Ventilator Manuscript
Transcript of Ventilator Manuscript
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AConstant-VolumeVentilatorandGas
RecaptureSystemforHyperpolarized
GasMRIofMouseandRatLungs
JohnNouls,ManuelFanardjian,Larry?,BastiaanDriehuys
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HyperpolarizedgasMRIhasintroducednewmeanstovisualizepulmonaryfunction
regionally,non-invasivelyandwithhighresolution.Thistechnologyhasseenwide-
rangingapplicationinclinicalresearch1-8,butonlymodestapplicationinanimal
studies9-12.ThisispartlybecausehyperpolarizedgasMRIismorestraight-forward
toconductinhumansubjects,whocaninhaleandholdtheirbreath,thanin
uncooperativeanimalswhichmustbeanesthetizedandventilated.Nonetheless,
manyapplicationsareemergingforhyperpolarizedgasMRIinsmallanimals,but
thishasbeenlimitedtoafewcentersthathavetheexpertiseneededtoprecisely
deliverhyperpolarizedgasestosmallanimals.Whilethemajorityofsmallanimal
hyperpolarizedgasMRItodatehasbeenconductedinrabbits13-15,guineapigs16,
andrats17-22,thereisalsoacompellingneedtoimagemicegiventheirprominent
roleinbiomedicalresearch.Thispresentsevengreaterchallengesfor
hyperpolarizedgasMRIbecausecomparedtorats,mouselungvolumesare10-fold
smaller,breathingrateis2-foldfaster,andhigherresolutionisrequiredtovisualize
theirairways.
Deliveryofhyperpolarizedgasesforsmallanimalimagingrequiresadedicated
ventilatorthatcanbeusedinproximitytoanMRmagnet.MR-compatible
ventilatorshavebeenavailablesincethemid80stofacilitatesmall-animalproton
imagingofthelungandintegratethecapabilitytoadministergaseousanesthesia,
controlbreathingandtriggerimaginginsynchronywiththerespiratoryandcardiac
cycles23-27.Specifically,itwasrecognizedthathigh-resolutionimagingofthesmall
animallungrequiredbuildingupimagesovermultiplebreaths,whichinturn
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requiredrepositioningthelungwithhighprecisionduringeachcycle.However,
theseventilatorswerenotdesignedtodeliverhyperpolarizedgases,whichmustbe
handledusingonlyspecificmaterialsthatpreservenuclearspinpolarization28,29.To
thisend,Hedlundetal,pioneeredthefirstventilatorsthatcoulddeliver
hyperpolarizedgasesinawell-controlledfashion,whileusingcomponentsthat
avoideddepolarization.Theseventilatorsenabledthefirstinvivo3Heimagesof
guineapiglungs16,andsubsequentimprovementsenabledthedeliveryofasmaller
tidalvolumeinrats30.Theseventilatorsreliedonacustom-made,pneumatically-
controlledvalvepositionedclosetotheanimal,containingseveraldelicateflexible
membranes31-33.Acommercialvalverecentlybecameavailable34.However,the
intricatedesign,rigorousfabricationrequirementsorphysicalsizeofthesevalves
limitedtheiradoptionatothercenters.
Recently,Chenetal.introducedadifferenthyperpolarizedgasventilator22that
eliminatedtheneedforacustomdeliveryvalve.Thischangesignificantlysimplified
thedesign,andwiththereductionofdeadvolumesandcontinuedevolution,
permittedhyperpolarizedgasMRItobecomepossibleinmice35.Thisventilator
designhasbeenusedbyourlaboratorytoconductstudiesusing3Heand129Xe,in
bothratsandmice36,37.Ourrecentstudiesusingbronchoconstrictivechallengeto
studyairwayshyperresponsivenessinmice38haveledustointroduceseveralnew
designelementsthatmaketheconstantvolumedeliveryofhyperpolarized3He
morerobustandpermitquantitativeanalysis39.Furthermore,thepaucityandcost
of3Heandthefrequentuseofexpensiveisotopicallyenriched129Xecreateastrong
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incentivetorecapturetheexhaledgasesafterimaging.Hence,itistheobjectiveof
thismanuscripttoclearlylayoutthekeydesignaspectsofthissimpleandrobust
ventilatorandrecapturesystem,toprovideanexperimentalvalidationofits
performance,andtoincludeacomprehensivelistofpartstoenableduplicationby
otherswishingtoconductpreclinicalhyperpolarizedgasMRimaging.
ConceptualOverview
Theventilatorisdesignedtodeliveramixtureofnitrogenandoxygenduring
normalbreathing(usually80%N2and20%O2)andtosubstitutehyperpolarized
gasinplaceofnitrogenduringhyperpolarizedgasMRI40.Asshowninfigure1,the
deliveryofnitrogenandoxygeniscontrolledbyfast-switchingsolenoidvalvesthat
resideinthe0.1Tfringefieldofthe2Teslamagnet.Afterpassingthroughthese
valves,thebreathinggasesaredeliveredthroughalong,butlow-deadvolume
polymertubetotheanimalinthemagnetbore.Asimilartubedirectsexpiredgasto
theexhalevalve,alsoresidinginthefringefield.Aswithmosthyperpolarizedgas
ventilatordesigns,thehyperpolarizedgasisdeliveredfromaTedlarbag,whichis
housedinsidearigid,pressurizedcylinder.
Akeydesignrequirementfortheventilatoristorepeatedlydeliverallnecessary
gasesinprecisevolumes,withoutneedingamixingvalvethatoperatesclosetothe
animalstrachea.Thisrequirementismetbyflowingthegasesfromapressure
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muchhigherthanphysiologiclungpressure(severalpsig),throughaprecisionhigh-
impedanceflowconstrictortoachieveawell-definedflowrate.Thetidalvolumeof
eachgasisthendeterminedbytheproductofthisflowrateandthedurationfor
whichthedeliveryvalveisopened(slightlyincreasedbymechanicaldeadspace).
Thisdesignensuresthatthegasflow,andthusthetidalvolume,aredominatedby
theimpedanceoftheflowrestrictorandarelargelyunaffectedbytheimpedanceof
theconnectingtubing,oranychangesinlungimpedanceduringimaging.
Theinspirationphaseendswhenthevalvescontrollingtheflowofoxygen,
nitrogenorhyperpolarizedgasareclosed,initiatingabriefbreath-holdduring
whichimagingdataistypicallyacquired.Afterthis,thesolenoidvalvecontrolling
exhalationisopenedtoinitiatepassiverelaxationofthelungsbacktofunctional
residualcapacity.Formice,typicaltimingoftheventilatorycycleisabreathingrate
of100breathsperminute,with150msforinspiration,a150msbreath-hold,and
300msforexpiration.
Theoperationofthehyperpolarizedgaslineisslightlydifferentfromthe
oxygenandnitrogenlinesbecausethehyperpolarizedgascannotpassthrougha
typicalmetallicsolenoidvalvewithoutsubstantialpolarizationloss.Hence,the
deliveryofthehyperpolarizedgasiscontrolledusingarapidlyswitchingpneumatic
valveconstructedentirelyfromTeflon.Thepneumaticvalveisopenedandclosed
bypressurechangescontrolledbyasolenoidvalve.Additionally,theflowrestrictor
usedonthehyperpolarizedgaslineismadeofsapphireembeddedinnylon;both
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materialsarenon-depolarizing.Infigure1,thepartsoftheventilatorthatmustbe
constructedfromnon-depolarizingmaterialsareindicatedbyaboldline.They
includethehyperpolarizedgasvalveandrestrictor,aswellastheinhaletubing.
PhysicalImplementation
Theventilatorisconstructedusinginexpensive,off-the-shelf,fast-switching
solenoid-actuatedvalves(modelEC-2-12-H,Clippard,Cincinnati,OH),whichcontrol
theflowofoxygen,nitrogen,exhalation,andtheactuationofthepneumaticvalve
deliveringhyperpolarizedgas.Foreachgasline,thepressureiscontrolledusing
compactpneumaticregulators(modelR7010,AirLogic,Racine,WI).Oxygenand
nitrogenflowthroughbrassflowrestrictors(modelMLP-1-BRtoMLP-5-BR,andL-
6-BRtoL-30-BR,O'KeefeControls,Trumbull,CT).Hyperpolarizedgasflowsthrough
afast-switching,pneumaticallyactuatedvalvewithall-Teflonconstruction(model
PV-1-1134,PartekDivision,ParkerHannifin,Tucson,AZ)andanon-depolarizing
sapphireconstrictor(modelF-3-NYtoF-30-NY,O'KeefeControls,Trumbull,CT).
Thesizeoftherestrictordependsonthetidalvolumerequiredbytheanimaland
thetypeofgasadministered(Table1).Asisdiscussedlater,itisimportantto
minimizethemechanicaldeadspacebetweentherestrictorsandthevalves,which
isdonebyintegratingtheconstrictordirectlyintothehosebarb,asshowninfigure
2.
Thenitrogen,oxygen,andhyperpolarizedgaslinesarecombined
immediatelyuponexitingtheirrespectivecontrolvalveintoasingle1-m-long,
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polyetheretherketone(PEEK)inhaleline(modelTPK130,ViciValcoinstruments,
Houston,TX),whichlinkstheventilatortotheanimalinthecenteroftheMRI
magnet.Becausethislinecarrieshyperpolarizedgas,itmustbeconstructedfrom
non-depolarizingmaterials,inthiscase,PEEK.Furthermore,hyperpolarizedgasand
oxygentraveltogetherthroughtheinhaleline,andoxygenisapotentsourceof
depolarization,itiscriticaltolimittheirinteractiontimebyminimizingthedead-
volume.Inoursystem,thedeadvolumeoftheinhalelineis0.4ml(inner-diameter
1/32in).Duringtheadministrationofhyperpolarizedgastoamouse,theusualtidal
volumeof0.25mlresultsinaninteractionbetweenoxygenandhyperpolarizedgas
lasting1.6breaths(960ms),whichresultsinlessthan10%polarizationlossduring
transit.
Exhalationproceedsthroughpolyurethanetubingwithaslightlylargerinner
diameter(1/16in)toprovidelowimpedanceandtoensurethatfullexhalation
occursaftereachbreath(modelURH1-0402,Clippard,Cincinnati,OH).Throughout
thebreathingcycle,theairwaypressureismonitoredusingacompactpressure
transducer(modelXFGM-6065KPGSR,FujikuraAmericaInc.,SantaClara,CA)
mountedatthejunctionoftheinhaleandexhalelines.Thissolid-statetransducer
wasselectedbecauseitprovidesrobustpressurereadingsuptoafieldstrengthof7
Tesla,whichisimportantbecauseitresidesintheboreoftheMRImagnetduring
imaging.
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Allsolenoidvalvesinthesystemareactuatedbysolid-staterelays,whichare
computer-controlledbyadatainput/outputboard(modelPCI-6602,National
Instruments,Austin,TX)drivenbyreal-timeinstrumentationsoftware(Labview
8.0,NationalInstruments,Austin,TX).Thissoftwareisusedtosetthedurationof
theinspiration,breath-hold,andexpiration,aswellasthebreathingrate.Italso
providesa5Vtriggersignalthatcanbepositionedanywhereintherespiratorycycle
(usuallyatend-inspiration)toinitiateMRacquisition.Thissoftwarealsocontrols
theanimal'sbodytemperatureandmonitorsheartrate.Althoughitisnotdiscussed
indetailinthismanuscript,thesoftwareisavailableasanon-linesupplementto
thismanuscript,alongwithdetailedplumbingandwiringdiagrams,schematicsof
thepowerdistributionelectronicsandanextensivelistofcomponentsand
suppliers,athttp://www.civm.duhs.duke.edu/VentilatorMouseRat.
Asshowninfigure1b,theventilatorassemblyiscompactandresidesona
portablecart.Duringimaging,theventilatorcartispositionedattheedgeofthe
magnetbore,connectedtotheanimalbytheinspirationandexpirationlines.The
ventilatorcartfacilitatesshuttlingtheanimalbetweentheanimalpreparationarea
andthemagnet,andcanbeusedondiverseimagingsystems.Itisconnectedtoan
externalsupplyofnitrogenandoxygenbyextensiblepneumaticlines,andtothe
computerandpower-distributionelectronicscontrollingvalveactuationbya25-pin
cable(D-subminiatureDB-25).
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GasRecapture
Duringhyperpolarizedgasimaging,exhalationiscontrolledbyadifferent
expirationvalvefromtheoneusedduringnormalnitrogen/oxygenbreathing.From
thisvalve,theexhaled3Heor129Xemixtureisdirectedtoacaptureballoonmadeout
ofmetalizedmylar.Byusingthisseparateexhalevalve,theballoonfillsonlywith
exhaled3Heor129Xe(plusresidualbreathinggases),andminimizesdilutionwithair
thatwouldoccurifcapturealsocontinuedduringnormalbreathing.Afterthe
imagingsession,themylarballoonisattachedtoaseparatestationthatfirst
withdrawsthegasfromtheballoonandthencompressesitintoagascylinderfor
storage(figure3).Thisisaccomplishedusingapneumatically-actuatedpiston(part
number6498k424,McMaster,Aurora,OH).Oncethestoragecylinderhasreached
capacity,itcanbesenttoareprocessingfacilitysothat3Heor129Xeisseparated
fromnitrogen,oxygen,carbondioxideandothergasesandrenderedsuitableforre-
useinsubsequentnon-clinicalorpre-clinicalhyperpolarizedgasstudies.
PerformanceMetricsandConsiderations
Areasonableruleofthumbforsmallanimalventilationistouseatidalvolumeofair
of1mlperminute,pergramofbodymass41,approximately.Atypical25gmouse
canbeventilatedat100breathsperminute,withatidalvolumeof0.25ml.Weuse
thisexampletofurtherdiscusstheperformancemetricsandlimitationsofthe
ventilatordesign.
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Foranyofthegaslines,theflowrateQisgivenby
Qsupplied =P
Rrestrict +Rtubing +Rlung
P
Rrestrict (1)
wherePisthepressuredropacrosstheentireflowpath,andtherelevant
resistancesRarethoseoftheflowrestrictor,thetubing,andthelungs.Bydesign,
wesetRrestrict>>Rtubing+Rlung,tomaketheapproximationvalid.Forreference,we
commonlyemployflowrestrictorswithanimpedanceof1250cmH2Os/ml,
whereasthetubingimpedancewasmeasuredtobe85cmH2Os/ml.Thelung
impedancerangesfrom0.5cmH2Os/mlnormallyto2cmH2Os/mlduring
bronchoconstriction42.
Takingtheoxygenlineasanexample,andassumingventilationofa25gmouse,the
inhalationandexhalationproceedsasfollows.Theoxygenpressureismaintainedat
2psigattheentranceofaflowrestrictorwithanimpedanceof0.26psimin/ml,
resultinginaflowrateof7.7ml/minwhenthevalveisopen.Duringthe150-ms-
longinspiration,0.019mlisdispensedtowardsthemouse.Attheendofinspiration,
thevalveclosesandoxygennolongerflowsthroughthevalve.However,oxygen
continuesflowingthroughtherestrictor:thepressureinthemechanicaldeadspace
betweentherestrictorandtheclosedvalverisesuntilitequilibrateswiththe
drivingpressureof2psig.Atthebeginningofthenextinspirationcycle,thevalve
opensandthisvolumeofcompressedgasisimmediatelyreleasedandaddstothe
nextinspiration.Specifically,thedeadspacewasmeasuredtobe0.030ml.That
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volumeofoxygen,originallycompressedto2psig,expandswhentheoxygenvalve
openstoavolumeof0.034mlclosetoatmosphericpressure.Hence,thetotal
volumeflowingthroughtheoxygenvalve,perinspiration,is0.019+0.034=0.053ml.
Tomitigatethepotentialinjurycausedbytheinstantaneousreleaseofcompressed
gastothelungsandavoidbarotrauma,themechanicalspaceinwhichthis
compressedgasaccumulatesmustbeminimized(figure2).
Thetidalvolumeofoxygenthatactuallyreachesthelungissmallerthancalculated
above:
TVlung=TVsupplied-Vdead
(2)
whereTVlungisthetidalvolumeofoxygendeliveredtothelungs,TVsuppliedisthe
tidalvolumeflowingthroughtheoxygenvalve,andVdeadisthedeadvolume
betweentheanimal'stracheaandthejunctionteeoftheinhaleandexhaleline.This
deadvolumemustbeminimizedtoensuresufficientoxygenationoftheanimal,as
illustratedbyfigure1and2c.Ingeneral,wealsoemployamixtureslightlyricherin
oxygen,consistingof25%O2ratherthan20%.
Theoperationofthenitrogenlineissimilartothatdescribedforoxygen;fora25g
mouse,itdelivers0.2mlofnitrogenperinspiration.Sincebothgasesemergefrom
high-impedanceflowrestrictors,theirvolumessimplyaddlinearlytoprovidethe
totaltidalvolumedeliveredof0.25mlofbreathingmixtureperinspiration.Asis
apparentfromthediscussionabove,theapproximatetidalvolumeofagivengascan
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bedeliveredbyidentifyinganadequateflowrestrictor,andthenmakingsmall
adjustmentsinthedrivingpressuretosetthevolumeexactly.Becauseofthis
operatingprinciple,theventilatorcanbesimplychangedtoventilatemiceandrats,
oradministerdifferenttypesofgas,byswappingtherestrictorsandtubingsizeas
outlinedintable1.
MeasurementofTidalVolume
Thetidalvolumeemergingfromtheendoftheendotrachealtubewasdetermined
byfeedingitsoutputintoaninvertedgraduatedcylinderinawaterbath,and
measuringthedisplacedwatervolumeduringaknownnumberofinspirations,as
illustratedinfigure4a.Thismethodwasusedtoshowthelinearincreasesintidal
volumesofoxygen,nitrogen,xenonandheliumthatareachievedbyincreasingthe
drivingpressure.Inaddition,animportantconsiderationistherobustnessoftidal
volumeagainstincreasinglungresistance.Thiseffectwassimulatedbyplacingthe
outputoftheendotrachealtubesuccessivelydeeperunderwater,therebyincreasing
theback-pressureagainstwhichtheventilatorwasworking.Asshowninfigure4d,
thetidalvolumedeliveredremainsconstantoveraphysiologicallyrelevantrangeof
pressures.
AnimalPreparationandInVivoImaging
Protocolsdescribinganimal-relatedworkandguaranteeinganimalwelfarewere
approvedbytheInstitutionalAnimalCareandUseCommitteeatDukeUniversity.
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Two6-to-8week-oldmaleBalb/C,20-to-25gmicewereanesthesized,underwent
tracheotomyandreceivedtail-veininjectionsofmethacholinefor
bronchoconstrictorchallengeasdescribedbyThomasetal38.
Theanimal'sendotrachealcatheterwasconnectedtotheventilatorprovidinga150
msinspiration,a150msbreathhold,anda300msexpiration,atabreathingrateof
100breathsperminute.Thetidalvolumewascomposedof0.07mloxygen,and
0.15mlnitrogenreplacedbyheliumorxenonduringhyperpolarizedgasimaging.
Heartrateandairwaypressureweremonitoredinreal-time.
Theanimalwasplacedintoadual-frequencyquadraturebirdcagecoil,providing
both1Hand3He,or1Hand129Xesignals(m2mimagingcorp.,Cleveland,OH).The
coilcontainingthemouse,linkedtotheventilatoronarollingcart,wasmovedfrom
theanimalpreparationtabletothemagnet,andthecoilwasinsertedintothebore.
Therodent'sbodytemperaturewasmeasuredbyarectalthermistorandfedback
intoasystemcirculatingwarmairinthemagnetbore,maintainingthebody
temperaturebetween35and37C.
Duringhyperpolarizedheliumimagingofthefirstmouse,onethree-dimensional
imagewasacquiredinfiveminutes(respiratorygatedradialacquisition,FOV
202032mm,TE0.9ms,TR5ms,BW31.25kHz,10,001projections,matrix
128128128,resolution156156250m3).Then,aseriesoftwo-dimensional
3Heimageswereacquiredconsecutively,before,duringandaftermethacholine
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challenge.Thesedatawereacquiredoneimageevery12seconds,foratotaloffour
minutes(respiratorygatedradialacquisition,FOV20x20mm,TE0.9ms,TR5ms,
BW31.25kHz,400projections,matrix128128,resolution156156m2).
Specifically,afteracquiringtworeferenceimages,a250g/kgbolusof
methacholinewasinjectedtoinduceseverebroncho-constrictionandimaging
continuedfor18moreimagestocapturetheresponse.Throughouttheimaging,the
peakinspirationpressurewasrecorded.Aftercompletionofthe3Heimaging,a3D
1Himagewasacquiredtoprovideananatomicalreference.Thisacquisitiontook10
min(respiratorygatedradialacquisition,FOV404040mm,TE0.9ms,TR5ms,
BW31.25kHz,20,001projections,matrix128128128,resolution313313313
m3).
Hyperpolarized129Xeimagesofthesecondmousewereacquiredover20min
(respiratorygatedradialacquisition,FOV303032mm,TE0.9ms,TR5ms,BW
31.25kHz,10,001projections,matrix12812832,resolution2342341000
m3).Thiswasagainfollowedbyan1Himageoftheanatomyasdescribedabove.
DiscussionofVentilatorPerformance
Theventilatordescribedhereisusedroutinelyatourlaboratorytoventilatemice
andrats,sometimesforperiodsoftimeupto6hrs.Inaddition,itenablesthe
acquisitionofHPgasimagesaccumulatedoverhundredsofbreaths,whichrequirea
highly-reproducibletidalvolumeandpositioningofthediaphragm.Itsperformance
forimaging1H,3Heand129Xeinamouseisillustratedbyfigure5.Notethegood
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airwaydelineationinboththe3Heand129Xemaximumintensityprojections.
Similarly,thesharplowerlungborderonthecentralslicefrom3D1Himages
indicatesreproduciblepositioningofthediaphragmoverthe4000breath-holds
requiredtoacquiretheimage.
Figure6illustratestheimportanceofconstanttidalvolumedeliveryovertheentire
durationoftheimageacquisition.Theleft-hand-sideimagewasacquiredwithalow
drivingpressureandlargediameterrestrictor.Duringtheprogressionofimage
acquisition,thetidalvolumedecreasesbecausethebagholdinghyperpolarizedgas
becomeslessandlesscompliantasitempties.Consequently,theimageisseverely
degradedbythegradualdecreaseintidalvolume.Conversely,theright-hand-side
imagewasacquiredwithahighdrivingpressureandasmallconstrictordiameter.
Thedrivingpressureissufficienttoovercomethechangesincomplianceofthebag.
Itenablesthedeliveryofaconstanttidalvolumeresultinginaimagedevoidof
motionartifacts.
Amorestringenttestoftheventilatoristheabilitytodeliveraconstanttidal
volumewhenthelungimpedancechanges,asisthecaseduringseverebroncho-
constriction.Theconsistencyof3Hetidalvolumecanbeassessedfromthe
magnitudeofthefirstdatapointofeachradialviewofk-spaceduringimaging.This
exploitsanadvantageofradialimaging:thecenterofk-spaceisacquiredoneach
viewanditsmagnitudeisdirectlyproportionaltotheamountofmagnetization
inhaled.AplotofthissignalintensityisshowninFigure7foralltheviewsacquired
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duringmethacholinechallenge,alongwiththecorrespondingpeakinspiration
pressure.Notethatthepeakinspirationpressureincreasesduringmethacholine
challengebecausetheventilatedlungvolumeisreducedwhiletheamountofgas
deliveredremainsfixed.The3Hesignalexhibitsaslowexponentialdecayovertime,
whichisattributableto3Herelaxationwithinthebagholdinghyperpolarizedgas.It
showsonlyaslightdecrease(10%)duringbroncho-constriction,indicatingthatthe
ventilatorcontinuestodeliverarelativelyconstanttidalvolumeof3He.
ConclusionandFutureDevelopment
Wepresentaconstant-volumeventilatorthatiseasytoreplicateandimplement.
Itssimplicitystemsfromcombiningoxygen,nitrogenandhyperpolarizedgas
distallyfromtheanimal.Longlinesdelivergastotheanimal'slungs.Byselecting
asufficientdrivingpressureandminimizingdeadvolume,theventilatordelivers
ofaconstanttidalvolumeofgas.Onlyoff-the-shelf,inexpensivecomponentsare
required,allowingrobustoperationandaneasyscalingoftheventilatorto
deliverothertidalvolumes.
Wedemonstratethattheventilatorachievesconstantvolumedelivery,even
duringdifferentstagesofbroncho-constrictionandenablesquantitative
hyperpolarizedgasquantitativeMRIofmiceandrats.Futuretechnical
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developmentsincludetheadditionofgaseousanesthesiaandanebulizerto
deliverdrugsbyinhalation.
Acknowledgements
TheauthorsgratefullyacknowledgeBomaFubaraandYiQiforanimalsupport,
MichaelFosterandErinPottsforusefuldiscussions.WorkperformedattheCenter
forInVivoMicroscopy,aNIH/NCRRNationalBiomedicalTechnologyResearch(P41
RR005959)andsupportedinpartbyR01-CA-142842.
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Figure1
a)Schematicoftheventilator.Fromtheupperrightcorneroftheschematics:
oxygenflowsthrougharegulator,apressuregauge,thenaflowrestrictor.Its
deliverytotheanimaliscontrolledbytheoxygenvalve.Thenitrogenlineoperates
similarly.HyperpolarizedgasisdeliveredfromaTedlarbagwhichresidesinarigid
chamberthatispressurizedbyN2.Thevalveandrestrictor,andtubingthathandle
HPgasarebuiltfrompolarization-preservingmaterials,asindicatedbythebold
line.Allgasesarecombinedatthevalveoutputsanddirectedthroughtheinhaleline
totheendotrachealcatheter.Afterinspirationandabriefbreath-holdforimaging,
gasesareexpelledbyopeningtheventingvalve(normalbreathing)orcapturevalve
(HPgasbreathing).Note:tubingrepresentedbyatriplelineindicatesthatthedead
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volumemustbeminimized.b)theventilatorandallthevalvesarepositionedinthe
fringefieldofthe2Teslamagnetduringimaging.One-meter-longlinesdirectthe
breathingmixturetowardstheanimalatthecenterofthemagnet,orrecollectthe
exhalemixture.
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Figure2
a)Tominimizethemechanicaldeadspacebetweentheconstrictorandthevalve,
thesolenoid-actuatedvalvesoftheoxygenandnitrogenlinesuseaconstrictor
integratedintothebrasshosebarb,highlightedbytheblackovalbackground.b)
Similarly,theflowrestrictorforhyperpolarizedgas(emphasizedbytheblackoval
background)islocatedascloseaspossibletotheTeflon-constructed,
pneumatically-actuatedvalve.c)Thevolumeoftubingfromthejunctiontee
betweentheinhaleandexhalelinetothetipoftheendotrachealcatheteris
subtractedfromthetidalvolumeoffreshmixtureinhaledbytheanimal.Thevolume
waslimitedto0.02ml(blackbackground).
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Figure3
Apparatustransferringtheexhaledmixturecontainedintheballoontoa
pressurizedcylinder.a)Aftertheballoonisconnectedtotherecapturesystem,the
pistonismovedup,withdrawingthecontentoftheballoonthroughacheckvalve
intothechamberofthepiston.Then,whenthepistonispushedin,anothercheck
valveforcesthecontentsofthepistontoflowtowardthecylinderwherethe
recapturedgasisstored.Thegasalsocontainsairandcarbondioxide.b)Mechanical
modelwherethecasingistransparenttoshowthemaincomponents,andc)the
deviceinuseatourlab.
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Figure4
Measurementoftidalvolume.a)Asmallgraduatedcylinderisfilledwithwaterand
placedupsidedowninawaterbath.Theoutputoftheendotrachealcatheter
displaceswaterfromthegraduatedcylinderandallowsthetidalvolumetobe
determinedoverafixednumberofbreaths.Totestrobustnessagainstimpedance
changes,thegasoutputcanbeplacedincreasinglydeeperinthewaterbathto
increasethebackpressure.b)Nitrogenandoxygentidalvolumesincreaseinlinear
proportiontotidalvolume.Theverticalbarwithineachmarkershowsthestandard
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deviationofthedatafittedlinearly.Inthisexample,thetidalvolumeofnitrogen
increaseswithaslopeof0.0440.011ml/psi,indicatinghowpreciselythetidal
volumecanbeadjusted.c)Thetidalvolumedispensedremainslargelyconstant
regardlessofbackpressure.Theverticalbarwithineachmarkershowsthe
standarddeviationofthedatafittedtoastraightline.Thedecreaseintidalvolume
versusbackpressureisnegligible,at0.72.5l/cmH2O.
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Figure5
a)maximumintensityprojection(MIP)ofavolumeimagesetacquiredonaBalb/C
mouseventilatedwithoxygenandhyperpolarized3He.b)MIPfromadifferent
Balb/Cmouse,ventilatedwithoxygenandhyperpolarized129Xe.Becauseof
differentdiffusionproperties,xenonrevealsairwaysmoreprominentlythanhelium.
c)313-micrometerthick1Hslicethroughthelungs.Thesharpedgeatthebaseof
thelungssuggeststhattheventilatoraccuratelyrepositionedthediaphragm4000
consecutivetimes,thenumberofbreathingcyclesrequiredtoacquiretheimage.d)
Therecordedairwaypressureincreasesduringthe150-msinhalation,followedbya
150ms-longplateau,indicatingbreathhold.Theairwaypressuredecreasesduring
the300msexpiration.Eachbreathingcycleisidenticalandlasts600ms.The
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imagingtriggers,located160-msintothebreathingcycle,indicatethestartofthe
partialacquisitionoftheimage,whichlasts100ms(shadedrectangle).
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Figure6
Effectofavariabletidalvolumeonimagequality.a)Athree-dimensional3Heimage
arrayofmouselungswasacquiredusingarespiratorygatedradialacquisitionover
500breaths;thecenter-sliceisdepicted.Alowdrivingpressureof8.5cmH2Owas
usedtomovehyperpolarizedgasthroughalargediameterconstrictor,which
resistanceiscomparabletothatofthelungs.Thiscausedthetidalvolumetovary
andgraduallydiminishoverthecourseof500breaths,asthe3Hesupplybag
depletedandbecamelesscompliant.Asaconsequence,theimagequalityis
degraded.b)Astandardhigh-impedanceconstrictorandadrivingpressureof4.5
psigwereused,allowingthetidalvolumetoremainconstant,thereforerepeatedly
positioningthebaseofthelungsatthesamelocation,andgivingrisetoahigh-
qualityimage.
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Figure7
a)Duringa4-minute-longchallengeinducedby250g/kgdoseofthebroncho-
constrictormethacholineinamouse,aseriesof20two-dimensionalimageswere
acquiredconsecutively,oneimageevery12second.Themagnitudeofthe3Hesignal
(k=0)remainslargelyconstant(fullline),althoughanexponentialdecayisapparent
duetorelaxationwithintheTedlarbag.Thedashedlineshowsthepeakinspiration
pressure,revealingaclearincreaseinairwayresistanceaftertheinjectionof
methacholine,24safterthestartoftheexperiment.Animageofthemouselungsis
shownbeforemethacholineinjection(left),duringbroncho-constriction(middle)
wherethelargerairwayshavedecreasedindiameter(arrows),andafterrecovery
(right).