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IntroductionTheidentificationofinhalednitricoxide(INO)asase-lectivepulmonaryvasodilator[1,2]togetherwiththefirstreportofthesuccessfulclinicaluseofINOinthetreatmentofpersistentpulmonaryhypertensionofthenewborn(PPHN)[3]haveledtothewidespreaduseandpopularityofthistherapywhichisstillexperimen-talinneonatalandpaediatricintensivecare.
Thepre-sentPhaseIIclinicalstudywasperformedbytheEuro-peanNeonatalandPaediatricNitricOxideStudyGroupinordertoelucidatethedosingrelationshipofINOinnewbornandpaediatricpatientswithpulmo-naryhypertensionandimpairedoxygenation.
Asecondobjectiveofthestudywastoevaluatetheshort-termsafetyofINO.
P.
A.
Lo¨nnqvistInhalednitricoxideinnewbornandpaediatricpatientswithpulmonaryhypertensionandmoderatetosevereimpairedoxygenation:effectsofdosesof3–100partspermillion*Received:15October1996Accepted:9April1997*ThisstudywascarriedoutbytheEurope-anNeonatalandPaediatricNitricOxideStudyGroup(ENPNOSG),seeappendixforfurtherdetailsP.
A.
Lo¨nnqvist())DepartmentofPaediatricAnaesthesia&IntensiveCare,KS/St.
Go¨ransChildren'sHospital,P.
O.
Box12500,S-11281Stockholm,SwedenFAX:+46(8)6721847AbstractObjective:Toassesstheeffectsofinhalednitricoxide(INO)3–100ppmonoxygenationinbothnewbornandpaediatricpatientswithpulmonaryhypertensionandimpairedgasexchange.
Design:Open,prospective,multi-centrestudy.
Setting:Tertiaryneonatalandpaedi-atricintensivecareunitsinuniversi-tyreferralcentres.
Patients:Newborn(ageK7days;n=26)andpaediatric(age8days–7years;n=16)patientswithpul-monaryhypertensionverifiedbyechocardiographyandanoxygen-ationindexof(OI)15–40werein-cludedinthestudy.
Interventions:ThepatientsweresubjectedtostepwiseincreasesindosesofINO(0,3,10,30,60,100ppm).
Measurementsandresults:Theef-fectonoxygenationwasmeasuredbyrepeatedbloodgasanalysis.
ApositiveresponsetoINOwasde-finedasareductioninOIofL25%comparedtobaseline(0ppm).
INOwasfoundtoimproveoxygenationinbothnewborn(p5%priortoinclusion.
12.
Thepatienthadneverhadanormalarterialbloodgasafterbirth,definedasPaO2>45mmHg(>6.
0kPa)andPaCO22.
5%wereobservedintwopatients,butvaluesinexcessof5%werenotobservedinanyofthepatientsexposedtocompassionatetreatmentwithINO.
Theoverallmor-talitywas33%(8/26and6/16inthenewbornandpaedi-atricgroups,respectively).
DiscussionThemajorfindingsofthisstudywerethatbothnew-bornsandolderchildrenwithpulmonaryhypertensionandmoderatetosevereimpairedgasexchangereactwithimprovedoxygenexchangewhenexposedtoINO.
Wealsoobservedatendencytoahigherresponserateatbetween3and100ppmNOinnewborns(77%)com-paredtopaediatricpatients(50%).
Inaddition,thedoseofINOgivingthemaximumdecreaseinOIvariedoverthewholedoserangestudiedinbothgroups,al-thoughdosesK30ppmweresufficienttodecreasetheOIbyL25%comparedtobaselineinthevastmajorityoftherespondingpatients.
Toourknowledge,thisisthemostcomprehensivepaediatricdosingstudywithINOperformedtodate.
TheparticipantsinthisstudyrepresentedsevenEuro-peancountriesinatotalof11neonatalandpaediatricintensivecareunits(ICUs).
Theywerealltertiaryrefer-ralcentres,pioneeringtheclinicaluseofINOintheirre-spectiveareas.
Inspiteofthisinterest,ittookoverayeartorecruit43patients,withsomeICUscontributingpatientsonlyoccasionally.
FromthisweconcludethattheclinicalsyndromesofPPHNandpaediatricARDSwerelesscommonthanexpectedfromclinicalimpres-sion.
Bothlow(<10ppm)andhighdoses(80ppm)ofINOhavebeenobservedtobringaboutanimprove-mentinoxygenationinbothadultandpaediatricpa-tients[6–8],andlastingimprovementsfromasingle,shortexposuretoINO[9],aswellasseverereboundre-776Fig.
2Concentrationsofinhalednitricoxidefirstcausingareduc-tionintheoxygenationindexbyL25%comparedtobaseline(=positiveresponse)Aandconcentrationsassociatedwithmaxi-mumimprovementofoxygenationB;opencolumnsnewborns,fil-ledcolumnspaediatricpatientsactionsuponacutediscontinuationofINO[8,10],havebeenreported.
Inaddition,theintroductionof10-min0ppmpointsbetweeneachnewdosewouldhavedou-bledthetimeofthedosingsequence.
Severelyillpa-tientsareknowntobeunstableandastudydurationof2hwouldthushavemadecomparisonslessreliablebe-tweenearlyandlatedoses.
Basedontheabove,wesawtheneedtostudyseveraldosesfrom3to100ppmINOandchosenottoinclude0ppmINOcontrolpointsbe-foreeachnewdoseofINOand,instead,usedastepwiseincreaseindosagedesign.
Wesawtworeasonstofocusonpatientgroupswithlessseveregasexchangedisturbance(OI15–40,whichisbelowgenerallyacceptedcriteriaforextracorporealmembraneoxygenation):(1)alessunstablepopula-tionwouldallowforbettercontrolledstudycondi-tions,whichwouldbepreferableforbothethicalrea-sonsandgeneralisationofdata;(2)basedonourownpreliminaryresultswithINO[11],earlyadministrationofINOmightimprovethechancesofapositivere-sponse.
Fineretal.
,inaninitialneonataldosingstudy,havereportedavariableoxygenationresponsebetween5and80ppmINO,withaconsiderablylowerresponserateinneonateswithoutsignsofpulmonaryhyperten-siononechocardiography[12].
Westudiedalargergroupofinfants,allofwhomhadverifiedpulmonaryhy-pertensionatinclusioninthestudy.
Inaddition,wealsostudiedtheresponsetoINOinpaediatricpatientsandthestudywasconductedinaccordancewithGCP,whichincludescarefulmonitoringofparticipatingcentresandsourcedataverification.
ResponserateAlthoughnotstatisticallysignificant,weobservedahigherresponserateinthenewborngroup(77%)com-paredtothepaediatricgroup(50%).
Thehigherre-sponserateinnewbornssuggestsapathophysiologywhich,toalargeextent,isduetovascularspasmandextrapulmonaryshunting.
Thesyndromeinpaediatricpatientsismorecomplexwithpredominantlyintrapul-monaryshuntingasseeninadultARDS,whichmightaccountforthe50%responserateseenintheolderpa-tientgroup.
Inbothnewbornandpaediatricpatients,oxygenationcanbeimprovedbyamicroselectiveva-sodilatationinventilatedlungregions[6,8],resultinginimprovedventilation-perfusionmatching.
However,innewbornswithPPHNandseverehypoxaemia,an-otherpotentialmechanismforimprovementinoxygen-ationispresent.
Aminorreductioninpulmonaryarte-rialpressure(PAP),leadingtoamorefavourablePAP/SAP(systemicarterialpressure)ratiowillresultinpartialortotalreversalofright-to-leftextrapulmo-naryshunting(attheatrialorductallevel).
Theselec-tiveactiononthepulmonarycirculationofinhaledva-sodilatorssuchasINOandprostacyclin[13,14]haveauniquepotentialforimprovingthePAP/SAPratiocomparedtointravenousvasodilators.
Thegeneralva-sodilatationinboththepulmonaryandthesystemiccirculationcausedbyvasodilatorsadministeredintra-venouslycarriesasubstantialriskfordetrimentaldete-riorationofthePAP/SAPratio,furtheraggravatinghypoxaemia.
SizeofresponseTherelativechangeinOIvariedconsiderablybetweenpatients,fromapproximately90to15%inbothgroups.
Wecanatpresentonlyspeculateupontherea-sonsforthisadditionalvariation.
Mercieretal.
[15]andKaramanoukianetal.
[16]claimareducedre-sponsetoINOinbabieswithmeconiumaspirationsyn-drome(MAS)andcongenitaldiaphragmatichernia(CDH).
ThishasrecentlybeenfurthersupportedbypreliminarydatapresentedbyKinsellaetal.
[17].
Ourstudynumbersweretoosmalltoallowforsubgrouping,butinourfewpatientswithMASandCDHweob-servedonlyaslightlylowerresponserate(6/9)com-paredtotheremainingpatients(14/17)inthenewborngroup.
DoseformaximumresponseThedoseassociatedwiththemaximumresponsevariedinourstudy.
Therewas,additionally,adiscrepancybe-tweenthedoseturningapatientintoaresponderandthedosegivingmaximumeffect,inbothnewbornsandinpaediatricpatients.
Thisisclinicallyimportant,aspa-tientsshowingamaximumresponseat60or100ppmINOalreadyhadmeaningfulimprovementsatmuchlowerdoses.
Inotherwords,limitingthemaximumdoseofINOto30ppmwouldmeandefining10%ofthepotentialresponders(2/20)asnon-respondersinthenewborngroup.
However,withthesamelimitationindose,nopotentialresponderswouldbemissedinthepaediatricgroup.
AdministeringhigherdosesofINO(60–100ppm)exponentiallyincreasestheamountofNO2formedininspiredoxygen-enrichedgas[18].
InsuchgasmixturesthecorrectmeasurementofNO2concentrationisveryproblematic[19,20],whichmakesclinicalmonitoringunreliable.
IntheSiemens300prototypesystem,NOandNO2concentrationsweremeasuredonexpiredgasafterthemixingchamber.
Thissystemallowedaby-passflowtriggertooperateunhamperedbyinspiratorylimbsamplingofgasformonitoring.
Insubsequentlab-oratorytestingithasbecomeclearthatNO2measure-mentsareextremelytimedependentinnitricoxideand777oxygen-richmixtures(Dr.
U.
Schedin,personalcommu-nication),andthetypeofmonitoringprovidedbysucharesearchprototypeNOdeliverysystemisnolongerrecommended.
WerecordedartefactuallyelevatedvaluesofK7.
9ppmNO2atthemaximumdoseof100ppmNO.
IntermittentinspiratorymeasurementsduringtreatmentwithINOandextensivelaboratorytestinghaveshownthattheactualNO2concentrationspresentintheinspiratorylimbofthe300prototypeiswithinthe2–3-ppmrangeat100ppmNOatanFIO2of0.
90[21].
However,theNOconcentrationsfortheneo-natalandpaediatricventilatorymodesremainadequateduetoasignificantby-passflow.
Intheconstantflowde-liverydevicesamplingwasperformedoninspiratorygasandthemeasuredNO2valuesshouldthusberepresen-tativeinthisset-up.
SincethemajorityofpatientsdisplayaclinicallymeaningfulresponseatdosesK30ppmINO,onlytheexceptionalpatientshouldbetreatedwithhigherdosesofINOandtheexposuretimeshouldbeasshortaspossible.
ProlongedexposuretomoremoderatedosesofINOhasrecentlyalsobeenfoundtocausefunction-alimpairmentofneutrophils[22].
INOisnotaregis-tereddrugandrandomisedstudieshavebeencalledforspecificallytoaddresstherisk/benefitrelationship[23].
Insummary,thisstudyfoundimprovedoxygenationinbothnewbornsandolderchildrenwithpulmonaryhypertensionandmoderatetosevereimpairedoxygen-ationduringexposuretoshort-term,lowdosesofINO.
Wealsoobservedahigherfrequencyofresponseinnewbornsthaninpaediatricpatients.
Inaddition,thedoseofnitricoxideachievingthemaximumdecreaseintheoxygenationindexvariedoverthedoserangestud-iedinbothgroups,althoughonlyalittleadditionalben-efitonoxygenationcouldbeachievedfromusingdosesinexcessof30ppm.
AppendixEuropeanNeonatalandPaediatricNitricOxideStudyGroupStudyDirector&ChairmanofStudyCommittee:P.
A.
Lo¨nnqvist,Stockholm,Sweden.
StudyCommittee:Prof.
H.
L.
Halliday,Bel-fast,UK;Prof.
W.
Kachel,Mannheim,Germany;C.
G.
Frostell,Danderyd,Sweden;G.
L.
Olsson,Stockholm,Sweden.
PrincipalInvestigators:S.
Renolleau,Paris,France;Prof.
H.
Hartmann,Han-nover,Germany;Prof.
B.
Roth,Cologne,Germany;N.
Gullberg,Stockholm,Sweden;J.
McKnight,Belfast,UK;J.
A.
Hazelzet,Rot-terdam,TheNetherlands;J.
Klinge,Erlangen,Germany;S.
Michel-sen,Oslo,Norway;J.
Mulier,Leuven,Belgium;V.
Varnholt,Mann-heim,Germany.
Monitoring,datahandling,andstatisticalanalysis:M.
Jountsenvirta,Norrko¨ping,Sweden;O.
Luhr,Danderyd,Sweden;K.
Uthne,So¨derta¨lje,Sweden;M.
Alenius,Stockholm,Sweden.
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