Consensus statement for inert gas washout measurement using

16 Pages·2013·0.66 MB·English

EurRespirJ2013;41:507–522
DOI:10.1183/09031936.00069712
Copyright(cid:2)ERS2013
ERS/ATS CONSENSUS STATEMENT
Consensus statement for inert gas washout
measurement using multiple- and single-
breath tests
PaulD.Robinson,PhilippLatzin,SylviaVerbanck,GrahamL.Hall,AlexanderHorsley,
MonikaGappa,CindyThamrin,HubertusG.M.Arets,PaulAurora,SusanneI.Fuchs,
GregoryG.King,SookyLum,KennethMacleod,ManuelPaiva,JaneJ.Pillow,
SarathRanganathan,FelixRatjen,FlorianSinger,SamathaSonnappa,JanetStocks,
PadmajaSubbarao,BruceR.ThompsonandPerM.Gustafsson
ABSTRACT: Inert gas washout tests, performed using the single- or multiple-breath washout AFFILIATIONS
technique, were first described over 60 years ago. As measures of ventilation distribution Forafulllistofauthoraffiliations,
pleaserefertothe
inhomogeneity, they offer complementary information to standard lung function tests, such as
Acknowledgements.
spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in
thedetectionofearlylungdamage.Thesebenefits haveledtoaresurgenceofinterestinthese CORRESPONDENCE
techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout P.D.Robinson
DeptofRespiratoryMedicine
equipment specifications, test performance and analysis are lacking. This manuscript provides
TheChildren’sHospitalatWestmead
recommendations about these aspects, applicable to both the paediatric and adult testing LockedBag4001
environment, whilst outlining the important principles that are essential for the reader to Westmead
understand. These recommendations are evidence based, where possible, but in many places Sydney
NSW2145
represent expert opinion from a working group with a large collective experience in the
Australia
techniques discussed. E-mail:[email protected]
Finally, the important issues that remain unanswered are highlighted. By addressing these
importantissuesanddirectingfutureresearch,thehopeistofacilitatetheincorporationofthese Received:
May022012
promising tests into routineclinical practice.
Acceptedafterrevision:
Sept072012
KEYWORDS: Adult, lungfunction, monitoring, paediatric, validation Firstpublishedonline:
Feb072013
CONTENTS Afterpublicationoftheerratuminthe
November2013issueofthe
Introduction .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 508
EuropeanRespiratoryJournal,the
Mechanisms ofventilation distribution inhomogeneity .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 509
onlineversionofthisarticlehasbeen
SBWand MBWtests .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 509 revised.
Equipment specifications . .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 510
Validationof washoutequipment . .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 510
Suitability ofcurrent washoutsystems acrossage groups . .. .. .. .. .. .. .. . .. .. .. .. .. 511
Outcomes .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 511
Functional residual capacity . .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 511
Measuresof ventilation distribution inhomogeneity .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 514
Trappedgasvolume . .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 515
Closing volume andclosing capacity .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 515
Impactofinert gas choice .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 516
Acceptability criteria fortesting .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. 516
c
EuropeanRespiratoryJournal
Foreditorialcommentsseepage500. PrintISSN0903-1936
Thisarticlehassupplementarymaterialavailablefromwww.erj.ersjournals.com OnlineISSN1399-3003
EUROPEANRESPIRATORYJOURNAL VOLUME41NUMBER3 507
ERS/ATSCONSENSUSSTATEMENT P.D.ROBINSONETAL.
Multiple-breath washout .. .. .. .. . .. .. .. .. .. .. .. . . 516 Single-breath washout . .. .. .. . .. .. .. .. .. .. . .. .. . 518
Test termination . .. .. .. .. .. .. . .. .. .. .. .. .. .. . . 518 Future work and conclusions . .. .. .. .. .. .. . .. .. . 518
FRC repeatability . .. .. .. .. .. .. . .. .. .. .. .. .. .. . . 518 References .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. . 520
INTRODUCTION adults) without need for maximal effort, thereby offering
Thearchitectureoftheairwaytreepromotesevendistribution feasibility in all age groups [5, 7, 9, 11–14], driving recent
andoptimalmixingofinhaledgaswithresidentgas.Multiple- strongpaediatricinterest.Despitethisanduniqueinsightsinto
breath and single-breath inert gas washout tests (MBW and disease onset, widespread clinical use has yet to be achieved
SBW,respectively)assesstheefficiencyofventilationdistribu- and further work that is required is limited by a lack of
tion[1,2]:inprinciple,efficiencyofinertmarkergasclearance carefully validated robust commercialwashout systems.
fromthelungs,orgasmixingwithinthetimeframeofasingle
Washout recording systems determine inspired and expired
breath,respectively.Suitableinertgasesmustbesafetoinhale
inert gas volumes, by continuously measuring inert gas
attheconcentrationsused,notparticipateingasexchange,and
concentrationssynchronisedwithrespiratoryflow.Theoverall
not dissolve significantly in blood or other tissues. Options
aims of this standardisation document are to promote and
include both endogenous (nitrogen: N , and argon) and
2 facilitate use of open-circuit washout systems (i.e. minimal
exogenous gases (sulfur hexafluoride: SF , helium: He, and
6 rebreathingofexpiredair),andachievequalityassuredresults,
methane).Markedventilationdistributionabnormalitiesoccur
comparable between laboratories, using validated systems
in obstructive lung disease [3, 4] despite normal ventilatory suitable across age groups and disease conditions. This paper
capacityasmeasuredbyspirometry[5–10].Washouttestsmay is directed to manufacturers, researchers, clinicians and
provideinsightintomechanismsbehindabnormal ventilation respiratorytechnicians.Recommendationsaremadefortesting
distributionandlocalisationofpathology.MBWisparticularly infants, children and adults, reflecting broad clinical and
attractive as it uses either relaxed tidal breathing (mostly in research interest. Application in different age groups may
paediatric settings) or a fixed tidal volume (usually 1L in requireage-specificmodifications,assumptionsandlimitations.
TABLE 1 Keyrecommendations fromthis standardisation document
Recommendationscontainedinthisdocumentarebasedonevidencewhereavailable.Ifnoevidenceexists,therecommendationsarebasedonexpertopinion,
andwillcontinuetoevolveovertimeandbeupdatedinfuturedocumentsasfurtherinsightisgained.
SBWandMBWtestingoffercomplimentaryinformation,butthechoiceoftestusedmaybeageanddiseasedependent.Dependingonthepathologyunderstudy,
relationshipsbetweenMBW-derivedindicesmayhelpidentifythetypeofstructuralchanges.
Aseriesofindividualequipmentcomponentrecommendationsareprovidedinthisdocument.Itis,however,unlikelythatallindividualcriteriaoutlinedwillbefulfilled
byanyonesystem,whichiswhyoverallsystemperformanceduringvalidationandsubsequenttestingisthecentralaspectofimportance.
FRCmeasurementvalidationisanessentialstepandshouldassessallthestagesofthemeasurementincludingpost-dataacquisitionprocessingprocedures,
suchasBTPScorrection.FRCmeasurementaccuracydoesnotensureaccuracyofallotherderivedindicesandbiologicalcontrolmeasurementsandmonitoring
isessential.
Responsibilityforcommercialsystemvalidationandongoingreliabilityofsystemperformanceshouldliewiththemanufacturer.However,closevigilancebytheend
userisessential.Biologicalcontrolmeasurementandmonitoringduringsubsequentclinicalandresearchtestingisanessentialcomponentofthis.
FRCandventilationinhomogeneityindicesmustrelatetothesamegeometricreferencepointintheairstream.FRCend-pointformeasurementduringthewashout
shouldcorrespondtotheendoftestthresholdusedforventilationinhomogeneityindexanalysis,e.g.LCIthreshold.
ThemethodofFRCdetermination,indicesofventilationdistributioninhomogeneitycalculation,andanycorrectionsperformed(e.g.VTorVC)mustbeclearly
described.Bothcorrectedanduncorrectedvaluesshouldbereportedtofacilitateapriorianalysisinthefuture.
Suitabilityofopen-systeminertgaswashoutequipmentforuseindifferentagerangesisdeterminedbytheoverallcontributionofcharacteristicssuchasequipment
deadspaceandanalyserdynamicproperties.
Thechoiceofinertgasusedisdependentonmanyfactors,butimpactsontheresultsobtained.Normativevaluesareinertgasspecific.Comparisonofmultiple
simultaneouslymeasuredinertgasesmayprovideadditionalinformationaboutthelocationofunderlyingpathology.CorrectionfortissueN2diffusionintothelung
isnotcurrentlyrecommendedduetoalackofappropriatedatatobasecorrectionson.
Avarietyoffactorsmayleadtodifferencesinreportedwashoutindicesbetweencentresandexperimentalconditionsunderwhichnormativedataareobtained
shouldbeclearlydescribed.
Qualitycontrolduringtestingiscriticalandextendsbeyondequipmentperformanceandsoftwarefeedbacktoalsoincludecloseobservationbytheoperator
ofthesubject’sbehaviourduringtestingandhowthisaffectsthedataobtained.Adequateoperatortrainingandappreciationofallfactorsinfluencingtestresults
isessential.
Breathingpatternsduringtestingshouldbekeptsimilarbetweensubjectstofacilitatecomparisonofresults.Inadultsthisisachievedbyusingstrictbreathing
regimenswherefeasibleandinyoungerchildren(agedf16yrs)bydistractiontoencouragerelaxedtidalbreathing.
TheendtestthresholdusedforMBWtestswilldependontheventilationdistributionindex(orindices)beingreported.
FormalFRCrepeatabilitycriteriaforMBWindicesshouldnotberoutinelyapplied,butFRCvalueswithin10%shouldbeviewedasencouraging.FRCvalues
differingbymorethan25%fromthemedianofthreetestvaluesshouldbeexcluded.
SBW:single-breathwashout;MBW:multiple-breathwashout;FRC:functionalresidualcapacity;BTPS:bodytemperature,ambientpressure,saturatedwithwater;LCI:
lungclearanceindex;VT;tidalvolume;VC:vitalcapacity;N2:nitrogengas.
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4405 SIII N2 %·L-1 a) 10..050000 Volum
e
35 0.000 L
30 III 75% VT,exp IV b) 80
70
% 25
60
2
N 20 % 50
25% VT,exp 2 40
15 N 30
20
10
II 10
5 0
I 0 30 60 90 120 150 180 210
0 Time s
0.0 1.0 2.0 3.0 4.0
Volume L
FIGURE 2. Exampleofatypicalmultiple-breathwashout(MBW)trace.Time
FIGURE1. Exampleofatypicalsingle-breathwashout(SBW)trace.Nitrogen seriesdisplayofa)volumeandb)nitrogengas(N2)fromanN2MBWtestina
female aged 15yrs with cystic fibrosis. Stable breathing and end-tidal inertgas
gas(N2)expirogramshowingcalculationofphaseIIIslope(SIII)inavitalcapacity concentrationareseenpriortocommencingthewashoutphase.
SBW test in a60-yr-old smoker. SIIIis calculated between 25% and 75% of the
expiredvolume(SIII4.4%?L-1),toavoidthecontributionofphaseIV.Thefourphases
CDI results from differences in specific ventilation between
oftheexpirogramarealsodemonstrated:phaseI(absolutedeadspace),phaseII
lung units sharing branch points in the conducting airway
(bronchialphase),phaseIII(alveolarphase)andphaseIV(fastrisingphaseatend
zoneincombinationwithsequentialfillingandemptyingamong
ofexpiration).Closingvolume(CV)istheexpiredvolume(L)fromthestartofthe
these units [24]. CDI contributes to increased SIII in SBW and
upwarddeflectionwherephaseIVstarts,totheendofthebreath.Ifresidualvolume
generates a continuous rise in SnIII through subsequent MBW
(RV) is known, closing capacity (CC) can be calculated: CC5CV+RV. VT,exp:
breaths [25]. Diffusion convection-interaction-dependent inho-
expiredtidalvolume.
mogeneity (DCDI), which occurs in the region of the acinar
entrance, increases SnIII if structural asymmetry is present at
Specificaimsofthisdocumentareto:1)describetheprinciples
branch points (e.g. differences in cross-sectional area and/or
and physiological concepts behind MBW and SBW tests; 2)
subtended lung volumes). In normal adult lungs, DCDI is the
outline equipment requirements, appropriate system quality
majorcontributortoSBWSIII[24]andDCDIcontributiontoMBW
controlandvalidation;3)describeavailablewashoutoutcomes,
SnIIIreachesitsmaximumatapproximatelyfivebreaths[25].
factorsinfluencingtheircalculation,andinsightsprovidedinto
underlying mechanisms of ventilation distribution inhomo-
geneity; 4) provide recommendations and test acceptability SBWANDMBW TESTS
criteria in different age groups; and 5) highlight important SBW and MBW assess ventilation distribution inhomogeneity
futureresearch. atdifferinglungvolumes.ThemostwidelyusedistheN SBW
2
test [1], which involves a vital capacity (VC) manoeuvre
Recommendations will continue toevolve asfurther insightis performedatlowconstantflow(400–500mL?s-1):exhalationto
gained.Clinicalutilityhasbeensummarisedelsewhere[15–19].
residual volume (RV), inhalation of 100% oxygen gas (O ) to
2
Keyrecommendationsaresummarisedintable1.
total lung capacity (TLC), then washout during exhalation
from TLC to RV [1, 26], where SIII is measured over the mid
MECHANISMS OFVENTILATION DISTRIBUTION portion of the expirogram (fig.1). For exogenous inert gas
INHOMOGENEITY SBW,theinertgasiswashedinduringinhalationfromRVto
Ventilation distribution occurs by convection and diffusion TLC, before washout during exhalation to RV. VC SBW SIIIis
[20].Threeprincipalmechanismsgenerateinhomogeneity[21]. influencedtoagreaterdegreebygravitationalandnongravita-
1)Convection-dependentinhomogeneity(CDI)intheconduct- tionalinter-regionaldifferencesingasdistributionandairway
ingairwayzone(i.e.airwaysproximaltoterminalbronchioles) closureduringtheinspiratoryphase[27–29],comparedtotidal
[22].2)Diffusion-limitationrelatedinhomogeneityinpatholo- breathing protocols. Actual peripheral airway contribution to
gicallyenlargedacinarstructures(rare).3)Interactionbetween VCSBWSIIIisuncertain.Modificationbyinitialwash-infrom
convectionanddiffusioninanintermediatezoneatthelevelof functional residual capacity (FRC) to either TLC or a volume
the diffusion-convection front. aboveFRC(e.g.1 L)[30],betterreflectsinhomogeneitypresent
duringnear-tidalbreathingandmaybeamoresensitiveindex
Inadulthealthylungs,thisquasi-stationarydiffusion-convection
ofperipheral airway involvement[31].
front,whichdetermineswherethesemechanismscanoperate,is
thoughttoarisearoundtheacinarentrance[23].Inhomogeneity MBW assesses ventilation distribution inhomogeneity during
ofventilationdistributionisreflectedindelayedMBWmarker- tidal breathing from FRC, by examining inert gas clearance
gas clearance, raised SBW phase III slope (SIII), explained in over a series of breaths. Exogenous gas washout requires an
figure1,andmagnitudeandprogressionofMBWconcentration initialwash-inphase.MBWrequiresonlypassivecooperation
c
normalised phase III slopes (SnIII) through subsequent breaths and minimal coordination, but is more time consuming. It
(fig.2);inthelatter,SIIInormalisationbyexpiredalveolarinert appearstobethemostinformativeofthesetests.Incontrastto
gasconcentrationisrequiredtocompareprogression. MBW,SBWSIIIusingasingleinertgasdoesnotseparateCDI
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and DCDI contributions, though some information about ideally occur across the mainstream to minimise the error
locationofpathologicalprocessesmaybegainedbycomparing introduced by streaming, and be synchronous with flow
simultaneous SBW SIII of inert gases with widely different signal. Mainstream gas analysers generally have shorter rise
molecularmass(asdescribed inthesectionentitled Impactof timesthansidestreamanalysersbutmayintroduceadditional
inert gas choice). SBW may be sufficient for some patient equipment deadspace, which in turn may have detrimental
groups:inpatients forwhomDCDIisthoughtto bethemain effects on ventilation during testing. Short analyser rise times
mechanism, SBW initiated from FRC approximates the first become increasingly important as breathing rate increases,
tidal expiration of a MBW, which contains most of the DCDI suchasinyounginfants.Overallcontributionofcharacteristics
information. Studies directly comparing SBW and MBW are suchasthesedeterminessuitabilityfordifferentageranges,as
rare or non-existent. illustrated by the detailed discussion of current published
systemsasshowninsectionE2.7intheonlinesupplementary
EQUIPMENT SPECIFICATIONS material.
Keycomponentsandprinciplesexistwhendesigningwashout
VALIDATION OFWASHOUT EQUIPMENT
devices (fig.3). Individual component recommendations are
Recommended washout equipment validation is FRC mea-
summarisedintable2andsectionE2intheonlinesupplemen-
surement accuracy: FRC values within 5% of known volume
tary material. It is unlikely that all individualcriteria outlined
foratleast95%ofvalues[32]acrosstherangeoflungvolumes,
willbefulfilledbyanyonesystem,whichiswhyoverallsystem
performance during validation and subsequent testing is the VT and respiratory rates encountered during subsequent
clinical testing [34, 35]. Validation should assess all stages of
centralaspect(table3).Recommendationsforonlineandoffline
measurement including post-data acquisition processing pro-
washoutsoftwarearesummarisedintables4and5.
cedures, such as body temperature, ambient pressure, satu-
Accuratelymeasuredflowandinertgasconcentrationmustbe rated with water (BTPS) correction. Recently, optimised lung
meticulouslysynchronised.Asynchronybetweenflowandgas modeldesign[36]hasincorporatedsimulatedBTPSconditions
signals in real-time measurement is due to gas sample transit forvalidationofbothestablishedandemergingMBWsystems
timefromairstreamtoinertgasanalyserand/orgasanalyser (fig.4) [35] and is the recommended approach. Validation
response time. Inert gas concentration measurements should should be repeated if significant changes in hardware or
Bias flow delivery system for supply of
wash-in and washout gas
Flow meter To fast responding
inert gas analyser
Mouthpiece of
facemask interface
Post-gas sampling
point equipment
deadspace volume
Inert gas
sampling point
Pre-gas sampling
point equipment
deadspace volume
FIGURE3. Schematicillustrationofagenericinertgaswashoutsystem.Thefigureillustratesagenericwashoutsystem.Hardwarerequiredforwashoutisrelativelysimple:
aflowmeter,afastrespondinginertgasanalyser,agasdeliverysystemandapatientinterface.Theequipment-relateddeadspacevolume(VD)canbedividedintopre-andpost-
gassamplingpoints.Post-gassamplingpointVDeffectivelyintroducesasmallrebreathingchamber.Pre-gassamplingpointVDisanextensionofanatomicalVD.
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TABLE 2 Summaryof component recommendations forinert gaswashout system characteristics
Component Recommendation
Flowmeasurement Instantaneousflowaccuracywithin5%acrosstherangeofflowsencounteredduringclinicaltestingandvolumeaccuracy
within3%usingaprecisioncalibrationsyringe.
Sampleflow Ideally,allside-streamwashoutsystemsshouldcorrectforsampleflow.Ifnotperformedorachievable,sampleflow
shouldbeminimised:,20mL?min1forpaediatricand,40mL?min-1foradultapparatuswheregassamplepointis
proximaltoflowmetre.
Volumedrift Accuratecorrectionofvolumedriftisproblematicduetodifficultyseparatingtechnicalandphysiologicalcomponentsto
observeddrift.Whenanexcessivedrift,beyondtherangeusuallyobserved,appears,attemptstoidentifyphysiological
and/ortechnicalcauses(e.g.leaks)shouldbemadeaspartoftheroutinequalitycontrol.
Gasanalyseraccuracy Linearitywithin1%relativeoffullscale(e.g.0–80%is¡0.8%at80%N2)toensureappropriateassessmentofstarting
concentration,andwithin5%relativeofanylowervalue(e.g.0.25%at5%N2)downto1/40ofthestartingconcentration.
Initialassessmentshouldincorporatebothdryandhumidconditions.Monitorgasanalyseraccuracy,stabilityandlinearity
annuallyusingatleastthreereferencepointsofgasconcentration.
Gasanalyserrisetime A10–90%analyserrisetimeof,100msisrecommendedacrossallagegroups.
Datasamplingfrequency Datasamplingshouldideallybeo100Hzforbothflowandinertgasconcentrationmeasurement.
Synchronisationofflowandgas Alignmentaccuracywithin10msoronesample(whicheverislonger).
signals
Equipment-relateddeadspace Totalequipmentdeadspaceforyoungchildrenshouldbe,2mL?kg-1bodyweight,andideally,1mL?kg-1ininfants.
Recommendationsshouldbeadheredtoinoldersubjects,untilfurtherevidenceisavailable.Anupperlimitof70mL
shouldbeadheredtoforadultsincludinghygienefiltersifused.
Equipment-relatedresistance ShouldbeminimisedforbothinspirationandexpirationtoavoideffectsonbreathingpatternandFRCduringtest.
ThetableisexpandedwithfurtherexplanationinsectionE2.6intheonlinesupplementarydata.N2:nitrogengas;FRC:functionalresidualcapacity.
software algorithms occur [39]. All MBW ventilation inhomo- and CO measurement [35] or changes in molar mass (MM)
2
geneity indices depend on accurate FRC determination, but [34] (see section E3 in the online supplementary material).
FRCvalidationalonemaynotbesufficienttoensureaccuracy Potential for additive errors with indirect measurement
ofderivedventilationdistributionindices.Duringsubsequent places even greater emphasis on adequate quality control.
clinical or research testing, biological controls should monitor
MMbasedmeasurementofSF orHearealsofeasible[44–46].
measurementstability(e.g.threetofourhealthystaffmembers 6
MainstreamMMSF washouthasbeenvalidatedininfants[46,
performing MBW in triplicate, monthly). Marked variation 6
47]; however, lack of validated correction algorithms for
beyond normal observed pattern should prompt further
detrimental temperature and humidity fluctuations limit
carefulevaluation of deviceperformanceand procedures.
utilitybeyondinfancy[48].SidestreamMMwashoutincorpor-
A variety of factors may generate differences in reported ating Nafion1 tubing to stabilise temperature and humidity
indices between centres (table 6), and until standardisation is [49] has been validated for older age groups [38, 50], but
achieved, normative data is at best tentative and likely to be current equipment deadspace volume (VD) precludes use in
inert gas, equipment and software specific. Experimental infancy.
conditions under which normative data are obtained should
Modified photoacoustic analyser based systems have been
be clearlydescribed inmanuscripts.
validatedforuseinadultsandschoolagechildren[9,51],but
are not currently commercially available. Feasibility into
SUITABILITY OF CURRENTWASHOUT SYSTEMS
youngerages will dependon minimisation of longeranalyser
ACROSSAGE GROUPS
response times. Detrimental impact of high sample flow used
The only current system applicable across all age groups is
in these systems on measured flows may be reduced by gas
custom built and based on the respiratory mass spectrometer
sensor placement distal to flow measurement, but requires
(RMS). RMS is the current gold standard gas analyser offering
careful evaluation. Sampling bias flow gas during low
simultaneousmeasurementofmultiplegasesinconstantcondi-
expiratory flows must also be avoided. The commercially
tions,fulllinearity,lowsampleflowandshortresponsetime[39].
availablephotoacousticanalyserbasedclosedcircuitsystemis
Thiscustomwashoutsystemexistsinseveralcentres[5,7,40–42],
not discussed inthismanuscript [52].
butmaybetooexpensiveandimpracticalforwidespreaduse.
OUTCOMES
In MBW using N , inhalation of 100% O may alter breathing
2 2
patterns in infants [43] and subsequent MBW outcomes, but Functional residualcapacity
impact on breathing pattern beyond infancy is considered FRCmeasuredbyMBW(FRCgas)representsthevolumeoflung
c
minimal. As an alternative to emission spectrophotometer N gas, at end expiration (assessed at the breath immediately
2
analyser systems (requiring vacuum pumps), indirect N mea- preceding washout), in direct communication with the airway
2
surementsystemshavebeenproposedbasedonsimultaneous O opening,excludinggastrappedinlungregionsnotventilatedby
2
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TABLE 3 Overallrecommendations forwashout systems
Instantaneousflowwithin5%,andVTandCEVmeasurementaccuracywithin3%.
QualityofgassignalsallowingdeterminationofFRC,end-tidalgasconcentrationandSIIIdownto1/40ofthestartinginert-gasconcentrationwithsufficientaccuracy
andresolution(seebelow).
FRCmeasurementaccuracywithin5%ofthetrueFRCvalue(for95%ofvalues),usingarealisticlungmodelincorporatingBTPSconditionsacrosstheintended
volumerangeandbreathingpatternofthesystem.Commercialsystemsmanufacturersshouldperformthisvalidationbothpriortosaleandwhenever
significanthardwareorsoftwaremodificationsaremadetoexistingdevices.Re-evaluationshouldbeperformedasnecessaryifmarkedvariationoccursbeyond
thenormalobservedpatternforbiologicalcontrolsduringclinicalresearchuse.
Thestaticanddynamicpropertiesofthegasanalyser(accuracy,responsetimeandsignal-to-noiseratio)shouldensurealinearandaccurategassignal.End-tidal
inert-gasconcentrationsshouldbewithin1%relativetoinert-gasconcentrationsatthestartand5%relativetoinert-gasconcentrationsattheendofthewashout
(i.e.at1/40ofthestartingconcentration).
Themanufacturersofcommercialinert-gaswashoutsystemsshoulddemonstratethesefeaturespriortocommercialrelease,withdatabeingincludedwithinsupporting
documentation.VT:tidalvolume;CEV:cumulativeexpiredvolume;FRC:forcedresidualcapacity;SIII:phaseIIIslope;BTPS:bodytemperature,ambientpressure,
saturatedwithwater.
tidal breaths. FRCgasis, therefore, often lowerthanplethysmo- sumoftheintegralproductsofexhaledflowandgasconcentra-
graphicFRC,especiallyinobstructivelungdisease[53].FRCgas tion for each washout breath, corrected for re-inspired gas,
5VIG/Cet,IG(initial–final),where:VIGisnetvolumeofinertgas containedwithintheVDafterthepost-gassamplingpoint(fig.3,
expired,andCetisend-tidalconcentrationofinertgas.VIGisthe seesectionE5.2inonlinesupplementarymaterial).
TABLE 4 Recommendations foronline washout software
Softwaretodisplayflow,volumeandrespiratoryratemonitoringareessentialforbothfixedbreathingprotocols(SBWandMBWinadultsand
olderadolescents)andtomonitorandstabilisetidalbreathinginyoungersubjects
VolumetimeseriesdisplayofBTPSadjusteddatashouldbeofsufficientlengthandsizetodetectvolumedrift
Differentiatingtechnicalcausesfromphysiologicalcausesofvolumedriftmaybedifficult
Suddenstepchangesinvolumemayindicateleak
Graphicaldisplayofinertgasconcentrationtracesbothduringthewash-inandwashoutphases
Toassesssuitabilityoftimingtostartthewashoutphase
Tomonitorforleaks(seetable5),thisshouldincludeacleardisplayofthe‘‘zero’’inertgasbaselineconcentrationlevel,whichmaynotbeachievedincases
suchasinsufficientwashoutassupplyorleak;ifanautomatedcorrectionofdeviationfromzerobaselineisperformedbythesoftware,themagnitudeofthis
deviationcorrectionmustbeclearlyvisibletoalerttheuser
Accuratebreathdetectionofstartandendofinspirationandexpirationadheringtoexistingstandardsforidentificationoftidalbreaths[32,33];
thesestandardsweredevelopedforinfantsbutareextendableforapplicationinadults
Distinguishingstartandendofinspirationsandexpirationsfromminorfluctuationsinflowduringpausesandirregularbreathingisusuallyaccomplished
usingflowthresholdsbutacombinationofflowandvolumebasedcriteriamaybebetter
Accuratedetectionofend-tidalinertgasconcentration
Averageover5–10samples(or25–50ms),endingfivesamples(or25ms)beforetheendofexpiration(seesectionE4.1intheonlinesupplementarydata)
Alternativelyaverageover95–98%oftheexpiredvolume
IfSnIIIprogressionisbeingmeasuredthendisplaythebreath-by-breathinertgasexpirogramtoallowtheusertoensuresufficientSIIIisvisible
(o50%oftheexpiredVT)
Toaidtheuserindeterminingwhenend-of-testthresholdsaremet,onlineanalysisshoulddisplay
End-tidalinertgasconcentration
IfSnIIIprogressionormomentratiosarebeingmeasured:FRCandlungturnover(CEV/FRCforeachbreath)asthewashoutproceeds
Tolimitthetimerequiredfortesting,automatedcalculationofthefollowingindicesshouldoccurattheendofeachtest
FRC
Breath-by-breathcalculationanddisplayofVD,aw(qualitycontrolforleakdetection)
Globalventilationdistributionindices
Offlineanalysisandqualitycontrolcanthenbeperformedasrequiredbytheoperator(asdetailedinthesectionentitledValidationof
washoutequipment)
Warningmessagesshouldinformtheoperatorwhenimportantqualitycontrolstepshavenotbeenfulfilled
SBW:single-breathwashout;MBW:multiple-breathwashout;BTPS:bodytemperature,ambientpressure,saturatedwithwater;SnIII:normalisedphaseIIIslope;VT:tidal
volume;CEV:cumulativeexpiredvolume;FRC:functionalresidualcapacity;VD,aw:deadspacevolumeoftheconductingairways.
512 VOLUME41NUMBER3 EUROPEANRESPIRATORYJOURNAL
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TABLE 5 Recommendations for offlinewashout software
Softwaretransparencyfor
Allcorrectionalgorithmsandfactorsappliedtodata(e.g.BTPSandtemperaturemodelling)
Allalgorithmsusedforsubsequentlycalculatedindices
Methodusedtosynchroniseflowandinertmarkergasconcentrationsignals
Normativedataorupperlimitofnormalincorporated,includingdetailsofsourceandpopulationcharacteristics(numberofsubjects,sexdistribution,agerange,ethnicgroup,etc.)
Generalrecommendations
Fullavailabilityofrawdata,calibrateddataandBTPS-converteddatawhichshouldbesavedandreadilyexportableinwidelyacceptableformats,e.g.ASCII(.txt)or.xls
Abilitytoassessaccuracyofflowandinertgasconcentrationsynchronisation,re-measureandmanuallyadjustasnecessary
Abilitytoreviewtidalvolumetracingtoensurecorrectidentificationofbreathdetection(startandend-points),andmanuallyadjustasnecessary
Abilitytoreviewinertgasexpirogramforeachbreath,andmanualadjustmentifnecessary,toensurecorrectestimationof
End-tidalinertmarkergasconcentration
SIIIifSBWorifMBWSnIIIanalysisisbeingperformed
Abilitytoexamineforandcorrectanygas-analyserdriftoccurringduringthetest.Thezerocalibrationpointmaybeusefulasareferenceformanyofthegasesused(N2,CO2,
HeandSF6)whilst100%canbeusedforO2.Anycorrectionappliedshouldbeclearlystated
Ifavailable,monitorend-tidalCO2valuesduringMBWtoscreenforhyperventilation
FRC
FRCismeasuredoverallbreathsofthewashout,andupdatedaftereachbreath,untiladefinedend-pointintime.Theend-pointusedforFRCdeterminationshould
correspondtotheend-testthresholdusedforventilationinhomogeneityindices(e.g.LCIthreshold)
Exhaledinertgasvolumemustbecorrectedforre-inspiredgasfromthepost-gasVDforeachbreath
ReportedFRCisthatmeasuredattheFRCgs.IfotherFRCvaluesarereported,e.g.FRCao(i.e.FRCgs–pre-gassamplingpointVD)thesevaluesshouldbedescribedappropriately
Reportmean,SDandCoVofthreetechnicallyacceptablemeasurements
Ifonlytwotechnicallyacceptablemeasurementsareavailable,reportmeanonly,andstatee.g.‘‘basedontwomeasurementsalone’’
IfFRCvaluesarenotwithin10%ofthehighestFRCvalue,thenalerttheoperator.ExcludeFRCvalueswhichdifferby.25%fromthemedianFRCvalueacrossthethree
tests.ExcludedtestsshouldnotbeusedforcalculationofotherMBWindices
Indicesofglobalventilationdistributioninhomogeneity(e.g.LCIandmomentratios)
CorrectVTforexternalVD(seesectionE6.2intheonlinesupplementarymaterial)
UseappropriatecorrespondingFRCforcalculation
Reportmean,SDandCoVofthreetechnicallyacceptablemeasurements
Ifonlytwotechnicallyacceptablemeasurementsareavailable,reportmeanand%difference,andstate‘‘basedontwomeasurementsalone’’
IfLCIvaluesaremorethan1.0TOapart(highestversuslowest),thenalerttheoperatortoperformfurthertests
SnIIIanalysis(ifperformed)
CalculationofSIIIandSnIII
SIIIlimitssettomaximisethephaseIIIusedforlinearregression,excludingphaseIIandphaseIVcontributions,andbemanuallyadjustable,typically50–95%oftheexpired
volumeinadultsand65–95%oftheexpiredvolumeinchildren
ManualadjustmentoftheSIIIforbreaths,wheremarkedlowfrequencynoise(orcardiogenicoscillations)orphaseIVphenomenaoccurifautomatedestimationsofSIII
ExpiredinertgasconcentrationusedforSIIInormalisation(e.g.meanexpiredconcentrationormeanSIIIconcentration)shouldbeclearlystated
Acceptancecriteriaforbreaths–identifyanddiscardSnIIIvaluesofbreathsthatdonotfulfilthefollowingcriteria
Specifictotidalbreathingprotocols(e.g.paediatrics)
AdequateexpiredvolumeforSnIIIcalculation:volumecorrespondingtoSIIIshouldbe.50%ofexpiratoryVT
Theexpiredvolumeshouldnotbeexcessive:volumecorrespondingtoSIIIshouldnotbe.75%ofexpiratoryVT
Note:totryandachievesuitablebreaths,aninitialtidalbreathingrangeof10–15mL?kg-1canbeusedbutmayneedtobeadjustedfortheindividualpatientdepending
ontheexpirogramseen
SpecifictoadultprotocolsusingVTof1L
Expiredvolumeshouldbe.0.950L
Expiredvolumeshouldnotbe.1.4L
AclearSIIIshouldbeidentifiable.FailuretoidentifySIIIduetothepresenceofartefact(e.g.breathhold,cardiogenicoscillations,cough)shouldpromptexclusionofthatSnIIIvalue
WhenSnIIIvaluesareexcludeddonotdiscardthecontributionofthatbreathtootherindices(e.g.FRCandTO),onlytheSnIIIvalue
TestsshouldonlycontributetooverallSnIIIanalysisifatleasttwooutofthreeofthebreathsremainafterSnIIIbreathexclusion.If.1/3ofSnIIIvalueshavebeenexcluded
duetoabovecriteriathenthatentiretestshouldbediscarded
NumberofexcludedSnIIIvaluesandreasonsforexclusionshouldbereported
PresentationofSnIIIdata
DatacollatedfromallacceptablebreathsofthethreetechnicallyacceptableMBWtests
AcceptablefirstbreathqualityonallthreetestsforsubsequentSacincalculation
InTOcalculation,FRCandVTarecalculatedfromthesameairstreamreferencepointusedinventilationinhomogeneityindices(seetheonlinesupplementarymaterialsectionE6.2)
DatadisplayedgraphicallyasSnIII(y-axis)versusTOforeachbreath(x-axis)
SnIIIandSnIII6VT(i.e.VT-correctedSnIII)displayedforeachbreathontwoseparategraphs.
TheseindicesrelyonthefactthatDCDIgeneratesahorizontalasymptoteandCDIdoesnotandarethereforeonlyvalidincaseswhereSnIIIprogressiondoesnotshowa
horizontalasymptote
Clinicalindicescalculation
Sacincalculation
RequiresthreetechnicallyacceptablefirstbreathSnIIIvalues
SacincalculatedasthemeanSnIIIofthethreefirstbreathsminustheScondcontribution(basedonthemeanTOvalueofthethreefirstbreaths)
Scondcalculation
ScondcalculatedasthelinearregressionofSnIIIvaluesbetweenapproximately1.5and6.0TO
Calculate95%CIoftheScondregression,rejectoutlyingvaluesandrepeatlinearregression;datashouldbepooledfromallthreeruns
IfSnIIIanalysisisperformedwithonlytwoorlesstechnicallyacceptableMBWtests,thisshouldbeclearlystatedonthereportandresultsinterpretedwithcaution
SBWSIII
Reportasmean,SDandCoVofthreetechnicallyacceptablemeasurements
Ifonlytwotechnicallyacceptablemeasurementsareavailable,reportmeanandactualdifference,andstate‘‘basedontwomeasurements’’
VCmeasurementsnotwithin10%ofhighestVCvalueacrosstheSBWtests,thenalerttheoperator
ReportbothSIII(%?L-1)andSIII6expiratoryVC(%)separately.
BTPS:bodytemperature,ambientpressure,saturatedwithwater;ASCII:AmericanStandardCodeforInformationInterchange;SIII:phaseIIIslope;SBW:single-breathwashout;MBW:
multiple-breathwashout;SnIII:normalisedSIII;N2,nitrogen;CO2:carbondioxide;He:helium;andSF6:sulfurhexafluoride;O2:oxygen;FRC:functionalresidualcapacity;LCI:lung
clearanceindex;VD:deadspacevolume;FRCao:FRCattheairwayopening;FRCgs:FRCmeasuredatthegassamplingpoint;CoV:coefficientofvariation;VT:tidalvolume;TO:lung
turnovers, calculated as cumulative expired volume/FRC; DCDI: diffusion convection-interaction-dependent inhomogeneity; Sacin: DCDI contribution to first breath SnIII. CDI: c
convection-dependentinhomogeneity;Scond:rateofincreaseofSnIIIfrom1.5–6TOs,alsoCDIcontributiontoSnIII;VC:vitalcapacity.
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TABLE6 Factorsthatleadtovariationinmeasuredindices
between centres andrecording systems
Factor Examples
Equipmentrelated Analyserrisetime
Analyserlinearity
Flowmeasurementlinearity
Sizeofequipmentrelateddeadspacevolume,
includingdistancebetweengasandflow
measurementpoints
Procedurerelated Inertgasused(andconcentration)
Breathingstability
Ageofsubjectstested
Analysisrelated Algorithmsusedforcalculationofindices
BTPScorrectionapplied
Correctionsappliedforequipment-related
deadspace
Driftcorrectionalgorithms
Synchronisationofflowandgasconcentration
signals
Acceptabilitycriteriaapplied(e.g.FRCvalues
within10%)
BTPS: body temperature, ambient pressure, saturated with water; FRC:
FIGURE 4. Recommendedlungmodelforfunctionalresidualcapacity(FRC) functionalresidualcapacity.
validationincorporatingbodytemperature,ambientpressure,saturatedwithwater
vapour(BTPS)conditionsandmimickinginvivoclinicaltestingconditions.Thelung
Measures ofventilationdistribution inhomogeneity
modelconsistsoftwoseparatechambers,aninnerandanouterchamber.The
innerchamberispartiallydivided (communicating atitsinferioraspect)intotwo A large number of ventilation distribution indices can be
compartments:thelungcompartment(A)andtheventilatedcompartment(B).FRC derivedfrominformationcontainedwithinSBWorMBW[21,
volumeisgeneratedbyfillingtheinnerchamberwithdistilledwatertoameasured 54,55](seesectionE6.1intheonlinesupplementarymaterial):
height and calculated from known geometric dimensions. Water in the outer 1)SBWSIII,reflectingcombinedCDIandDCDIcontributions,
chamberisheated(C)suchthatinnerchamberwatertemperaturereaches37uC, unlesssimultaneouslyperformedwithmarkergasesofwidely
andaportableventilator(D)isconnectedtotheventilatedcompartmentoftheinner different MM. 2) MBW global ventilation inhomogeneity
chamberandtransmittedhydraulicpressuregeneratesthelungchamberbreathing indices, reflecting efficiency of marker gas clearance. 3) MBW
pattern:chosentosimulatephysiologicaltidalvolume(VT)/FRC,VTandrespiratory SnIII analysis, distinguishing CDI and DCDI mechanisms. 4)
rateslikelytobeencounteredduringintendedclinicaltesting[35].Forexample, Airway closure and trapped gas volume (VTG) assessment
whilst VT remains similar (8mL?kg-1) across age ranges, FRC changes from from SBWandMBW, respectively.
,20mL?kg-1ininfants[37]to40mL?kg-1inadults[38].Multiple-breathwashout
Depending on the pathology under study, relationships
equipment can be attached to the outlet of the lung compartment (E) during
between MBW-derived indices (e.g. Sacin, Scond and LCI) may
validationtests.
help identify the type of structural changes generating
increased ventilation distribution inhomogeneity [56].
MeasuredFRCcanbecorrectedtorepresentdifferentpointsin
theairstream:FRCattheairwayopeningiscalculatedasFRC
Global measures
measured at the gas sampling point, FRCgs, minus pre-gas
LCI is the most commonly reported MBW index in current
sampling point VD. FRC used in ventilation inhomogeneity
paediatric literature, and defined as the number of FRC lung
index calculations must correspond to a common airstream
turnovers (TO; calculated as CEV/FRC) required to reduce
measurementpoint(seesectionE6.2intheonlinesupplemen-
alveolar tracer-gas concentration to a given fraction of its
tary material).
starting concentration, historically 1/40 (2.5%) [57]. Alveolar
CalculatedFRCmaycontinuetoincreasethroughthewashout, tracer-gasconcentrationhasbeenestimatedinvariousways.In
particularly in subjects with airway disease and in N2-based paediatric studies Cet is widely used, despite potential
MBW (see section entitled Impact of inert gas choice), yet variability inend-tidal point. Identification of end-test thresh-
studiesrarelydisclosewhenFRCmeasurementisdetermined. old for LCI has not been systematically validated, but we
FRCendanalysisthresholdshouldcorrespondtotheend-test recommendusingthefirstofthreeconsecutivebreathswitha
thresholdusedforventilationinhomogeneityindices(e.g.1/40 Cet ,1/40 to avoid premature test termination with small
of starting end-tidal concentration for lung clearance Index breaths. LCI is calculated as the ratio of cumulative expired
(LCI). The effect of variation in FRC end-point on other FRC- volume (CEV) to FRC, with CEV defined as the sum of all
derived indices may be significant. Methodology for reported expiratory VT over the washout including this first post-
FRCvalues should be clearlydescribed. threshold. This introduces a small bias (overestimation);
514 VOLUME41NUMBER3 EUROPEANRESPIRATORYJOURNAL
P.D.ROBINSONETAL. ERS/ATSCONSENSUSSTATEMENT
however, the value of interpolatedormorecomplicatedcurve Scond
fit methods to determine exact threshold crossing values is 0.90 SnIII,measured
unclear.Alternatemethodsusedshouldbeexplicitlystated. 0.80 ▲ SnIII,DCDI
▲ Sacin
Ideally indices should be assessed at airway opening without 0.70
external VD. However, this is, not feasible and VT should be 0.60
ctVhoDerreoccnatlenidnefboesrueprqepullieiapmbmleynentaetrsVytiDmmaaastteeadrpipaflrr)o.opmProiastwte-ga(atseseresasdemicsptpilolianncgEem6p.o2einnintt; -1n %·LIII00..5400 ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
however, pre-gas sampling point VD determination may be S ▲
0.30
challenging,duetostreamingwithinthefacemaskorfilter[58]. ▲
Applied pre- and post-gas sampling point corrections should 0.20
beclearlydescribed.WhereVDcorrectionisimplemented,itis
0.10
advised that both corrected and uncorrected LCI values are
reported. 0.00
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0
In clinical and modelling studies indices, such as LCI, have TO
small but significant relationships to underlying respiratory
patterns (VT, VD and FRC) particularly under disease condi- FIGURE5. NormalisedphaseIIIslope(SnIII)analysis.Multiple-breathwashout
tions[54,59,60].EffectsofvariationinrespiratoryrateandVT recordingillustratingderivedphaseIIIslopeparameters.Measuredconcentration
can be minimised using moment analysis (see section E6.4 in SnIII, (SnIII,measured) for each breath is plotted against its corresponding lung
the online supplementary material). This describesthe degree turnover,calculatedascumulativeexpiredvolume/functionalresidualcapacity(TO),
ofskewnessofthewashoutcurvetotheright,asmeandilution value.ProgressiveSnIIIvaluesincreasethroughouttheTOrangeconsidered.Ifthis
numbers (MDN) or moment ratios [61]. VD-independent doesnotoccur,thequalityoftherecordingshouldbecloselyexamined.Theindex
assessment is feasible by correcting CEV for airways VD ofconvection-dependentinhomogeneity(CDI;Scond),iscalculatedastheincrease
(VD,aw) and using cumulative expired alveolar volume in inmeasuredSnIIIperunitTObetween,1.5–6.0TOperunitTO.Forexplanation
calculations (CEValv; e.g. alveolar MDN [59] and alveolar LCI purposes the diffusion convection-interaction-dependent inhomogeneity (DCDI)
[62]). VD,aw, measured using Fowler or Langley methods (see contributiontotheSnIIIforeachbreathisalsoplotted(SnIII,DCDI)Thisiscalculated
section E4.2 in the online supplementary material) [63, 64], bysubtractingtheCDIcontributiontoSnIIIforeachbreathfromtheSnIII,measuredfor
shouldbebasedonCO2VD,aw,orthefirstfewwashoutbreaths eachbreath.Inotherwords,foreachbreath,SnIII,measuredvalueequalsSnIII,DCDI
ofinertgasVD,aw,asthelatterincreasesduringMBW[25]due valueminusCDIcontribution.SacinisdefinedastheDCDIcontributiontothefirst
to early washout of very well ventilated lung regions with breath SnIII,DCDI. The complete contribution of the DCDI mechanism reaches a
shortpathwaystotheairwayopening.However,momentratio plateaubeyondTO1.5andisequivalenttotheinterceptoftheScondregression
truncation to facilitate between–subject comparison (e.g. to line.TheseindicesrelyonthefactthatDCDIgeneratesahorizontalasymptoteand
8 TO [65]), may detrimentally affect sensitivity [66], and CDIdoesnotandare,therefore,onlyvalidincaseswhereSnIIIdoesnotshowa
feasibility. Healthy subjects may also require longer washout horizontalasymptote.
periods to reach these higher turnover values, and accurate
add to signal noise. Automated SnIII calculation algorithms
measurement may be compromised by limited signal resolu-
exist[80],butsubjectiveobservationisstillnecessarytoreview
tion and high relative noise at the low gas concentrations
estimatedslope accuracy.
encountered.
Trappedgas volume
Normalised SnIIIanalysis
Airway closure occurs in lung units approaching regional RV
MBW SnIII analysis has a theoretical [67], experimental [68],
[81], but may also occur at higher regional lung volumes in
and lung modelling basis [69–72] from morphometric data in
infants,olderadults[82],obesesubjects[83],andinthepresence
healthy adults [22], to distinguish ventilation inhomogeneity
of peripheral airway obstruction. It may be a prominent
arising from DCDI and CDI mechanisms, expressed as the
phenomenon in airway disease. If present, the VTG can be
clinical indices Sacin and Scond, respectively [72] (fig.5). For
measured during MBW by including five inspiratory capacity
SacinandSconddetermination,SIIIandgasconcentrationsmust
breaths after conventional end-test threshold is reached and
be accurately determined down to breaths with very low
measuringthevolumeoflungrecruited(seesectionE6.3inthe
concentrations (see section E6.6 in the online supplementary
online supplementary material). VTG measurement with both
material) andmaynot be feasiblefor allwashoutsystems.
residentandexogenousMBWhasbeenestablishedforinfants
SIIIisdependentonmanyfactors,bothlinearandnon-linear,at and children [84, 85]. Importantly, this method estimates only
least in healthy adult lungs: pre-inspiratory lung volume, thegasvolumesrecruitableduringtheselargebreaths.
inspired and expired volumes, and flow [1, 20, 42, 73–78].
Consequently, these factors should ideally be kept similar Closing volumeandclosing capacity
between subjects to maintain diffusion-convection front loca- Closing volume (CV) and closing capacity require accurate
tion, and allow changes in indices to be linked to changes in determination of SBW phaseIII to phase IV transition (fig.1).
correspondinglungstructures.Breathholdsatend-inspiration CV reflects airway closure occurring preferentially in depen-
c
flattenSIIIandshouldbeminimised[30,63].Thebeatingheart dent lung regions and peripheral airway obstruction [81, 86,
generatesflowpulseswithinairways[79]causingcardiogenic 87]. Relative merits of these indices have been reviewed
gas mixing. Cardiogenic oscillations superimposed onto SIII elsewhere [88]. Although feasible in adults [89], paediatric
EUROPEANRESPIRATORYJOURNAL VOLUME41NUMBER3 515
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utilityofCVislimited[90].Automatedidentificationofphase duringtestingandhowthisaffectsthedataobtained.Adequate
IVisfeasible [91]. operatortrainingandappreciationofallfactorsinfluencingtest
results is essential. Recommended acceptability criteria for
IMPACTOF INERTGAS CHOICE MBWandSBWaresummarisedintables7and8.
Derived indices may differ depending on the gas used for a
numberofreasons.Gasdiffusionrateisinverselyproportional Multiple-breath washout
to the square root of the MM, but convective distribution is
Primary index of interest may differ between paediatric and
unaffected.Consequently,diffusion-convectionfrontlocationis
adulttesting(e.g.LCIandSnIIIindicesinthecurrentliterature,
more proximal for lighter gases versus heavier gases (e.g. He
respectively) influencing test termination criteria and accept-
versus SF MM is 4 versus 146g?mol-1, respectively). Greater
6 ability. Recommendations contained within this document
seriesVDforSF6,comparedtoHe,generateshigherLCIvalues, attemptto providea unified approach.
irrespective of ventilation distribution itself. In healthy lungs
SF6 SIII are greater than He SIII, but may reverse in lung Breathing pattern
pathology[92–94].Inaddition,rateofdiffusiveequilibrationin
Measured FRC reflects lung volume at which washout is
enlarged peripheral air spaces (e.g. emphysema) may differ
commenced(i.e.end-expiratorylevel).Stabilityofrestinglung
depending on gas choice generating differential SIII increase.
volumesbeforeandthroughoutwashoutiscritical [46,48].In
Homogeneityofgasdistributionpresentatthestartofwashout
infants, intrinsic FRC resetting during critical periods, visible
maydifferdependingonwhethernaturallyresidentorexogen-
as sighs, should prompt test exclusion. In general, large
ousgas is used.Measurable differencesmaybe informative.In
inspiratory breaths during washout may mobilise trapped
simultaneousHeandSF measurements,diseaseprocessesdistal
6 gas and small inspiratory or expiratory breaths may result in
totheacinarentrancegenerategreaterabnormalityinSF indices,
6 steeper SIII. End-tidal volumes below FRC may result in
whereasdiseaseprocessesproximaltotheacinarentrancebutin
steeper SIII and occurrence of phase IV, especially in
thezoneoftheconvection-diffusionfrontwillaffectHeindices
obstructivelungdisease.ForSnIIIanalysis,firstbreathquality
preferentially.However,ifdiseaseprocessesaffectSF6andHeSIII (in particular adherence to target inhalation and exhalation
toasimilarextent,norelativeSIIIdifferenceoccurs[95].
volume) iscritical for accurate Sacin.
Advantages of N washout include widespread availability
2
Relaxed tidal breathing has historically been used for global
and affordability of 100% O , and avoidance of patient
2
connection to equipment during wash-in periods between MBWderivedindices.Studiesintroducing adultSnIIIanalysis
tests minimising patient discomfort. N is resident in all lung used a strict 1L VT breathing regimen [101], chosen as a
2
compromise between 1) maintaining physiological breathing
unitsincludingveryslowlyventilatedlungcompartmentsand
conditions, 2) obtaining sufficient phase III to compute its
may offer improved sensitivity to detect abnormality, com-
pared to other inert gases, which may not equilibrate fully slope,and3)havingsufficientSnIIIdatapointsforstatistically
validregressionfrom,TO1.5–6.0[101].Thisstrictprotocolis
withintheseregionsduringwash-in.However,disadvantages
not feasible in all ages, or in more advanced obstructive
alsoexist.Thresholdsatwhichfactorssuchasage,sleepstate
andsedationinteractwith100%O toaffectbreathingpattern disease.Inaddition,duetomarkedvariationsinlungsize,1 L
2
remainunclear.N2isnottrulyinertandtissueN2,presentdue may greatly exceed normal VT and not be appropriate. In an
to high atmospheric N partial pressure, diffuses from blood attempt to implement SnIII analysis in younger ages during
2
into alveoli along concentration gradients. This diffusion is regular breathing (typically aged f16yrs), the following
greatest in well-ventilated lung regions washed out during criterion forbreath acceptability, basedon asimilar principle,
initialportionsofthetest,andcontributetoexhaledN laterin is proposed: each breath must have sufficient phase III to
2
the washout, potentially introducing greater error in longer compute SIII (at least 50% of VT). For tests fulfilling this
tests (e.g. FRC overestimation). Estimation and correction of criterion, volume compensation is then performed on SnIII:
tissueN contributionisdifficultduetolimitedavailabledata SnIII is multiplied by FRC (to correct for differences in lung
2
to base correction [96], and adjustment for tissue N is not size)andthenbyVT/FRC(toaccountforvariationsinSIIIdue
2
currently recommended[97]. tochangesinbreathingpattern).ThisnetmultiplicationofSnIII
byVT(inL)facilitatescomparisonamongsubjectsofdiffering
Whilst differentinert gasconcentrations used intheliterature lung sizes, yet needs to be critically interpreted in any
are safe (e.g. 4% SF and 4% He), additional factors influence
6 particular study setting (see section E6.5 in the online
inert gas selection. SF may have adverse health effects at
6 supplementarymaterial).Whereimplemented,werecommend
higherconcentrations[98]andsignificantgreenhousepotential
thatbothcorrectedanduncorrectedSacinandScondvaluesare
[99].Feasibilityofscavengingfollowingtestingisunclear.SF
6 reported,suchthatposteriorianalysesarepossible,ifandwhen
is not universally approved for testing (e.g. USA and France).
thisorothercorrectionmethodsarevalidated.InsufficientSIII
LowdensityofHerendersitmoresusceptibletoleaksduring
for accurateestimation limitsfeasibility ininfants [105].
testing, which may aid leak detection. Cost of exogenous gas
is increasing in many countries, partly due to increasing Visualbreathingpatternfeedbackmaybeusefultoguideolder
logistical requirementswhen used asa medical gas. adolescents and adults [9] but is problematic in younger
subjects, for whom distraction with videos is recommended
ACCEPTABILITY CRITERIA FORTESTING [6].Measurementsininfantsshouldbeperformedduringquiet
Quality control during testing is critical and extends beyond nonrapid eye-movement sleep, with or without the use of
equipmentperformanceandsoftwarefeedbacktoalsoinclude sedation. No comparative study exists showing the potential
close observation by the operator of the subject’s behaviour effect ofsedationon washoutindices.
516 VOLUME41NUMBER3 EUROPEANRESPIRATORYJOURNAL