinsufficientinformationtoconsiderarecommendationforanyofmedicationstohelppromotesleepinthecriticallyill.Althoughtheiradverseeffectsarewelldescribed,theirbenefitsintermsofsleeppromotionareunknown. EvidenceGaps:Large,well-controlledtrialsofmedicationsadministeredatnightforthesolepurposeofsleeppromotionincriticallyillpatientsarelacking.Thisisespeciallytrueformedicationssuchastricyclicantidepressantsandatypicalantipsychoticsthatarefrequentlyusedforthispurposebecausetheyarelesslikelytoprecipitateanepisodeofdelirium,havefewerhemodynamicandrespiratorydepressanteffects,andbecausetheirsedatingsideeffectssuggestthepossibilityofsleeppromotion.Thesemedications,however,shouldberigorouslystudiedtoassesstheirefficacyinthispopulationtodetermineifthebenefitsjustifytheirpotentialharms. Sleep-PromotingProtocol Question:Shouldasleep-promotingprotocolbeusedtoimprovesleepincriticallyilladults? Recommendation:Wesuggestusingasleep-promoting,multicomponentprotocolincriticallyilladults(conditionalrecommendation,verylowqualityofevidence.) Rationale:Protocolsareacommonwaytoincorporatemultipleinterventionsatonceintoaclinicalpracticeguideline(526),includingthosedescribedbelowforsleepqualityimprovementincriticallyillpatients.Thesleep-promotingprotocolseligibleforinclusionvariedintheircomponents,asdescribedbelow(459,527–529).Allincludedofferingearplugsandeyeshadestopatientswhocouldchoosetousethemortodiscontinuetheiruseiftheywishedandtwoalsoincludeduseofrelaxingmusic(459,526).Amongthetwocomposedofamorecomplexcombinationofinterventions,onespecifiedapharmacologicguidelinethatdiscouragedtheuseofsedatingmedicationsknowntoaltersleepand/orprecipitatedeliriumandintroducedinterventionsinstagesovera5-monthperiod(459).Inallstudies,protocolswereappliedtoallICUpatientsanddidnottargetasubsetofpatientsknowntohavepoorsleepquality. Thecriticaloutcomesexaminedweresleepstages,sleepduration,sleepfragmentation,circadianrhythm,delirium,durationofmechanicalventilation,mortality,LOS(ICUandhospital),andpatientexperience.Currentpublisheddatacontainfourstudiesreportingoutcomesrelevanttothisquestion,oneRCT(527),andthreeobservationalstudies(459,528,529)(SupplementalTable48SupplementalDigitalContent58,https://links.lww.com/CCM/D816).OnesmallRCTinopen-heartsurgerypatientsdemonstratedthatearplugs,eyeshades,andrelaxingmusicimprovedself-reportedsleepquality(528).Amongthethreeobservationalbefore-and-afterstudies,onefoundanimprovementinsleepinamixedICUpopulation(529),whereastheothertwodidnot(459,528).Pooledanalysisofthethreestudiesdemonstratedanoverallreductionintheprevalenceofdeliriumwithasleep-promotingprotocol(RR,0.62;95%CI,0.42–0.91;verylowquality).OneoftheobservationalstudiesusedasimilarinterventiontoHuetal(527),earplugs,eyeshades,andmusic,whereastheothertwotestedmorecomplexinterventionsincludingtheseinterventionsplusenvironmentalchanges,namelyclusteringofcaretominimizeinterruptionsovernightandearlymobilization(459,529).Onestudyalsospecificallyincludedpharmacologicguidelines,administeringzolpidemtopatientswithoutdeliriumandhaloperidoloranatypicalantipsychoticforpatientswithdelirium(459).Inanefforttominimizetheinfluenceofmedicationsonoutcomes,Pateletal(529)excludedpatientswhohadreceivedsedativesinthe24hoursbeforeenrollment.Whichoftheinterventions,orwhichcombinationsoftheinterventions,areeffectiveinimprovingsleepandreducingdeliriumcannotbediscernedfromtheabovestudies.Overallevidencewasloworverylowqualityduetoriskofconfounding,imprecision,andthepotentialforriskofbiasintheincludedstudies.Thepanelmadeaconditionalrecommendationbasedonthepotentialforbenefit(e.g.,deliriumreduction)andminimalanticipatedharm.Thepanelrecognized,however,thatimplementingandsustainingmultifacetedclinicalpracticeprotocolscanberesourceintensive(530). EvidenceGaps:Futureresearchshouldinvestigatewhichoftheinterventions,orwhichcombinationsoftheinterventions,areeffectiveinimprovingsleepandreducingdelirium.Theeffectonreductionindeliriuminthereviewedstudiesbutlessdemonstrableonsleepqualityisnotable,reinforcingthatmoreworkontheassessmentofsleepincriticallyilladultsisneeded,asrecommendedabove.Althoughmanythousandsofpublicationsonthescienceofimplementingevidenced-basedclinicalpracticeguidelinesexist,relativelyfewaddressimprovingsleepincriticallyilladultpatients;thisspecifictopicwouldbenefitfromfurtherinvestigation.Mortality,ICULOS,anddurationofmechanicalventilationwerereportedinthereviewedstudies,butnumbersweretoosmalltodrawanyconclusions.These,aswellaspatientexperienceandpatient-centeredmid-tolong-termoutcomessuchassleepquality,psychologichealth,andqualityoflifedeterminantssuchasautonomouslivingremainunexplored. ConcludingCommentsonSleep:StudiestodateareconsistentindemonstratingthatcriticallyillpatientssleeppoorlyasaresultofbothpatientandICUfactors.TheimportanceofimprovingsleepinthispopulationmaybeunprovenbyRCTbutisintuitiveand,atleast,couldbeconsideredanimportantcomfortmeasurethatwouldimprovepatients’ICUqualityoflifeifnototheroutcomes.Althoughonlyaselectfewinterventionstudieshavebeenpublished,availabledatasuggestthatamulticomponentprotocolizedapproachtoimprovingsleepthatfavorsnonpharmacologicmeasuresmayofferourpatientstheirbestchanceforabetternight’ssleep.Futureresearchneedstofocusonimprovedmethodsformeasuringsleepandonimplementinginterventionstargetingpatient-centeredoutcomes.Sleephabitsarehighlyvariableamonghealthyindividuals;therefore,amoreindividualizedapproachshouldbeconsidered. SUMMARY Thousandsofhourswereinvestedbytheseguidelines’authors,whowereinturnsupportedbyformalandinformalcollaborators,overthe3.5yearsittooktoproducethiseffort.AsexpertsmandatedbytheSocietyofCriticalCareMedicine,weaimedtoprovidetherecentinformationcliniciansneedtobettercareforcriticallyilladults(531,532)usingthemostrigorousandtransparentprocessesatourdisposition.Becausesuchprocessdoesnotnecessarilyensureacceptabilityamongknowledgeprovidersandusers(533),weestablishedwaysinwhichtoaddressrelevantandpatient-centeredpain,sedation,delirium,immobility,andsleeppractice-relatedquestions.Thediversityofourexperts(534),representingmanyprofessionsonthreecontinents,generatedvigorousdiscussionsastoclinicalapproachesandcareaspectsthatdifferedbygeographicalavailability(ofmedicationinterventions,forinstance)andbyinstitutionalculture.BecausewedidnotlimitourreviewstoEnglishlanguagepublications,theevidencegatheredtosupportourrecommendationsrepresentsliteraturefromaroundtheworld. Therecommendationrationales,fueledbydebateanddiscussion,circledbacktothebedsideexperience—andtheperspectiveofwhatwasbestforpatients—heldbyallpanelistsandmethodologyexperts.Insectionsaddedtotheseguidelinessincetheirlast2013version(1)(rehabilitation/mobilityandsleep),wesoughttoclarifyconceptualdefinitionswithintheserelativelynewcriticalcareresearchdomains.Wewantedtomakethemaccessibletofacilitateincorporatingthemintothecomplexpatientmanagementreasoninganycriticalcareclinicianmightconsider.Wechallengedcommonpracticessuchasadministeringantipsychoticstodeliriouspatients.Weinvitedclinicianstoexpandtheproposedinterventionsincomparisontothe2013guidelines(1);oneexampleistheconsiderationofmultiplepharmacologicandnonpharmacologiccoanalgesicapproachestotheICUpatient.Whenthepublishedevidencewasinsufficient,limitedtoanarrowpopulationorspecificintervention(e.g.,forproceduralanalgesia),oroutrightabsenttoanswerthequestionsweposed,westructuredevidencegapdescriptorstoinformclinicianswheretheuncertaintylay,andintendedtoprovidesufficientinformationtoappriseandinviteresearcherstoaddressthesegaps. Wearemindfulofthelimitationsinherenttoourwork.“Goodevidence”requirementsforrandomizedtrialsinvolvingmanypatientshaveitscaveats;practicemisalignment(535)anddiagnosticconfounders(312)were,totheextentitwaspossible,considered,but“unknown”factorswiththepotentialtoinfluenceevidencelikelyexist.Oneexampleistherecentintroductionofstratificationbyfrailty(536)intrialsinvolvingthecriticallyill,whichcouldnotbeconsideredbecausethiscomorbidityhadnotbeentakenintoaccountinmuchoftheliteraturejustifyingourrecommendations.AnotheristhefactthatalthoughallpatientswereadmittedtoanICU,boththereasonsleadingtotheirICUadmissionandseverityofillnessvariedconsiderably,warrantingindividualtailoringofourrecommendationstoindividualpatientconsiderations.Adegreeofuncertaintyisasinherenttoclinicalpracticeasitistotheresearchprocessanditsresultingconclusions(537).Thequesttomakeourdecisionmakinganditerativeinnovationstransparentandaccessiblemotivatedthemethodsarticlethatwaspreparedseparatelyfromthisguidelineinitiative(13). Finally,thedevelopmentofguidelineslikethesedoesnotensuretheiruse(538).Someeducationalprogramsandtheprovisionoffeedbackinrelationshiptoattaininganalgesiaandsedation-targetedperformancegoalshavebeendisappointinglyineffectivewhenstudiedprospectively(3,4).Weconsidertheeffectivenessandlimitationsofdifferentdisseminationmethodsandapproachesgermanetothisguideline’stopicsinaseparatepublicationasatooltoinformeducationalprogrammingandqualityimprovementinitiativesthatwillevolvefromthisguideline(2).Inadditiontobridgingthegapbetweentheknowledgewegatheredanditsapplication,webelievethatthiswillprovidetangiblesupporttoclinicians,stakeholders,anddecisionmakersinimplementingqualityinpain,agitation,delirium,earlymobility,andsleepandfurtherfostertheapplicationofwhatweunderstandtobeusefulintheprovisionanddeliveryofexcellentcare. ACKNOWLEDGMENTS Weacknowledgethemanydirectandindirectcontributorstothiseffort:MargaretMcIvor,anICUsurvivorwhosecontributionwaslimitedbysubsequentillness;students,trainees,andcolleagues(JulieC.Reid,PT,MSc;AnastasiaNewman,PT,MSc;DavidJ.Gagnon,PharmD;LaurenE.Payne,PharmD;NicoleKovacic,PharmD;KimiaHonarmand,MD,MSc;JamieLe,MD;SinduMohan,MD;PeterJ.Hurh,MD;JustinD.Dumont,DO,MS;M.FarhanNasser,MD;VenkatR.Venna,MD;AparnaNallagangula,MBBS;KimberlyJ.Terry,PharmD;andJeremyR.DeGrado,PharmD)helpedwithabstractandfull-textscreening,supervisedbyseveraloftheauthors;GradingofRecommendationsAssessment,DevelopmentandEvaluationgroupmembers(FayezAlshamsi,MD)whoprovidedhelpwithdataanalyses;CharlieKishman,MSL,whoinitiatedtheliteraturesearchesasacontinuationofhiscontributiontothe2013PADguidelines;MattDuprey,PharmD,forhisvaluablesupportatthe2017Hawaiimeeting;LoriHarmonandSylviaQuintanillawhoprovideddirectionandorganizationalinfrastructure;andDebMcBridecopywroteandeditedthefinalarticle.Thepanelcoauthors’effortwouldnothavebeenpossiblewithouttheexplicitandimplicitsupportofcolleagues,families,andfriends.ThetimecommittedtothePain,Agitation/sedation,Delirium,Immobility(rehabilitation/mobilization),andSleep(disruption)initiativehadtobeweighedagainstavailabilitytoattendpersonalandprofessionalchallenges.Wewishtoacknowledgeallthosewhoshoulderedotherresponsibilities,indirectlyfacilitatingthecreationandwritingoftheseguidelines.Finally,wewishtothankthepatients,teachers,andcolleagueswhoinspiredthiseffortandwhochallengedustohonor,andrisetothechallengeof,thisacademiceffort. 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CitedHere Keywords:delirium;guidelines;immobility;intensivecare;mobilization;pain;sedation;sleep SupplementalDigitalContent CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC1.docx;[Word](29KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC2.docx;[Word](26KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC3.docx;[Word](26KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC4.docx;[Word](346KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC5.docx;[Word](1.55MB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC6.docx;[Word](23KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC7.docx;[Word](17KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC8.docx;[Word](50KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC9.docx;[Word](271KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC10.docx;[Word](15KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC11.docx;[Word](15KB) CCM_46_9_2018_06_11_DEVLIN_CCMED-D-18-00069_SDC45.docx;[Word](227KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC46.docx;[Word](115KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC47.docx;[Word](26KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC48.docx;[Word](20KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC49.docx;[Word](25KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC20.docx;[Word](40KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC21.docx;[Word](28KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC22.docx;[Word](31KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC23.docx;[Word](31KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC24.docx;[Word](26KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC25.docx;[Word](25KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC26.docx;[Word](155KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC27.docx;[Word](104KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC28.docx;[Word](178KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC29.docx;[Word](151KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC30.docx;[Word](258KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC31.docx;[Word](40KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC32.docx;[Word](29KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC33.docx;[Word](33KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC34.docx;[Word](31KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC35.docx;[Word](125KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC36.docx;[Word](33KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC37.docx;[Word](33KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC38.docx;[Word](25KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC39.docx;[Word](24KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC40.docx;[Word](30KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC41.docx;[Word](53KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC58.docx;[Word](30KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC57.docx;[Word](15KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC56.docx;[Word](14KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC55.docx;[Word](38KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC54.docx;[Word](40KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC53.docx;[Word](107KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC52.docx;[Word](904KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC51.docx;[Word](141KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC50.docx;[Word](25KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC44.docx;[Word](59KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC43.docx;[Word](24KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC42.docx;[Word](3.08MB) CCM_46_9_2018_06_11_DEVLIN_CCMED-D-18-00069_SDC19.docx;[Word](58KB) CCM_46_9_2018_06_11_DEVLIN_CCMED-D-18-00069A_SDC18.docx;[Word](95KB) CCM_46_9_2018_06_11_DEVLIN_CCMED-D-18-00069_SDC17.docx;[Word](33KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC16.docx;[Word](2.82MB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC15.docx;[Word](99KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC14.docx;[Word](24KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC13.docx;[Word](25KB) CCM_46_9_2018_06_08_DEVLIN_CCMED-D-18-00069_SDC12.docx;[Word](28KB) Copyright©2018bytheSocietyofCriticalCareMedicineandWoltersKluwerHealth,Inc.AllRightsReserved.Viewfullarticletext Source ClinicalPracticeGuidelinesforthePreventionandManagementofPain,Agitation/Sedation,Delirium,Immobility,andSleepDisruptioninAdultPatientsintheICU CriticalCareMedicine46(9):e825-e873,September2018. 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ThisarticlehasbeensavedintoyourUserAccount,intheFavoritesarea,underthenewfolder"". ​ ​Forresourcesrelatedtothisguideline,pleasevisitthe SurvivingSepsisCampaignwebsite. ​​​​​​​​​​​​​SurvivingSepsisCampaignGuidelinesNowavailable: SurvivingSepsisCampaign:InternationalGuidelinesforManagementofSepsisandSepticShock2021.​​​​​Clickhere​foradditionalSurvivingSepsisCampaignResources.​ Toaccesstranslatedversionsofthisguideline,pleasevisittheSurvivingSepsisCampaignwebsite. ArticleasEPUB ExportAllImagestoPowerPointFile AddtoMyFavorites Colleague'sE-mailisInvalid YourName:(optional) YourEmail: Colleague'sEmail: Separatemultiplee-mailswitha(;). Message: Thoughtyoumightappreciatethisitem(s)IsawatCriticalCareMedicine. Sendacopytoyouremail Yourmessagehasbeensuccessfullysenttoyourcolleague. Someerrorhasoccurredwhileprocessingyourrequest.Pleasetryaftersometime. EndNoteProciteReferenceManager Savemyselection Viewthedatavisualizationrelatedtothisarticle: KeywordHighlighting Highlightselectedkeywordsinthearticletext. delirium guidelines immobility intensivecare mobilization pain sedation sleep SearchforSimilarArticles Youmaysearchforsimilararticlesthatcontainthesesamekeywordsoryoumay modifythekeywordlisttoaugmentyoursearch. delirium\r,guidelines\r,immobility\r,intensivecare\r,mobilization\r,pain\r,sedation\r,sleep ArticlesinPubMedbyJohnW.Devlin,PharmD,FCCM(Chair) ArticlesinGoogleScholarbyJohnW.Devlin,PharmD,FCCM(Chair) OtherarticlesinthisjournalbyJohnW.Devlin,PharmD,FCCM(Chair) Dataistemporarilyunavailable.Pleasetryagainsoon. ExecutiveSummary:ClinicalPracticeGuidelinesforthePreventionandManagementofPain,Agitation/Sedation,Delirium,Immobility,andSleepDisruptioninAdultPatientsintheICU SurvivingSepsisCampaign:InternationalGuidelinesforManagementofSepsisandSepticShock:2016 SurvivingSepsisCampaignGuidelinesontheManagementofAdultsWithCoronavirusDisease2019(COVID-19)intheICU:FirstUpdate ClinicalPracticeGuidelinesfortheManagementofPain,Agitation,andDeliriuminAdultPatientsintheIntensiveCareUnit GuidelinesfortheManagementofAdultAcuteandAcute-on-ChronicLiverFailureintheICU:Cardiovascular,Endocrine,Hematologic,PulmonaryandRenalConsiderations:ExecutiveSummary Thiswebsiteusescookies.Bycontinuingtousethiswebsiteyouaregivingconsenttocookiesbeingused.ForinformationoncookiesandhowyoucandisablethemvisitourPrivacyandCookiePolicy. Gotit,thanks!