Lung injury prediction score for the emergency department: first step towards prevention in patients at risk

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Title:
Lung injury prediction score for the emergency department: first step towards prevention in patients at risk
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English
Creator:
Elie-Turenne, Marie-Carmelle
Hou, Peter C.
Mitani, Aya
Barry, Jonathan M.
Kao, Erica Y.
Cohen, Jason E.
Frendl, Gyorgy
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Springer Open Journal(International Journal of Emergency Medicine)
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Abstract:
Background: Early identification of patients at risk of developing acute lung injury (ALI) is critical for potential preventive strategies. We aimed to derive and validate an acute lung injury prediction score (EDLIPS) in a multicenter sample of emergency department (ED) patients. Methods: We performed a subgroup analysis of 4,361 ED patients enrolled in the previously reported multicenter observational study. ED risk factors and conditions associated with subsequent ALI development were identified and included in the EDLIPS model. Scores were derived and validated using logistic regression analyses. The model was assessed with the area under the receiver-operating curve (AUC) and compared to the original LIPS model (derived from a population of elective high-risk surgical and ED patients) and the Acute Physiology and Chronic Health Evaluation (APACHE II) score. Results: The incidence of ALI was 7.0% (303/4361). EDLIPS discriminated patients who developed ALI from those who did not with an AUC of 0.78 (95% CI 0.75, 0.82), better than the APACHE II AUC 0.70 (p≤ 0.001) and similar to the original LIPS score AUC 0.80 (p = 0.07). At an EDLIPS cutoff of 5 (range −0.5, 15) positive and negative likelihood ratios (95% CI) for ALI development were 2.74 (2.43, 3.07) and 0.39 (0.30, 0.49), respectively, with a sensitivity 0.72(0.64, 0.78), specificity 0.74 (0.72, 0.76), and positive and negative predictive value of 0.18 (0.15, 0.21) and 0.97 (0.96, 0.98). Conclusion: EDLIPS may help identify patients at risk for ALI development early in the course of their ED presentation. This novel model may detect at-risk patients for treatment optimization and identify potential patients for ALI prevention trials
General Note:
Publication of this article was funded in part by the University of Florida Open-Access publishing Fund. In addition, requestors receiving funding through the UFOAP project are expected to submit a post-review, final draft of the article to UF's institutional repository, IR@UF, (www.uflib.ufl.edu/UFir) at the time of funding. The institutional Repository at the University of FLorida community, with research, news, outreach, and educational materials.
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Elie-Turenne et al. International Journal of Emergency Medicine 2012, 5:33 http://www.intjem.com/content/5/1/33; Pages 1-11
General Note:
doi:10.1186/1865-1380-5-33 Cite this article as: Elie-Turenne et al.: Lung injury prediction score for the emergency department: first step towards prevention in patients at risk. International Journal of Emergency Medicine 2012 5:33.

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ORIGINALRESEARCHOpenAccessLunginjurypredictionscorefortheemergency department:firststeptowardspreventionin patientsatriskMarie-CarmelleElie-Turenne1,2*,PeterCHou3,4,5,6,AyaMitani5,7,14,JonathanMBarry4,5,EricaYKao3,5,15, JasonECohen8,9,16,GyorgyFrendl5,6,7,17,OgnjenGajic10,11,12,18andNinaTGentile13OnBehalfofUSCriticalIllness andInjuryTrialsGroup:LungInjuryPreventionStudyInvestigators(USCIITG – LIPS1AbstractBackground: Earlyidentificationofpatientsatriskofdevelopingacutelunginjury(ALI)iscriticalforpotential preventivestrategies.Weaimedtoderiveandvalidateanacutelunginjurypredictionscore(EDLIPS)ina multicentersampleofemergencydepartment(ED)patients. Methods: Weperformedasubgroupanalysisof4,361EDpatientsenrolledinthepreviouslyreportedmulticenter observationalstudy.EDriskfactorsandconditionsassociatedwithsubsequentALIdevelopmentwereidentified andincludedintheEDLIPSmodel.Scoreswerederivedandvalidatedusinglogisticregressionanalyses.Themodel wasassessedwiththeareaunderthereceiver-operatingcurve(AUC)andcomparedtotheoriginalLIPSmodel (derivedfromapopulationofelectivehigh-risksurgicalandEDpatients)andtheAcutePhysiologyandChronic HealthEvaluation(APACHEII)score. Results: TheincidenceofALIwas7.0%(303/4361).EDLIPSdiscriminatedpatientswhodevelopedALIfrom thosewhodidnotwithanAUCof0.78(95%CI0.75,0.82),betterthantheAPACHEIIAUC0.70( p 0.001)and similartotheoriginalLIPSscoreAUC0.80( p =0.07).AtanEDLIPScutoffof5(range Š 0.5,15)positiveand negativelikelihoodratios(95%CI)forALIdevelopmentwere2.74(2.43,3.07)and0.39(0.30,0.49),respectively, withasensitivity0.72(0.64,0.78),specificity0.74(0.72,0.76),andpositiveandnegativepredictivevalueof0.18 (0.15,0.21)and0.97(0.96,0.98). Conclusion: EDLIPSmayhelpidentifypatientsatriskforALIdevelopmentearlyinthecourseoftheirED presentation.Thisnovelmodelmaydetectat-riskpatientsfortreatmentoptimizationandidentifypotential patientsforALIpreventiontrials.BackgroundAcutelunginjury(ALI)iswidelyrecognizedasanimportantcauseofpooroutcomeincriticallyillpatients. Acuterespiratorydistresssyndrome(ARDS),asevere variantofALI,wasoriginallydescribedin1967by Ashbaughetal.astheacuteonsetoftachypnea,hypoxemia,andpoorpulmonarycomplianceresistantto traditionalmedicaltherapies.Atthetime,theauthors suggestedthattheuseofpositiveendexpiratorypressureandcorticosteroidsmaybeofutility[1].This promptedinvestigationsanddialogueofaninternational scalethatestablishedstandardizedparametersusedto describeALI,the1994AmericanEuropeanConsensus Conferencecriteria:acutehypoxemiawitharatioofthe partialpressureofarterialoxygentothefractionof inspiredoxygen(PaO2:FiO2)of300mmHgorless (ARDSisdefinedasPaO2:FiO2200mmHgorless),bilateralinfiltratesseenonafrontalchestradiographthat areconsistentwithpulmonaryedema,andnoclinical evidenceofleftatrialhypertension[2]. *Correspondence: elie@ufl.edu1DepartmentofEmergencyMedicine,UniversityofFloridaCollegeof Medicine,POBox100186,1329SW16thStreet,Gainesville,FL32610,USA2EmergencyDepartment,ShandsUniversityofFloridaMedicalCenter, Gainesville,FL,USA Fulllistofauthorinformationisavailableattheendofthearticle 2012Elie-Turenneetal.;licenseeSpringer.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33 http://www.intjem.com/content/5/1/33

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Traditionally,ALIhasbeengenerallyrecognizedasan intensivecareunit(ICU)condition;acomplicationof protractedillnessduringaninpatientstay,infrequently diagnosedintheemergencydepartment(ED)[3].Numerousreports,however,haverevealedthatALIdevelopmentisoftenearly,with50%ofcasesoccurring withinthefirst24hofadmission[4].AmongEDpopulations,ithasbeendocumentedtodevelopwithinhours ofinitialpresentation[5-7].Mostcommonly,patients areresuscitatedforrespiratorydistressandsubsequently experienceaprecipitousdeclineinclinicalstatuspromptingintubation,mechanicalventilation,theuseofincreasingdosesofsupplementaloxygen,andpositiveend expiratorypressure(PEEP).Becauseofsimilaritiesin presentation,theseALIcasesmayhavebeendifficultto diagnoseandweremanagedascardiogenicpulmonary edema[5]. ThesourceoftheinitiatinginsultinALImaybepulmonary(i.e.,aspiration,pneumonia)orextrapulmonary (sepsis,shock,pancreatitis)inorigin.Thepathophysiologyinvolvesthedisruptionofthealveolarcapillary interface,resultingintheextravasationofprotein-rich fluidintoalveoli,theinductionoflocalinflammatory mediators,andhypercoagulability[8-10].Theclinical pictureischaracterizedbyprofoundhypoxemia,ventilationperfusionmismatch,andrestrictivelungdisease [11].Theoutcomeisfrequentlyprolongedmechanical ventilationandICUlengthofstay,andultimatelydeath. Evenpreviouslyhealthysurvivorshavelong-termphysicalandcognitiveimpairment[12]. Asofthedateofthispublication,aPubMeddatabase searchoftheliteratureyieldsover25,000articlespublishedsince1967withkeywordsacutelunginjuryor acuterespiratorydistresssyndrome.Despitecountless large-scaleinvestigations,ALIandARDSaffectwellover 200,000personsintheUSannually,fewbeneficialtreatmentshaveemerged,andthemortalityrateis38-44% [13,14]. Todate,supportivecarewiththeuseofalowtidal volumeventilationstrategyremainsthesoleeffective therapeuticmeasureforALI[15].Recognizingthepaucityoftherapies,investigatorshavepositedwhethera roleforpreventivestrategiesmayexisttocurbtheprogressiontoALIintheat-riskpatient. PreviousresearchofALIhaslargelybeenlimitedto ICUpopulations;hence,recruitmentintostudyprotocolsoftenoccurswellafterthediagnosisofALIhas beenestablished[3,16].Thisapproachlikelyidentifies patientsthatarebeyondthepre-morbidwindowof intervention.Thepresentationofknownpredispositions toALIsuchaspneumonia,sepsis,shock,andtraumato emergencyroomsmayprovideopportunitiestolimita patient ’ sriskofdevelopingdownstreamdirectandindirectpulmonaryinsults.Hence,reliableidentificationand riskstratificationofEDpatientsforALImayproveaviableapproachforearlygoal-directedinterventionsand preventivemeasures. WhilethepathophysiologyofALIiswelldocumented, modelspredictingtheriskfordevelopingALIarenot wellestablished.Whilescoreshavebeendevelopedfrom mixedpopulations,nonehasbeenderivedandvalidated inanexclusivelyemergencydepartmentpopulation[17]. Thepurposeofthisstudyistodevelopamodelusing readilyaccessibleclinicaldatafortheidentificationofED patientsatriskforALI.UsingapreviouslypublishedpredictionmodelforALI,theLungInjuryPredictionScore (LIPS),weperformamulti-centerderivation,modelrefinement(EDLIPS),andvalidationstudyofemergency departmentpatientspresentingwithpredisposingrisk factorsofALIpreviouslyidentifiedintheliterature[17].MethodsStudydesignThisisasubgroupanalysisofdatafromamulticenter, observationalcohortstudy,theUnitedStatesCriticalInjuryandIllnessTrialGroup-LungInjuryPrevention Study1(USCIITG-LIPS1).Eachparticipatingcenter soughtapprovalfromitslocalinstitutionalreviewboard.StudysettingFromMarchthroughAugust2009,22centers(20 Americanand2Turkishhospitals)enrolledpatients withatleastoneALIpredispositionadmittedfromthe ED.Patientswereenrolledprospectivelyat19studysites andretrospectivelyat3sites.SelectionofparticipantsConsecutiveadultEDpatientsadmittedtoacademicand communityacutecarehospitalswereeligibleforthe studyiftheypresentedwithoneormorestudydefined ALIpredisposingconditions.Patientswereexcludedif theypresentedwithALIatinitialassessment,transferred fromanin-patientsetting,diedintheED,wereadmitted forcomfortorhospicecare,orwerere-admittedduring thestudyperiod.Hospitaladmissionlogswerereviewed tominimizethepossibilitythatpatientswithpredisposingconditionweremissed.Afteridentificationofat-risk EDpatients,theywerefollowedthroughtheirhospitalizationsprospectivelyin19hospitals.Inthreehospitals thatenrolledretrospectively,investigatorsfollowedthe sameprotocolanddefinitions,butdatawerecollected afterpatientdischarge.DatacollectionandprocessingToderiveandvalidatetheproposedEDLIPSprediction model,asubgroupanalysisofalargerprospectivecohortstudywasperformed[17].Baselinecharacteristics includingdemographics,co-morbidities,andclinicalElie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page2of11 http://www.intjem.com/content/5/1/33

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variableswerecollectedduringthefirst6hofED evaluation.Weusedclinicalvariablespreviouslydocumentedintheliteratureassociatedwiththedevelopment ofALI[3,18-21].Eachpatientwasscreenedfor24predisposingconditionsandALIriskmodifiers.Predisposingconditionsincludedshock,aspiration,sepsis, pneumonia,acuteabdomen,high-risktrauma(traumatic braininjury,smokeinhalation,neardrowning,lungcontusion,multiplefractures),andnecessityforemergency andhigh-risksurgeries(thoracic,spine,abdominal,cardiac,aorticvascular).ALIriskmodifiersincludedalcohol abuse,obesity,chemotherapy,diabetesmellitus,smoking,tachypnea,hypoxemia,oxygensupplementation, hypoalbuminemia,andacidosis.Duringdatacollection,a specificdefinitionofeachclinicalvariablewasexplicitly outlined.ThestudyoutcomeusedtoderivethepredictionrulewasthediagnosisofALI. De-identifiedsubjectinformationwasenteredateach centerintothesecure,password-protectedNIH-supportedwebform(REDCaphttp://www.project-redcap. org).Electronicrangechecksandvalidationruleswere utilizedtoeliminateerroneousdataentryandartifacts innumericvalues.Priortostudyinitiationateachsite, investigatorsandstudycoordinatorsreviewedstructured onlinetraining(http://depts.washington.edu/kclip/about. shtml)forALIassessmentandfordefinitionsofeach riskfactor(seeAppendix1).Inaddition,aformaltrainingsessionwasprovidedduringthe2009USCIITG meetinginNashville,TN.Theprincipalinvestigators fromeachsiteprovidedawrittenstatementstatingtheir responsibilityforthequalitycontrolofdatacollection andentry.DataanalysisAllclinicalvariableswerecollectedforeachpatient.The criterionfordiagnosisofALIwasderivedfromthe American-EuropeanConsensusConferencedefinition: bilateralpulmonaryinfiltratesandhypoxemia(ALI: PaO2/FIO2<300;ARDS:PaO2/FIO2<200)intheabsenceofclinicalsignsofleftatrialhypertensionasthe mainexplanationforpulmonaryedema. Theprimaryanalysisconsistedofavalidationofthe predictiveabilityoftheEDLIPSmodel,modifiedfrom thepreviouslyvalidatedLIPSmodelderivedinadiverse multi-disciplinarycohort[17].Allemergencydepartmentpatientswereincludedinthesub-cohortanalyses. Anymissingdataweretreatedasanabsentdiseasestate oranormalvariable.Tosimplifythecalculation,variableswithminimalornoeffectsizewereremoved(i.e., pancreatitis,alcoholabuse,smoking,andtachypnea). Figure1 Studyschematic. Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page3of11 http://www.intjem.com/content/5/1/33

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Table1ComparisonofderivationandvalidationcohortsTotalDerivationValidation Variable*( n =4,361)( n =2,000)( n =2,361) p -value Demographics Medianage56.0(41.0,71.0)56.0(42.0,71.0)56.0(41.0,71.0)0.596 Male,no.(%)2,422(55.5%)1,104(55.2%)1,318(55.8%)0.680 Caucasian,no.(%), n =4,2202,608(61.8%)1,193(61.6%)1,415(62.0%)0.765 Admissionsource,no.(%) n =4,311 0.131 Home3,331(77.3%)1,557(78.8%)1,774(76.0%) Nursingfacility338(7.8%)151(7.6%)187(8.0%) OutsideED440(10.2%)183(9.3%)257(11.0%) Other202(4.7%)85(4.3%)117(5.0%) APACHEII10.0(6.0,15.0)10.0(6.0,15.0)10.0(5.0,15.0)0.770 Predisposingconditions Shock395(9.1%)180(9.0%)215(9.1%)0.903 Aspiration210(4.8%)92(4.6%)118(5.0%)0.541 Sepsis1,806(41.4%)856(72.8%)950(70.2%)0.087 Pancreatitis323(7.4%)140(7.0%)183(7.8%)0.345 Pneumonia1,227(28.1%)568(28.4%)659(27.9%)0.721 High-risktrauma Traumaticbraininjury490(11.2%)214(10.7%)276(11.7%)0.302 Smokeinhalation27(0.6%)10(0.5%)17(0.7%)0.356 Neardrowning3(0.1%)2(0.1%)1(0.0%)0.597 Lungcontusion188(4.3%)87(4.4%)101(4.3%)0.907 Multiplefractures330(7.6%)141(7.1%)189(8.0%)0.235 High-risksurgery Thoracic(noncardiac)5(0.1%)3(0.2%)2(0.2%)0.526 Orthopedicspine17(0.4%)6(0.3%)11(0.5%)0.381 Acuteabdomen295(6.8%)133(6.7%)162(6.9%)0.782 Cardiacsurgery20(0.5%)6(0.3%)14(0.6%)0.154 Aorticvascular14(0.3%)5(0.3%)9(0.4%)0.445 Riskmodifiers Alcoholabuse421(9.7%)191(9.6%)230(9.7%)0.831 Obesity1,020(29.1%)456(28.5%)564(29.6%)0.451 Chemotherapy158(3.6%)82(4.1%)76(3.2%)0.121 Diabetesmellitus1,042(23.9%)485(24.3%)557(23.6%)0.612 Smoking( n =4019) 0.892 None2,060(51.3%)932(50.9%)1,128(51.6%) Former888(22.1%)408(22.3%)480(22.0%) Active1,071(26.7%)493(26.9%)578(26.4%) Emergencysurgery339(7.7%)154(7.7%)185(7.8%)0.868 RR20.0(18.0,24.0)20.0(18.0,24.0)20.0(18.0,24.0)0.658 Tachypnea315(7.6%)145(7.6%)170(7.6%)0.948 SpO295.6(95.4,95.7)95.2(95.2,95.7)95.7(95.5,95.9)0.068 SpO2>95%2,662(62.3%)1,203(61.4%)1,459(63.1%)0.254 FiO20.2(0.2,0.3)0.2(0.2,0.3)0.2(0.2,0.3)0.561 Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page4of11 http://www.intjem.com/content/5/1/33

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Variablesidentifiedtobepresentinfewerthanten patientswerealsoremoved(i.e.,neardrowning,thoracic surgery). EDLIPSweightingpointswereadjustedbasedonlogisticregressionanalysisresultsfromatrainingdataset (arandomsampleof2,000patientsfromthecohort).If statisticallysignificant( p <0.05),theEDLIPSpointvalue wasderivedbydoublingtheparameterestimateand roundingtotheclosest0.5.Thevariableswithless robust p -values( p >0.05)hadparameterestimates roundedtotheclosest0.5.Subsequently,themodelwas independentlyvalidatedintheremainingpatients(validationcohortof2,361).Modeldiscriminationwas assessedbycalculatingtheareaunderthereceiveroperatingcharacteristiccurve(AUC).Thethresholdscore providingthebestcombinationofsensitivityandspecificitywasdeterminedbyAUCanalysis.Corresponding positiveandnegativepredictivevalues,positiveand negativelikelihoodratios,andtheir95%CIswerecalculated.Asensitivityanalysiswasperformedtodetermine themodelperformanceatdifferentcutoffpoints. Insecondaryanalyses,todeterminethemortalityburdenduetothedevelopmentofALI,weperformedalogisticregressionanalysisadjustedforALIdevelopment, EDLIPS,andbaselineseverityofillness(AcutePhysiologyandChronicHealthEvaluation[APACHE]II score).Inaddition,wecomparedtheperformanceof EDLIPStotheoriginalLIPSpreviouslydescribedinthe literature[17].Allstatisticalanalysiswasoperatedin SAS9.2(SASInstitute,Cary,NC).ResultsCharacteristicofstudysubjectsTwenty-twocentersscreened5,992adultpatients,of whom4,361wereadmittedfromtheemergencydepartmentandhadatleastoneALIriskfactor.Onehundred sixty-sixpatientswereexcludedwithALIonpresentation,EDdeath,orothercriteria.Predisposingconditions (aspiration,pneumonia,sepsis,shock,high-riskand emergencysurgery,andhigh-risktrauma:lungcontusion,multipleribfractures,traumaticbraininjury, smokeinhalation,andnear-drowning)andclinicaland physiologicalriskfactorsassociatedwithALIdevelopmentwereidentified(Figure1). TheoverallincidenceofALIintheEDsubgroupwas 7.0%(303/4,361).TheincidenceofALIinthederivation Table2EDLIPSpointsderivedandassignedbyweightPredispositionsEstimate95%CIp-valueEDLIPSPoints Malegender0.5120.0890.9350.0181 Aspiration0.9000.2041.5950.0112 Pneumonia0.5500.0521.0470.0301 Sepsis0.5000.0310.9690.0371 Shock0.9590.4061.5120.0012 Lungcontusion0.823 Š 0.0321.6790.0591 Smokeinhalation1.505 Š 0.1003.1090.0661.5 Longbonefractures1.1220.3411.9040.0052 Braininjury1.1030.4261.7800.0012 Cardiacsurgery2.5840.6194.5490.0105 Aorticsurgery2.6190.1905.0490.0355 Spinesurgery2.7270.6234.8320.0115 Acuteabdomen1.2720.5062.0380.0012.5 Riskmodifiers Diabetesmellitus Š 0.381 Š 0.8960.1330.146 Š 0.5 Cirrhosis0.928 Š 0.0781.9340.0711 Chemotherapy1.1810.4051.9570.0032 Obesity(BMI>30)0.7950.3521.2370.0001.5 Acidosis(pH<7.35)0.8520.3481.3570.0012 FiO2>0.35(>4l/min)0.9040.4431.3650.0002 Albumin<3.50.7920.3591.2260.0001.5 SpO2<95%0.7330.3171.1480.0011.5 Excludedvariables* Pancreatitis0.273 Š 0.8661.4130.638Thoracicsurgery1.187 Š 2.4764.8490.525Neardrowninga14.509 Š 7692.17721.10.997Alcoholabusea0.099 Š 0.6180.8170.786Smoking Š 0.054 Š 0.5040.3970.816Tachypnea0.074 Š 0.5960.7450.828*Variableswereremovedsecondarytominimaleffectsize;afewerthanten patientswithvariable. Table1Comparisonofderivationandvalidationcohorts (Continued)FiO2>0.35,no.(%)841(19.3%)381(19.1%)452(19.1%)0.937 Albuminlevel3.5(2.9,4.0)3.5(3.0,4.0)3.5(2.9,4.0)0.068 Hypoalbuminemia945(47.1%)414(45.4%)531(48.5%)0.167 pHmedian7.4(7.3,7.4)7.4(7.3,7.4)7.4(7.3,7.4)0.632 Acidosis(pH<7.35)476(45.9%)206(43.6%)270(47.8%)0.173 Outcome ALI/ARDS303(7.0%)127(6.4%)176(7.5%)0.153 Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page5of11 http://www.intjem.com/content/5/1/33

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andvalidationgroupswas6.4%(127/2,000)and7.5% (176/2,361),respectively, p =0.15.Therewerenostatisticallysignificantdifferencesdetectedbetweenthederivationandvalidationcohorts(Table1).DerivationofpredictionruleTheweightingofEDLIPSpointswasadjustedbasedon themultivariatelogisticregressionanalysisinthederivationcohortof2,000randomlyselectedpatientsand wasvalidatedintheremaining(2,361)patients(Table2). Emergencydepartmentadmissionsrequiringcardiac, aortic,orspinesurgerieshadthehighestassignmentsof EDLIPSpoints,conferringthehighestassociatedrisk forALIdevelopment.Otherfactorswerealsoobserved tohavesignificanteffectincludingthepresentationof acuteabdomen,multiplelongbonefractures,traumatic braininjury,aspiration,shock,chemotherapy,acidosis, oranoxygenrequirementof>0.35FiO2.AmodestinfluenceonprogressiontoALIwasobservedwithmale gender,pneumonia,sepsis,lungcontusion,obesity, hypoalbuminemia,andhypoxemia.Incontrast,the pre-admissiondiagnosisofdiabetesmellitusconferred protectionfromALIwithanassignmentofnegative0.5 points.TheEDLIPSmodelcalculationworksheetand examplesofhowtocalculatethescorearepresented. (Table3). Themodelwaswellcalibratedinbothtrainingand testingdatasets.EDLIPSscoresrangedfrom 0.5to15, median3.5(IQR:2.0,5.0).AmongpatientswhoultimatelydevelopedALI,themedianLIPSscorewas6.5 (IQR:4.5,8.0)comparedtothosewhodidnot,median 3.5(IQR:2.0,5.0).Overall,theincidenceofALI increasedwithincreasingLIPSscore.EDLIPSscore 7 wasassociatedwitha27.9%frequencyofALIdevelopment,whileascoreof 3hadafrequencyof1.7%.Hospitalmortalitywas19.2%forthosewithanLIPSscore 7 comparedto2.6%forthosewithascoreof 3(Figure2). EDLIPSdiscriminatedpatientswhodevelopedALI fromthosewhodidnotwithanAUCof0.78(95%CI 0.75,0.82)(Figure3).AtanEDLIPScutoffof5.0(range 0.5-15),positiveandnegativelikelihoodratios(95%CI) forALIdevelopmentwere2.74(2.43,3.07)and0.39 (0.30,0.49),respectively,withasensitivityof0.72(0.64, 0.78),specificityof0.74(0.72,0.746),positivepredictive valueof0.18(0.15,0.21),andnegativepredictivevalue of0.97(0.96,0.98)(Table4). Incontrast,theAPACHEIIscorehadlimitedprognosticaccuracyforALIdevelopmentofAUC0.70(95% CI0.66,0.74), p value<0.001,comparedtoEDLIPS (Figure3). In-hospitalmortalitywashigherforpatientswithALI comparedtothosewithout(27.7%vs4.6%, p <0.001). TheunadjustedoddsratioofdeathfromALI/ARDSis 7.90(95%CI:5.90,10.56), p <0.001.Afteradjustingfor bothEDLIPSandAPACHEIIscores,theoddsratiofor hospitalmortalityis1.29(95%CI:1.23,1.36), p <0.001, and1.17(95%CI:1.15,1.19), p <0.001,respectively. WhencomparedtotheperformanceoftheEDLIPS score,therewasnostatisticallysignificantdifference fromtheoriginalLIPSinpredictingthecohortof patientswhodevelopedALI:originalLIPSAUC[0.80 (95%CI:0.76,0.83) p =0.07]. Table3EDLIPSscorecalculationworksheetUsingTable2examples i.Patientwithhistoryofcirrhosiswithsepticshockfrom pneumoniarequiringFIO2>0.35intheemergencyroom: Sepsis+shock+pneumonia+cirrhosis+FIO2>0.35 1+2+1+1+2=7 ii.Motorvehicleaccidentwithtraumaticbraininjury,lung contusion,andshockrequiringFiO2>0.35 Braininjury+lungcontusion+shock+FiO2>0.35 2+1+2+2=7 iii.Patientwithhistoryofdiabetesmellituspresentswith urosepsis,acidosisandshock Sepsis+shock+acidosis+diabetes 1+2+2 – 0.5=4.5InthiscohortthelowestandhighestEDLIPSscoresachievedwere 0.5,15. Figure2 FrequencyofALI/ARDSdevelopmentandhospitalmortalityaccordingtoEDLIPSvalue( n =4,361). Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page6of11 http://www.intjem.com/content/5/1/33

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DiscussionSincethe1990s,UShospitalshaveexperienceda55% increaseincriticallyillpresentationstoEDs.Withover 110millionvisitsayear,thetrendinemergencymedicineinvestigationshasbeendirectedatearlyriskstratificationandgoal-directedcare,particularlyinthe criticallyill.Houetal.reportthatintheat-riskpopulationofEDpatients,upto7%developALIwithinamedianof2days(IQR2 – 5)[22]. ALIcanrepresentadevastatingpulmonaryprocess associatedwithincreasedlengthofstay,costs,andlongtermpooroutcomes[23,24].Moreover,itrepresentsa diseasethathasthepotentialtoimpartaburdenacross ayoungerandhealthierpopulationthanpreviously recognized[25].ThemedianageofthisEDLIPScohort was56years.Inone5-yearlongitudinaltrial,survivors complainedofpersistentneuropsychologicalimpairment andhighpersonalmedicalexpenditures[26].Persistent exerciselimitationandpulmonaryfibrosisarecommon [26-28].PreventingALIandprogressiontoARDShas thepotentialtofacilitatethereturnofviableat-risk patientsbacktotheircommunitieswiththecapacityto providemeaningfulcontributionstosociety. ThispreliminarystudysuggeststhattheriskofprogressiontoALImaybeascertainedusingtheEDLIPS.The scoreandconsequentdegreeofriskvariesaccordingto Figure3 ReceiveroperatingcharacteristiccurvesforEDLIPSpoints,LIPSpoints,andAPACHEIIinthevalidationgroup( n =2361). AUC (95%CI)forLIPS:0.784(0.748-0.820),AUC(95%CI)forAPACHEII:0.704(0.663-0.744),P-value<0.001(ComparedtoLIPS),AUC(95%CI)Original LIPS:0.797(0.763,0.831),P-value=0.069(ComparedtoLIPS). Table4Sensitivityanalysis:EDLIPSperformanceatdifferentcutoffpoints( n =2,361)EDLIPScutoffpoints EDLIPSperformance 5* 4 6 PrevalenceofALI/ARDS(95%CI)0.075(0.065,0.086)0.075(0.065,0.086)0.075(0.065,0.086) Sensitivity(95%CI)0.716(0.643,0.781)0.852(0.791,0.901)0.557(0.480,0.632) Specificity(95%CI)0.738(0.719,0.757)0.592(0.571,0.613)0.848(0.832,0.862) Positivepredictivevalue0.181(0.153,0.211)0.144(0.123,0.167)0.227(0.189,0.270) Negativepredictivevalue0.970(0.961,0.978)0.980(0.971,0.987)0.960(0.950,0.968) Likelihoodratio(+)(95%CI)2.735(2.434,3.073)2.088(1.928,2.261)3.654(3.099,4.308) Likelihoodratio( Š )(95%CI)0.385(0.304,0.487)0.250(0.175,0.357)0.523(0.443,0.618) C-statistic(95%CI)0.727(0.692,0.762)0.722(0.694,0.750)0.702(0.748,0.820)*Depictsoptimalcutoff.Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page7of11 http://www.intjem.com/content/5/1/33

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thetypeandnumberofpredisposingconditions.Thefindingthatemergencyhigh-risksurgeries,traumaticinjuries, andshockwerestrongindicatorsisconsistentwiththeliterature,whichcitesahighincidenceofARDSinthese populations[29].Ourmodelalsofoundthattherequirementof>4l/minandchemotherapywasadeterminatein progressiontoALI,similartopreviouslypublishedwork byLevittetal.[30]. Otherpredisposingconditionsanalyzed,suchasnear drowning,mayhavealsoproventobestrongpredictors; however,thereweretoofewcasestoreliablydetectan effect.Itremainsunclear,however,whytheexistenceof diabetesmellitusconfersprotectiontopatients.Previous investigationshavenotedalowerincidenceofALI amongdiabeticscomparedtotheirnon-diabeticcohorts. HonidenandGongsuggestthathyperglycemiaaswell asthetherapeuticinteractionofmedicationsmayalter theinflammatoryresponseassociatedwithALI/ARDS development[21]. Itisinterestingthatconditionssuchaspneumonia andpancreatitiswerenotstrongerpredictorsinthis cohort.Thestudywasnotdesignedtoassessthe severityofillness.Thehighnumberofpatientspresentingwithlesscomplicateddiseasemayhavedampened anyresultingsignalfromseverecasesofpneumoniaor acutepancreatitis.However,theconcomitantexistence ofhypoxemia,highoxygenrequirement,and/oracidosis, forexample,wouldincreaseapatient ’ sriskfordevelopingALI. Whencomparedtothepreviouslypublishedscoring methodologyofLIPS,theEDLIPSaffordsanumberof advantages.ItidentifiespatientswhoareatriskforALI fromabroaderscaleofpotentialpresentingsymptoms andpredisposingconditionsintheED.WhileEDLIPS didnotout-performoriginalLIPS,itsabilitytodiscriminatepatientswhowouldgoontodevelopALIiscomparableinthisstudy.Moreover,EDLIPSisderivedfrom atargetedpopulationofEDpatientsandlackstheheterogeneityincludedintheoriginalLIPScohortof patientsadmittedfromtheEDandpatientsundergoing high-riskelectivesurgeries. ThisaffordsthepotentialforEDLIPStodiscernfactorsuniquetotheEDpopulation.Itisnotablethatin one8-yearlongitudinalstudyofARDS,thehospitaland ICUpopulationsexperiencedadramaticreductionin ARDSattributedtoclinicalinterventions,whiletheincidenceofearlyonsetARDSwithin6hofEDadmission remainedunchanged[31].Thissuggestspotentialdifferencesinthemechanisticpathwaysinthedevelopment ofALI. ThisEDLIPSscoringmethodisdesignedfortheED settingutilizingroutinelyavailableclinicalvariablesthat canreadilybeidentifieduponpresentationforrisk stratificationpredictingprogressiontoALIandinpatientmortality.Moreover,thescoringsystemhasthe potentialtoallowfortheinvestigationofpreventive measuresintheemergencydepartment.Whilethe authorsacknowledgeAPACHEIIwasnotdesignedor intendedtopredictALI,itisabroadlyrecognizedassessmenttoolutilizedamongcriticallyillpatients.APACHEIIisconsistentlyreferencedasthemodelwhen validatingtheperformanceofcustomizedscoresina heterogeneouspopulationofcriticallyillpatients.As such,itisnotsurprisingthatitlacksdiscriminatingcapacityinpredictingALIwhencomparedtoEDLIPS. However,itisnotablethatEDLIPSwithincreasing scorespredictedanincreasingtrendofmortality,suggestinganincreasedseverityofillness,forwhichpurposetheAPACHEhadbeenoriginallydesigned. Moreover,fromthestandpointofclinicalpractice,when comparedtoEDLIPS,APACHEIIrequires12separate physiologicaldatapointsandasophisticatedcalculation schemetoderiveascoreovera24-hperiod.Itsusein theEDisnotfeasible[32,33]. Afrequentconsequenceofcriticalillnessintheemergencydepartmentisintubationandmechanicalventilation,ahallmarkofEDresuscitationandarequisite componentoftheclinicalmanagementoftheALI/ ARDSpatient.Studiessuggestthatearlyventilatorsettingsinfluencedownstreamoutcomeofcriticallyill patients[34].Theapplicationofmechanicalventilation caninducepulmonarydamagebymeansofaprocess termedventilator-associatedlunginjury(VALI).Both animalandhumanstudiesdemonstrateupregulationof inflammatorycytokines,whichcompromisethealveolar capillarymembranewhenincreasedvolumesareapplied tothelungparenchyma.Thismechanicalstresscanproduceastimulusthatinducesthetransformationofa normallungtoalungwithhistologicalappearanceindistinguishablefromALIinducedbysepsis,shock,or pneumonia[35-38].TheclinicalimpactofhightidalvolumeventilationwasunderscoredbytheAcuteRespiratoryDistressSyndromeNetworkstudy.Utilizingthe lowertidalvolume,mortalityfromARDSwasreduced from39.8%to31%[15].Todate,theprimarystrategy proventobeeffectiveatreducingmortalityfromALIis lowtidalvolumeventilationbytargetingareductionin VALI.Evenmorecompellingisaninvestigationby Determannetal.demonstratingthatrandomlyselected patientswithoutALIplacedonmechanicalventilation withlowtidalvolumesof6ml/kgwerelesslikelytodevelopALIthanthoseplacedon10ml/kgpredictedbody weight(2.6%,13.5%, p =0.01[39]). Assumingpreventivestrategiesareidentified,the EDLIPShasthepotentialtoresultinsubstantialmorbidityandmortalityreductionaswellascostsavings.Specifically,anEDLIPSof 5shouldprompttheclinician teamtocloselymonitorthepatientandcommunicateElie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page8of11 http://www.intjem.com/content/5/1/33

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thepotentialneedtoaddressacutechangesinrespiratorystatustothereceivingservice;thisinturnwould allowfortheinstitutionofpreventivemeasures. ThetransitionofALIstudiesfromtheICUtotheED populationmaynotonlybeprudentbutobligatoryas studiesdemonstratethepreponderanceofARDScases arelikelytostemfromEDadmissionssecondaryto insultsexposedinthecommunity.Hence,investigations evaluatingtheuseofantiplateletandstatintherapies,a lowtidalvolumeventilationstrategy,andrestrictive transfusionintheEDmayindeedbeneededtomitigate ALIdevelopment[40-43].Designedasabundle,these interventionshavethepotentialtocurbtheprogression ofillnessinapatientidentifiedatriskwheninstituted early.LimitationsWhiletheEDLIPSmodeldidaccuratelyidentifymost ALIpatientsathigherLIPSscores,itisnotablethatthe modelhasamodestAUC.So,whilearobustnegative predictivevalueof0.97rendersthemodelusefulin screeningpatientswithlowriskforALI,theweaker positivepredictivevaluedoeslackprecisioninidentifyingthoseathighriskforALI.Alternatively,theuseofa higherthresholdscoremayenhancethemodel ’ sperformanceintheclinicalsetting.FuturedirectionsThisstudyrepresentsaninitialattempttorefineascoringmethodologyofemergencydepartmentpatientsfor thepurposeofpredictingALIdevelopment.External validationwillbenecessarytodeterminewhether EDLIPScanbegeneralizedtoclinicalpractice.Moreover,itisunclearwhatspecificimpacttheimplementationofthisscoringsystemwillhaveonphysician practice,patientoutcomes,orresourceutilization.Furtherstudieswillbeneededtoassesstheapplicationof thisscoringsysteminconjunctionwithoutlinedstrategiesknowntohaveanimpactonclinicalparametersin patientsatriskforALI.ConclusionsInthisstudy,wedescribeavariationonanovelscoring methodthatscreensandstratifiespatientsatgreatest riskfordevelopingALIintheED.Althoughtheoverall performanceismodest,anexcellentnegativepredictive valuemakesitausefulscreeningtool.EDLIPSperformancewassimilartotheoriginalLIPSmodelandsignificantlybetterthanAPACHEIIinpredictingALI development.ConfirmationoftheseresultsinotherED populationsandtheidentificationofadditionalriskfactorscouldaidboththeidentificationofsusceptibleindividualsandthetargetingoftherapies.Abbreviations ALI:Acutelunginjury;ARDS:AcuteRespiratoryDistressSyndrome; APACHE:AcutePhysiologyandChronicHealthEvaluation;ED:Emergency department;EDLIPS:EmergencyDepartmentLungInjuryPredictionScore; ICU:Intensivecareunits;LIPS:LungInjuryPredictionScore;AUC:Receiveroperatingcharacteristiccurve;PEEP:Positiveendexpiratorypressure; VALI:Ventilator-associatedlunginjury. Competinginterests Dr.Frendlprovidedinternalfundingforresearchstaffandbiostatistic supportfromSTARCenter,BrighamandWomen ’ sHospital,Boston,MA.Dr. GajicissupportedinpartbygrantsfromtheNationalHeart,Lung,and BloodInstituteHL78743-01A1;NationalCenterforResearchResources1KL2 RR024151.Dr.GentileissupportedinpartbyagrantfromtheNational InstituteofNeurologicalDisordersandStroke5U10NS059039.Therestofthe authorshavenodisclosuresorconflictofinterest. Authors ’ contributions ME,PCH,OG,andNTGconceivedthestudyanddesignedthetrial.PCHand GFobtainedresearchfundingandresources.ME,PCH,OG,andNTG supervisedtheconductofthetrialanddatacollection.AMandOG managedthedata,includingqualitycontrol.AM,ME,PCH,andOGprovided statisticaladviceonstudydesignandanalyzedthedata.MEdraftedthe manuscript,andallauthorscontributedsubstantiallytoitsrevision.MEtakes responsibilityforthepaperasawhole. Authordetails1DepartmentofEmergencyMedicine,UniversityofFloridaCollegeof Medicine,POBox100186,1329SW16thStreet,Gainesville,FL32610,USA.2EmergencyDepartment,ShandsUniversityofFloridaMedicalCenter, Gainesville,FL,USA.3DepartmentofEmergencyMedicine,Brighamand Women ’ sHospital,75FrancisStreet,Boston,MA02115,USA.4Divisionof Burn,Trauma,andSurgicalCriticalCare,BrighamandWomen ’ sHospital, Boston,MA,USA.5SurgicalIntensiveCareUnitTranslationalResearch(STAR) Center,BrighamandWomen ’ sHospital,Boston,MA,USA.6HarvardMedical School,DepartmentofEmergencyMedicine&DivisionofBurn,Trauma,and SurgicalCriticalCare,DepartmentofSurgery,BrighamandWomen ’ s Hospital,75FrancisStreet,NevilleHouse312-B,Boston,MA02115,USA.7DepartmentofAnesthesiology,PerioperativeandPainMedicine,Brigham andWomen ’ sHospital,Boston,MA,USA.8DepartmentofEmergency Medicine,AlbanyMedicalCenter,Albany,NY,USA.9AlbanyMedicalCollege, Albany,NY,USA.10DepartmentofMedicine,DivisionofPulmonaryand CriticalCareMedicine,MayoClinic,Rochester,MN,USA.11Multidisciplinary EpidemiologyandTranslationalResearchinIntensiveCare(METRIC),Mayo Clinic,Rochester,MN,USA.12MayoMedicalSchool,Rochester,MA,USA.13DepartmentofEmergencyMedicine,TempleSchoolofMedicine, Philadelphia,PA,USA.14DepartmentofMedicine,StanfordHospitalsand Clinincs,300PasteurDrive,Room:S102,MC:5110,Stanford,CA94305,USA.15F.EdwardHebertSchoolofMedicine,UniformServicesUniversityofthe HealthSciences,4301JonesBridgeRoad,Bethesda,MD20814-4712,USA.16AlbanyMedicalCenterEmergencyMedicineGroup,47NewScotland Avenue,MC139,Albany,NY12208,USA.17DepartmentofAnesthesiology PerioperativeandPainMedicine,BrighamandWomen ’ sHospital,75Francis Street,Boston,MA02115,USA.18MayoClinic,PulmonaryandCriticalCare Medicine,OldMarianHall,SecondFloor,Room115,200FirstSt.SW, Rochester,MN5590,USA. Received:5April2012Accepted:14August2012 Published:3September2012 References1.AshbaughDG,BigelowDB,PettyTL,LevineBE: Acuterespiratorydistress inadults. Lancet 1967, 2: 319 – 323. 2.BernardGR,ArtigasA,BrighamKL,CarletJ,FalkeK,HudsonL,LamyM, LegallJR,MorrisA,SpraggR: TheAmerican-EuropeanConsensus ConferenceonARDS.Definitions,mechanisms,relevantoutcomes,and clinicaltrialcoordination. AmJRespirCritCareMed 1994, 149: 818 – 824. 3.FergusonND,Frutos-VivarF,EstebanA,GordoF,HonrubiaT,PenuelasO, AlgoraA,GarciaG,BustosA,RodriguezI: Clinicalriskconditionsforacute lunginjuryintheintensivecareunitandhospitalward:aprospective observationalstudy. CritCare 2007, 11: R96.Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page9of11 http://www.intjem.com/content/5/1/33

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Chest 2010, 139: 289 – 295. 41.MasciaL,ZavalaE,BosmaK,PaseroD,DecaroliD,AndrewsP,IsnardiD, DaviA,ArguisMJ,BerardinoM,DucatiA: Hightidalvolumeis associatedwiththedevelopmentofacutelunginjuryaftersevere braininjury:aninternationalobservationalstudy. CritCareMed 2007, 35: 1815 – 1820.Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page10of11 http://www.intjem.com/content/5/1/33

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42.VamvakasEC,BlajchmanMA: Transfusion-relatedmortality:theongoing risksofallogeneicbloodtransfusionandtheavailablestrategiesfortheir prevention. Blood 2009, 113: 3406 – 3417. 43.YilmazM,KeeganMT,IscimenR,AfessaB,BuckCF,HubmayrRD,GajicO: Towardthepreventionofacutelunginjury:protocol-guidedlimitation oflargetidalvolumeventilationandinappropriatetransfusion. CritCare Med 2007, 35: 1660 – 1666.doi:10.1186/1865-1380-5-33 Citethisarticleas: Elie-Turenne etal. : Lunginjurypredictionscorefor theemergencydepartment:firststeptowardspreventioninpatientsat risk. InternationalJournalofEmergencyMedicine 2012 5 :33. Submit your manuscript to a journal and bene“ t from:7 Convenient online submission 7 Rigorous peer review 7 Immediate publication on acceptance 7 Open access: articles freely available online 7 High visibility within the “ eld 7 Retaining the copyright to your article Submit your next manuscript at 7 springeropen.com Elie-Turenne etal.InternationalJournalofEmergencyMedicine 2012, 5 :33Page11of11 http://www.intjem.com/content/5/1/33