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Neurogenicpulmonaryedema

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Neurogenicpulmonaryedema
Authors
MatthewWemple,MD
MatthewHallman,MD
AndrewMLuks,MD

SectionEditor
PollyEParsons,MD

DeputyEditor
GeraldineFinlay,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Apr02,2014.
INTRODUCTIONNeurogenicpulmonaryedema(NPE)isanincreaseinpulmonaryinterstitialandalveolar
fluidthatisduetoanacutecentralnervoussysteminjuryandusuallydevelopsrapidlyaftertheinjury[1].Itis
sometimesclassifiedasaformoftheacuterespiratorydistresssyndrome(ARDS),butitspathophysiology
andprognosisaredifferent.
Theclinicalfeatures,differentialdiagnosis,diagnosis,etiology,pathogenesis,andtreatmentofNPEare
reviewedhere.ARDSandnoncardiogenicpulmonaryedemaduetoothercausesarediscussedelsewhere.
(See"Acuterespiratorydistresssyndrome:Clinicalfeaturesanddiagnosisinadults"and"Noncardiogenic
pulmonaryedema".)
CLINICALPRESENTATIONNPEcharacteristicallypresentswithinminutestohoursofaseverecentral
nervoussysteminsultsuchassubarachnoidhemorrhageortraumaticbraininjury.However,morerapidonset
(immediate)anddelayedonset(hourstodays)havebeendescribed[24].Resolutionusuallyoccurswithin
severaldays[5].
Dyspneaisthemostcommonsymptom,althoughmildhemoptysisispresentinmanypatients.Thephysical
examinationgenerallyrevealstachypnea,tachycardia,andbasilarrales.Chestradiographstypicallyshowa
normalsizeheartwithbilateralalveolaropacities,althoughunilateralopacitieshavealsobeendescribed[68].
HemodynamicmeasurementsareusuallynormalbythetimeNPEisdiagnosed,includingthebloodpressure,
cardiacoutput,andpulmonarycapillarywedgepressure.
ThereisabroadrangeofseveritiesofNPEandmildcasesmayneverbedetected.WhileNPEcanbe
fulminantandcontributetodeath,mortalityismorecommonlyduetotheneurologicinsultthatprecipitatedthe
onsetofNPE.
DIFFERENTIALDIAGNOSISTheclinicalfindingsofNPEmaybeconfusedwithaspirationpneumonitis.
Reliabledifferentiationbetweenthesesyndromesisdifficultbecausetheyarebothcommoninsettingsof
alteredconsciousness,suchaspostictalstates.NPEtendstodevelopmorerapidlythanaspiration
pneumonia,whilefeverandfocalopacities,particularlyinthelowerlungzones,favoraspiration.Inaddition,
NPEtendstoresolvemorerapidlythanlunginjuryrelatedtoaspiration,particularlyifaspirationpneumonia
develops.
Othercausesofpulmonaryedemashouldalsobeconsidered,suchasheartfailureandacuterespiratory
distresssyndrome.(See"Evaluationofthepatientwithsuspectedheartfailure"and"Acuterespiratorydistress
syndrome:Clinicalfeaturesanddiagnosisinadults".)
DIAGNOSISDefinitivediagnosisofNPEisdifficultbecausetheclinicalsignsandroutinediagnostictests
arenonspecific.Thus,NPEisaclinicaldiagnosisbasedupontheoccurrenceofpulmonaryedemainthe
appropriatesettingandintheabsenceofamorelikelyalternativecause.Thefollowingcriteriaforthediagnosis
andclassificationofNPEhavebeenproposed,buthavenotbeenwidelyaccepted[9]:

Bilateralopacities
PaO2/FiO2ratio<200
Noevidenceofleftatrialhypertension
PresenceofCNSinjury(severeenoughtohavecausedsignificantlyincreasedintracranialpressure)
Absenceofothercommoncausesofacuterespiratoryfailureoracuterespiratorydistresssyndrome

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(ARDS)(eg,aspiration,massivebloodtransfusion,sepsis)
ETIOLOGYTheprimaryprecipitantsofNPEareepilepticseizures,traumaticbraininjury,andcerebral
hemorrhages(table1)[3,10].
EpilepticseizuresAmongallpatientswithepilepsytheoccurrenceofNPEisrare.However,severalcase
seriesreportedthatuptoonethirdofpatientswithfatalstatusepilepticushadclinicalevidenceofNPE,while
anautopsystudyfoundthat87percentofpatientswithepilepsyandunexplainedsuddendeathhadNPE[10
12].ItisuncertainwhetherNPEwastheproximatecauseofdeathinthesestudies,butitisclearthatthe
NPEismorelikelywithincreasingseizureseverity.
NPEduetoepilepticseizuresgenerallyoccursduringthepostictalperiodanditmayoccurrepeatedlyina
givenindividual[3,13,14].(See"Convulsivestatusepilepticusinadults:Classification,clinicalfeatures,and
diagnosis".)
TraumaticbraininjuryBluntorpenetratingheadinjuryandneurosurgicalprocedurescancauseNPE
[2,3,15].TheNPEisusuallyassociatedwithelevatedintracranialpressure(ICP),butraisedICPisnota
necessarycondition[16].TheincidenceofNPEintraumaticbraininjuryhasbeenestimatedat20percent,and
appearstoincreasewithincreasingseverityofinjury[17].(See"Evaluationandmanagementofelevated
intracranialpressureinadults".)
CerebralhemorrhageNPEcancomplicateupto43percentofcasesofsubarachnoidhemorrhage[4,7,18
21].Inaseriesof78casesoffatalsubarachnoidhemorrhage,31percenthadantemortemclinicalevidenceof
NPEand71percenthadpathologicalevidenceofNPEatautopsy[18].Onsetistypicallywithinminutesto
hoursofthehemorrhagealthoughlateonsetdaysafterhemorrhageorrecurrenceafterapparentresolutionhave
alsobeendescribed[22].NPEhasalsobeenreportedduringcoilembolizationofarupturedcerebralaneurysm
[23].ThemostimportantriskfactorsforNPEfollowingsubarachnoidhemorrhagearetheclinicaland
radiographicseveritiesofthehemorrhagesaswellasavertebralarterysourceofthehemorrhage[1,21].NPE
canalsobeseeninupto35percentofpatientswithintracerebralhemorrhage,withtheprimaryriskfactorsin
suchpatientsbeinghigherAcutePhysiologyandChronicHealthEvaluation(APACHE)IIscoresand
increasedlevelsofseruminflammatorymarkers[24].(See"Clinicalmanifestationsanddiagnosisof
aneurysmalsubarachnoidhemorrhage".)
Otherlesscommonetiologiesarelistedinthetable(table1)[2528].
PATHOGENESISTheneurologicalstructuresthatarecriticaltothedevelopmentofNPEareknown.
However,themechanismbywhichlesionsinthesestructuresleadtoNPEisnotwellunderstood.
NeurologicstructuresThemedullaoblongataandhypothalamusareconsideredthecriticalanatomic
structuresinvolvedinthepathogenesisofNPE.Theimportanceofthemedullaissupportedbytheobservation
thatbilaterallesionsinthenucleusofthesolitarytract,areapostremaandlesionsintheA1andA5
neuroadrenergicneurons(allofwhichareinthemedulla)cancausesystemichypertensionandNPE[2932].
Themedullaoblongataprobablyactsviathesympatheticcomponentoftheautonomicnervoussystem,as
suggestedbythefollowingevidencefromanimalmodels[3335]:
Alphaadrenergicblockade(eg,withphentolamine)canpreventthedevelopmentofNPE
NPEcanbepreventedbyspinalcordtransectionatorabovetheC7level,belowwhichsympathetic
fibersleavethelateralpartofthecordtoformtheparaspinalsympathetictrunks
NPEcanbepreventedbydenervationbytransectionofthesplanchnicsympatheticfiberstothelungs
NPEmaybeproducedbystimulationofthecordattheC7C8level,withthecordandsympathetic
nervesintact
Inadditiontotheroleofthemedullaoblongata,theoriesregardingthepathogenesisofNPEhavecenteredon
thepotentialcontributionsofthehypothalamus,elevatedintracranialpressure,andactivationofthe
sympathoadrenalsystem[29,30,3345].Experimentalmodelshaveshown,forexample,thatinducing
hypothalamiclesionsprecipitatesNPE[46],whileacaseseriesof22patientswithNPEfoundthathalfof
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themhadradiographicevidenceofhypothalamicinjury,afindingassociatedwithworseoutcome[47].
MechanismsofedemaformationNPErequiresacentralnervoussysteminjuryorevent(eg,seizure)that
alterstheStarling'sforcesinawaythatincreasesthemovementoffluidfromthecapillariestothepulmonary
interstitium,increasesthepermeabilityofthepulmonarycapillaries,orboth(figure1).
CapillaryhydrostaticpressureIncreasedcapillaryhydrostaticpressureistheStarling'sforcethatis
mostlikelytocontributetoNPE,sinceitisunlikelythatacentralnervoussysteminjuryoreventcouldchange
capillaryorinterstitialoncoticpressurerapidly[3].Thisissupportedbytheobservationthatalveolarfluidhasa
lowfluidtoserumproteinratioearlyduringthecourseofNPE,consistentwithhydrostaticpulmonaryedema
[48].
Experimentalstudiesusinganimalmodelsanduncontrolledobservationsinhumanssuggestseveral
mechanismsbywhichpulmonarycapillaryhydrostaticpressuremayincreaseacutely:
Pulmonaryvenoconstrictionmayoccurwithintracranialhypertensionorsympatheticstimulation.This
increasesthepulmonarycapillaryhydrostaticpressure,producingpulmonaryedema[33,4952].Alpha
adrenergicantagonistsmayattenuatetheeffect[53].
Excessivesystemicvenoconstrictionmayoccurleadingtoasignificantincreaseinvenousreturntothe
rightheartandpulmonarycirculation.Supportforthisconceptcomesfromanimalstudiesinwhich
prophylacticphlebotomy(15percentofbloodvolume)priortoCNSinsultpreventeddevelopment
neurogenicpulmonaryedema[54].
Leftventricularperformancemaydeteriorateforseveralreasons:directmyocardialdamageorstunning
secondarytobraininjury,increasedafterloadduetosystemichypertension,andnegativeinotropicand
chronotropicinfluencesofexcessivevagaltone[52,55,56].Thiscancausepassiveelevationoftheleft
atrialandpulmonarycapillarypressures,leadingtopulmonaryedema[38,39,55,5761].
DespitetheevidencethatincreasedpulmonarycapillaryhydrostaticpressureplaysaroleinNPE,thereare
likelyadditionalcontributors.ThisnotionisbaseduponreportsofNPEoccurringwithlittleornoelevationin
thepulmonarycapillarywedgepressureandintheabsenceofleftatrialorsystemichypertension[49].
PulmonarycapillarypermeabilityIncreasedpulmonarycapillarypermeabilitymaycontributetoNPE.
ThisideaissupportedbythefindingofproteinrichedemafluidinanimalmodelsandsomepatientswithNPE,
aswellastheobservationthatNPEcanoccurintheabsenceofthehemodynamicalterationsassociatedwith
pulmonaryedema[4,48,62,63].
Asanexample,astudyusedthermalgreendyetechniquestomeasureextravascularlungwaterin18patients
witheitherheadtraumaorsubarachnoidhemorrhageand13controlpatients(traumapatientswithouthead
injury)[4].Nineofthe18patientswithbraininjurieshadpulmonaryedema,definedasextravascularlungwater
valuesgreaterthantwostandarddeviationsabovethecontrolgroupmean.Thepulmonaryedemawas
independentofintracranialorpulmonaryvascularpressure,suggestingincreasedvascularpermeability.
Themechanismbywhichneuralinfluencesproducechangesinpulmonaryvascularpermeabilityhavenotbeen
elucidatedwell.However,severalhypothesesexist:
Epinephrineornorepinephrinemaydirectlyincreasevascularpermeability.Supportingthisideaarethe
observationsfromanimalmodelsthatalphaadrenergicblockadecanprotectagainstNPEand
sympatheticstimulationcanproduceit[53].However,thehypothesisisimperfectbecausedirectinfusion
ofthesesubstancesintothepulmonarycirculationdoesnotproducesuchaneffect[64].
Alphaadrenergicagonistsreleasedinresponsetobraininjurymaycausethereleaseofasecond
mediator,whichincreasesvascularpermeability(eg,endorphins,histamine,bradykinin)[3].
Aninitialrapidincreaseinpulmonaryvascularpressure(eg,duetopulmonaryvasospasmand/or
increasedsystemicvenousreturn)maycausepulmonarymicrovascularinjurywithasubsequent
increaseinpermeability[65].Thistheory,sometimescalledthe"blasttheory"issupportedbystudiesin
rabbitsshowingthatpulmonarycapillariesaredamagedwhenpressuresexceed40mmHg[66].Itisalso
supportedbytheobservationthatpatientswithNPEfrequentlyhavemildhemoptysisorpulmonary
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hemorrhage[2].Thehypothesisisimperfectbecausetherapiddevelopmentofacutepulmonary
hypertensionisnotanecessaryconditionforNPE[67,68]andinanimalmodelselevatedpulmonary
vascularpressuresdonotinvariablyleadtoNPE[69].
Inflammatorymechanismsmayalsocontributetoincreasedcapillarypermeability[45].Evidencefor
inflammatoryresponsestoseverebraininjuryinclude:
Excesscatecholaminescanthemselvesleadtothereleaseofinflammatorymediators[70,71].
S100B,aserumbiomarkerofbraininjury,hasbeenshowntoinducethereleaseofproinflammatory
cytokinesinalveolartype1likecellsinvitro[72].
Braininjuryhasbeenassociatedwithincreasedintracranialproductionofproinflammatorymediatorsand
subsequentreleaseofthesemediatorsintothesystemiccirculation[73,74].
AratmodelofSAHdocumentedincreasedexpressionofendothelialactivationmarkersonpulmonary
endothelialcells,andincreasedpulmonaryTNFexpression,whichwasattenuatedbyadministrationof
theimmunemodulatorIFN.
Whethertheseobservedinflammatoryresponsespredisposetoedemaformationremainsasubjectofdebate.
TREATMENTTheoutcomeofpatientswithNPEisusuallydeterminedbythecourseoftheneurologic
insultandnottheNPE.Thus,treatmentshouldfocusontheneurologicaldisorderwhileNPEismanagedina
supportivefashion.ManyepisodesofNPEarewelltoleratedandmostresolvewithin48to72hours.
SupportivecareMostpatientswithNPEarehypoxemicandrequiresupplementaloxygen.Somepatients
mayrequiremechanicalventilation.
WhilemostpatientswithNPEarehypoxemicandrequiresupplementaloxygen,thereisinsufficientevidence
tosupportspecificoxygenationgoals.Maintenanceofanoxyhemoglobinsaturation88percentorPaO255
mmHgisgenerallyacceptableinundifferentiatedlunginjury,butspecifictargetsinNPEshouldalsotakeinto
considerationtheeffectthatrelativehypoxemiamayhaveontheunderlyingneurologicalinjury.
Oxygenationgoalsmaybeachievedinsomepatientswithnoninvasivemeasuressuchasoxygenbynasal
cannulasimplefacemask,nonrebreathermask,orhighflowdeliverysystems,butmechanicalventilationmay
benecessaryinothercircumstances.Mechanicalventilationandthedecisiontointubateapatientare
discussedseparately.(See"Overviewofmechanicalventilation"and"Noninvasivepositivepressure
ventilationinacuterespiratoryfailureinadults"and"Thedecisiontointubate".)
MechanicalventilationinpatientswithNPEissimilartothatinpatientswithothercausesofrespiratoryfailure,
althoughtherearesomeimportantdifferences:
Highlevelsofpositiveendexpiratorypressure(PEEP)canreducecerebralvenousreturnandworsen
intracranialhypertension[75,76].(See"Positiveendexpiratorypressure(PEEP)",sectionon'Intracranial
disease'.)
Hypercapnia,whichisoftentoleratedinpatientswithARDS,cancausecerebralvasodilation,thereby
increasingcerebralbloodflowandpotentiallyincreasingICP[1].(See"Permissivehypercapnia",section
on'Contraindications'.)
IfICPelevationisaclinicalconcern,ICPmonitoringmaybeconsideredtoguidemechanicalventilation.
Singlecasereportsdocumenttheuseofproneventilation,inhalednitricoxide,andextracorporeal
membranousoxygenation(ECMO)inpatientswithNPEandseverehypoxemia,butthereisnosystematic
evidencesupportingabenefitfromthesepracticesinsuchcircumstances[7779].BecauseECMOcarriesthe
riskofintracranialhemorrhage,extremecaremustbetakenwithitsapplicationinpatientswithcentralnervous
systeminjury.(See"Proneventilation"and"Extracorporealmembraneoxygenation(ECMO)inadults".)
Maintenanceoflowcardiacfillingpressureswithdiureticsandlimitationofintravenousfluidsmaydecrease
pulmonaryedema.However,caremustbetakentoavoidcompromiseofcardiacoutputandcerebralperfusion.
Pulmonaryarterycatheterizationwashistoricallythoughthelpfulinguidingtherapy,buthassincefallenoutof
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favoraspartofroutinefluidmanagement[5].(See"Pulmonaryarterycatheterization:Indications,
contraindications,andcomplicationsinadults".)
Theutilityoflessinvasivemethodsofassessingcardiacfunctionandpulmonaryedematoguidetreatmentin
NPEisnotwellstudied.Simultaneousassessmentofcardiacoutput,extravascularlungwater,globalend
diastolicvolume,andpulmonaryvascularpermeabilityusinglessinvasivehemodynamicmonitorshasbeen
proposedasamethodtoguidemanagementdecisions,butthedataareinsufficienttosupportspecific
recommendations[80].Small,limitedstudieshavealsoevaluatedtheutilityoflungultrasoundexamsinNPE
[81].
MedicationsAvarietyofmedicationshavebeenusedtotreatpatientswithNPE,buttheireffectivenessis
unproven.Theseinclude:
Betaadrenergicantagonistsarethoughttoincreaselymphflow,decreaseedemaandreducehistamine
inducedaugmentationofpulmonaryvascularpermeability[3]
Dobutamine,whichmayincreasecardiacoutput,decreasespulmonarycapillarywedgepressure,and
promotediuresis[82,83]
Chlorpromazinemayblockalphaadrenergicreceptorstoreduceedema[84]
AlphaadrenergicantagonistshavebeenshowntopreventNPEorhastenitsresolutioninanimalmodels,while
arecentreportdemonstratedrapidimprovementsinoxygenationfollowingadministrationofphentolamineina
singlepatientwithNPEduetoarupturedarteriovenousmalformation[53].However,unopposedalpha
adrenergicantagonistsmayprecipitatesystemichypotensionandcerebralhypoperfusion,andintheabsence
ofdatafromcontrolledtrials,routineuseoftheseagentscannotberecommendedatthistime.(See
"Antihypertensivetherapytopreventrecurrentstrokeortransientischemicattack"and"Evaluationand
managementofelevatedintracranialpressureinadults".)
OutcomesAlthoughmanyepisodesofNPEarewelltoleratedandmostcasesresolvewithin48to72
hours,thedevelopmentofNPEisassociatedwithworselongtermoutcomes.Asanexample,arecent
observationalstudyof108patientswithnontraumaticintracranialhemorrhage,foundthatcomparedtothose
withoutNPE,thosewhodevelopedNPEhadahigheroneyearmortalityof(37versus14percent)[24].
SUMMARYANDRECOMMENDATIONS
Neurogenicpulmonaryedema(NPE)isanincreaseinpulmonaryinterstitialandalveolarfluidthatisdue
toanacutecentralnervoussysteminjury.Itusuallydevelopsrapidlyfollowingtheinjury.(See
'Introduction'above.)
NPEcharacteristicallypresentswithinminutestohoursofaseverecentralnervoussysteminsult.
Dyspneaisthemostcommonsymptom,althoughmildhemoptysisispresentinmanypatients.The
physicalexaminationgenerallyrevealstachypnea,tachycardia,andbasilarrales.Chestradiographs
typicallyshowanormalsizeheartwithbilateralalveolarfilling,whilehemodynamicmeasurementsare
usuallynormal.(See'Clinicalpresentation'above.)
NPEisaclinicaldiagnosisbasedupontheoccurrenceofpulmonaryedemaintheappropriatesettingand
intheabsenceofamorelikelyalternativecause.(See'Differentialdiagnosis'aboveand'Diagnosis'
above.)
TheprimaryprecipitantsofNPEareepilepticseizures,traumaticbraininjury,andcerebralhemorrhages
(table1).(See'Etiology'above.)
ThetreatmentofNPEshouldfocusontreatingtheneurologicaldisorderwhileNPEismanagedina
supportivefashion.ManyepisodesofNPEarewelltoleratedandmostresolvewithin48to72hours.
(See'Treatment'above.)
MostpatientswithNPEarehypoxemicandrequiresupplementaloxygen.Somepatientsmayrequire
mechanicalventilation,whichdiffersfromthatforothercausesofrespiratoryfailureintwoways:
permissivehypercapniaandhighlevelsofpositiveendexpiratorypressure(PEEP)shouldbeused
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cautiously.(See'Supportivecare'above.)
AvarietyofmedicationshavebeenusedtotreatpatientswithNPE,buttheirefficacyinthissettinghas
notbeenestablished.(See'Medications'above.)
AlthoughmanyepisodesofNPEarewelltoleratedandresolve,thedevelopmentofNPEisassociated
withworselongtermoutcomes
ACKNOWLEDGMENTTheeditorialstaffatUpToDate,Inc.wouldliketoacknowledgeFrankDrislane,
MD,andJessMandel,MD,whocontributedtoanearlierversionofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Causesofneurogenicpulmonaryedema
Majorcauses
Epilepticseizures,particularlystatusepilepticus
Cerebralhemorrhage
Headinjury

Minorcauses
GuillainBarrsyndrome
Multiplesclerosiswithmedullaryinvolvement
Nonhemorrhagicstrokes
Trigeminalnerveblock
Bulbarpoliomyelitis
Vertebralarteryligation
Rupturedspinalarteriovenousmalformation
Airembolism
Braintumors
Electroconvulsivetherapy
Inductionofgeneralanesthesia
Colloidcyst
Hydrocephalus
Reyesyndrome
Bacterialmeningitis
Viralmeningoencephalitis
Cervicalspinalcordinjury
Graphic57483Version2.0

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Capillaryhemodynamicforces

Schematicrepresentationofthecapillaryandinterstitialfluid
hydraulic(P)andoncotic()pressurescontrollingfluidmovement
acrossthecapillarywallbetweentheplasmaandtheinterstitialfluid.
Thearrowspointinthedirectionoffluidmovementinducedbyeach
oftheforces.
Graphic66819Version1.0

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Disclosures

Disclosures:MatthewWemple,MDNothingtodisclose.MatthewHallman,MDNothingtodisclose.AndrewMLuks,MDNothing
todisclose.PollyEParsons,MDNothingtodisclose.GeraldineFinlay,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultile
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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