JPediatr(RioJ).2017;93(4):313---316
www.jped.com.br
EDITORIAL
Administering
surfactant
without
intubation
---
what
does
the
laryngeal
mask
offer
us?
夽
,
夽夽
Administrac
¸ão
de
surfactante
sem
intubac
¸ão
---
o
que
a
máscara
laríngea
nos
oferece?
Peter
A.
Dargaville
a,baRoyalHobartHospital,DepartmentofPaediatrics,Hobart,Australia
bUniversityofTasmania,MenziesInstituteforMedicalResearch,Hobart,Australia
Inourmanagementofthepreterminfantinneedof respi-ratorysupport, wearecurrentlygrapplingwithcompeting priorities.Avoidingintubationatthebeginningoflife(other than for advancedresuscitation) appears tobe asensible proposition,bothininfants≤29weeksgestation,1and cer-tainlyinthosebeyond29weeks.Ontheotherhand,avoiding intubationmeansforgoingtheusualconduittodeliver sur-factant, the very drug that over the years has been our securityblanketindealingwiththescourgeof respiratory distresssyndrome(RDS).Combiningcontinuouspositive air-waypressure(CPAP)withselectivesurfactantdeliveryina minimally-invasiveprotocol offersagreatdealof promise forpreterminfantsofallgestations,2,3avoidingthepitfalls ofmechanicalventilationnomatterhowexpertlyapplied.
Simplyput,whatisneededisanapproachwherewecan recognizeatanearlystagetheinfantsonCPAPwhohave sig-nificantRDS,andselectivelyadministersurfactanttothese infantswithoutresortingtointubation.Butatpresent,the pathtowardthissimplegoalisbesetbyconfusionand uncer-tainty.Itisnotyetclearwhichinfantstoselect,andwhat totake into account.What combination of CPAP pressure level,FiO2,andage,andforwhichgestations?Willithelp totakeanX-ray4ordoafunctionalsurfactantassay?5
Hav-夽 Pleasecitethisarticleas:DargavillePA.Administering
surfac-tantwithoutintubation---whatdoesthelaryngealmaskofferus?J
Pediatr(RioJ).2017;93:313---6.
夽夽SeepaperbyBarbosaetal.inpages343---50.
E-mail:peter.dargaville@dhhs.tas.gov.au
ing made a decision to give surfactant, the methods for deliveringit aremultiplying,atestamenttotheingenuity ofneonatologistsindevelopingnewtechniques,andalong withthem,newacronyms.6Butseveralkeyquestionshave yettobeanswered:Shouldit bebolussurfactant instilla-tion,oraerosolization,seeminglytheleastinvasivemethod, butnotyet widelyavailable inthe clinic.7 Acknowledging theclinicalavailabilityofbolusadministration,howshould itbedelivered?Intra-trachealviaathincatheterinserted underdirectvision,orsupra-glotticviaalaryngealmask air-way(LMA)orbypharyngealdeposition?Shouldanalgesiabe used,oravoided?
A study in this issue of Jornal de Pediatria examines howsurfactantinstillationbyLMAcompareswith adminis-trationafterintubationinpreterminfantsat28---35weeks gestation.8 In a single-center randomized controlled trial (RCT), infants with RDS managed on CPAP and reaching treatment criteria (based on respiratory symptomatology and oxygen requirement) were randomized to receive surfactant via LMA or endotracheal tube (ETT). Those in theETT group werepre-medicated withremifentaniland midazolam, and extubation occurred at an unspecified time (but some hours) after surfactant administration. Redosingof surfactantwasaccording tospecified criteria. The primary outcome was the proportion of infants in whom FiO2 was ≤0.30 at 3h post-intervention, assessed irrespectiveofwhetherintubatedoronCPAP.Thisprimary outcome wasreached by 20 out of 26 infants in the LMA group(77%)and17of22intheETTgroup(77%),withthe trial stoppedshortof thecalculated 30 infantsper group
http://dx.doi.org/10.1016/j.jped.2017.02.001
0021-7557/©2017SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND
314 DargavillePA
inviewofequivalenceinthisoutcomeatinterimanalysis. Redosingofsurfactantwasrequiredin23%and18%ofthe LMAandETTgroups, respectively.Onlyaroundhalfofthe LMAgroup ultimatelyavoidedintubation, andthetimeof mechanical ventilation was longer in these infants than in the ETT group. The study was not powered to detect differencesinotherin-hospitaloutcomes.
The study by Barbosa et al. has the strengths of ran-domizedcontrolleddesign,asoundresearchquestion,and application of failure and redosing criteria to help clini-ciansactinanunbiasedmannergiventhelackofblinding. Weaknesses of the study include the small sample size, and the comparison of physiological indicators (e.g. FiO2 andSilverman-Anderson score)that have different mean-ingsinventilatedandnon-ventilated infants.Additionally, theestimateofsurfactantdeliverytothelung(administered volumeminusaspiratedgastricfluidvolume)isof question-ablevalueanddoesnotappeartohavebeenvalidated.The measure assumes that any gastric fluid aspirated is undi-luted surfactant,and that all the surfactantdeposited in thestomachwillbeaspirated.Neitherassumptionislikelyto hold,renderingthemeasuretooimprecisetogiveacredible answertothequestionofhowmuchsurfactantwasactually deliveredtothelung.
ThestudybyBarbosaetal.addstoabodyofevidence on surfactant administration by LMA that has burgeoned in the past year. It is one of two recent RCTs that have comparedLMAadministrationwithsurfactanttherapyafter intubation.8,9TheotherwasostensiblyacomparisonofLMA surfactantwiththeintubate-surfactant-extubate(INSURE) approach,exceptthat narcoticpremedication usedinthe INSUREgroupledtodifficulties withextubation,and pre-determinedthatmoreinfants inthis groupwouldachieve the primaryoutcome (need for mechanical ventilation or naloxonewithin1h).9 Insome other respects thefindings weresimilarinthesetwotrials,includingtheobservationof aratherhighrateofsurfactantredosingafterLMA adminis-tration(38%inthetwostudiescombined).Afigureofaround 20%mightbeexpectedininfants ofgestation≥28weeks,
bothwithETTadministrationorbythincatheter.10
TwootherRCTshavecomparedsurfactantadministration byLMAwithcontinuationofCPAPininfants≥28weeks11,12; in one case, the results as yet have only been reported in abstract form.12 The design of these two studies was similartoothersexamininglessinvasivemethodsof surfac-tantdelivery,13,14withthethresholdforenrollmentbeingan FiO2above0.30,andthecontrolgroupremainingonCPAP withoutsurfactanttherapy.Bothstudiesconcludedthat sur-factant seemed to be successfully administered by LMA, afterwhichintherecentstudybyRobertsetal.therewas areductionintheneedforintubationpost-intervention.12
Sobywhatyardstickshouldwegaugetherelativemerits ofLMAadministration,alongwiththeothernewmethodsof surfactantadministrationinthenon-intubatedsubject?The followingmeasuresaresuggested:familiarity(ofthe tech-niquetotheproceduralist),applicability(ofthemethodto thetargetpopulation),tolerability(theprofileofunwanted effects),andcapability(ofthetechniquetodeliver surfac-tanttothelungandoptimizeitsdistribution).
Using the above rubric, surfactant administration by laryngeal mask has a mixed scorecard. Whilst the LMA is increasingly promoted as a tool for
facilitat-ing resuscitation,15,16 many neonatologists and neonatal traineeshavelittleornofamiliaritywiththedeviceorits techniqueofinsertion.Learningtheessentialsmaybeonly amatteroftraining,butaswithmostneonatalprocedures, full mastery of laryngeal mask placement will inevitably require some good and bad experiences. In this respect, surfactantdeliverybyLMAiscurrentlytrumpedbytracheal catheterization,becausedirectlaryngoscopyisfamiliarto any neonatal proceduralist, and the insertion of a thin catheterthroughthevocalcordsisnotdissimilartoinsertion ofanendotrachealtube.
Themeasureofapplicabilityfindssurfactantdeliveryby LMA in a thorny position, becauseas of now the method cannotrealisticallybeusedininfants<28weeksgestation and<1.2kg,whorepresentasubstantialproportion(atleast one-third)ofallpreterminfantsdestinedtorequire surfac-tanthavingstartedlifeonCPAP.17SoifanLMAistobeusedto deliversurfactantinthoseabove1.2kg,anothermethodwill beneededforsmallerinfants,andproceduralcompetency willneedtobemaintainedfortwotechniques.Ontheother hand,LMAplacementmaybeeasierinawakespontaneously breathinginfantsabove1.2kgthandirectlaryngoscopy,with thetoneofthepharyngealmusculaturebeingproblematic forproceduralistsnowaccustomedtousingpremedication, includingmusclerelaxantsfornon-emergentintubation in morematureinfants.18Thispremisehasyettobetestedin ahead-to-headcomparisonofLMAplacementagainstthin catheterinsertion;suchacomparisonwillbeimportantin choosingalessinvasivesurfactantdelivery method appro-priateforthispatientgroup.
It is in relation totolerability that LMA placementfor surfactant instillation has the most promise, potentially involving less directpressureon theanterior hypopharyn-geal wall and less mucosal trauma than during standard laryngoscopy. This form of instrumentation for surfactant delivery maythusbeappliedwithfewersideeffects,and without the need for sedation. Indeed,reported rates of reflexbradycardiaintheLMAstudies(0---7%)9,19,20doappear tobelowerthanwhatisnotedwithtracheal catheteriza-tion(6---35%),10,13,21althoughtheincidenceofhypoxiadoes notclearlydiffer. Again,onlybydirectcomparisonof the methodswilltherelativefrequencyofunwantedeffectsbe properlyassessed.
The final measure to be applied is whether the LMA is capableof effective deliveryand distributionof exoge-nous surfactant. In advance of definitive information on the fractional delivery of a surfactant dose to the lung, it can be stated that LMA administration is likely to be superior to aerosolization in this respect, given that the latter technique results in <10% pulmonary deposition of theadministeredsurfactantinmoststudies.7Whetheritis superiortosimplepharyngealdepositionisunknown. Assum-ing correct catheter placement, tracheal catheterization assuressurfactantdeliverytothetracheaatthefirstpass, butcertainlydoesnotprecluderefluxbackintothepharynx, asnotedinupto30%ofcases,10andalsoseeninsomeofthe LMAstudies.Theultimate fateofsuchrefluxedsurfactant is indeterminate,butat leastsome ofitwill re-enterthe tracheaduringfurtherspontaneousinhalations.
Surfactantadministrationbylaryngealmask 315
potentially found lacking, because with an LMA, positive pressure ventilation (PPV) is needed to disperse the sur-factantfrom thebowl of theLMA into the lung. Thereis mounting evidencesuggesting that pulmonary distribution and/ortissueincorporationofexogenoussurfactantis bet-ter when achieved by spontaneous breathing rather than applicationofPPV.Clinicaltrialscomparingadministration ofequivalentdosesofsurfactantdeliveredbytracheal cath-eterization(withnoPPV)orbyintubation(withPPV)haveall notedbenefitsoftheformerapproach.22Beyondthelackof anotherexplanation,theargumentthatthesebenefitsare duetobettersurfactantdistributionisstrengthenedbythe findingofa morehomogeneousincreasein aeration when surfactant is delivered by spontaneous breathing23 com-paredwith PPV. Experimental studies in which surfactant distributionhasbeendirectlymeasuredduringspontaneous breathing are few, and the results are thus far contra-dictory. Onestudy in preterm rabbits found better tissue incorporation of surfactant withspontaneous breathing,24 whereasanotherin pretermlambs(n=4 pergroup)found surfactantdistributiontobesomewhatworse,withgreater surfactant deposition in the right upper lobe than with ETT administration.25 The fact that an infant’s respira-toryeffortmayimprovesurfactantdispersionisawindfall we didnot necessarily expectasthis newareaof surfac-tant research opened up. It must now bepursued to the fullest extent, with well-conducted experimental studies that provide clarity onthe mechanism and extent of any benefitofspontaneousbreathinginaidingsurfactant distri-bution.
Insummary,placementofanLMApotentiallylendsusthe opportunitytoadministerexogenoussurfactanttopreterm infants beyond 1.2kg (some of whom who may tolerate directlaryngoscopypoorly),whichwiththeaidofPPV prob-ably enters the lung in high proportion, but may spread less wellthan underconditionsof spontaneousbreathing. Westillneed toknow whetherthetechniquecanbecome widely applicable, how much surfactant actually reaches the lung, and whether in larger studies this approach is superior to continuation of CPAP, or to alternative forms ofsurfactantadministration,includingtracheal catheteriza-tion.Onlywhenthesegapsinknowledgearefilledwillwe fullyunderstand whatthe LMAhas toofferfor surfactant therapyinthepreterminfant.
Conflicts
of
interest
The author is Chief Investigator of the OPTIMIST-A trial, investigating surfactantadministration by tracheal cathe-terizationinpreterminfantsoncontinuouspositiveairway pressure.Forthisstudy,hehasreceivedsupportfromthe RoyalHobartHospitalResearchFoundation,theAustralian NationalHealthandMedicalResearchCouncil,andin-kind supportfromChiesiFarmaceutici.
References
1.SchmölzerGM,KumarM,PichlerG,AzizK,O’ReillyM,Cheung PY.Non-invasiveversusinvasiverespiratorysupportinpreterm infantsat birth: systematic review and meta-analysis. BMJ. 2013;347:f5980.
2.SollRF.Currenttrialsinthetreatmentofrespiratoryfailurein preterminfants.Neonatology.2009;95:368---72.
3.BlennowM,BohlinK.Surfactantand noninvasiveventilation. Neonatology.2015;107:330---6.
4.Tagliaferro T, Bateman D, Ruzal-Shapiro C, Polin RA. Early radiologic evidence of severe respiratory distress syndrome as a predictor of nasal continuous positive airway pressure failure inextremely lowbirthweight newborns. JPerinatol. 2015;35:99---103.
5.FioriHH,FritscherCC,FioriRM.Selectivesurfactant prophy-laxisinpreterminfantsbornat<or=31weeks’gestationusing thestablemicrobubbletestingastricaspirates.JPerinatMed. 2006;34:66---70.
6.Dargaville PA. Innovation in surfactant therapy I: surfactant lavageandsurfactantadministrationbyfluidbolususing mini-mallyinvasivetechniques.Neonatology.2012;101:326---36.
7.Pillow JJ, Minocchieri S. Innovation in surfactant therapy II: surfactant administration by aerosolization. Neonatology. 2012;101:337---44.
8.BarbosaRF,SimõeseSilvaAC,SilvaYP.Arandomizedcontrolled trialoflaryngealmaskairwayforsurfactantadministrationin neonates.JPediatr(RioJ).2017;93:343---50.
9.PinheiroJM,Santana-RivasQ,PezzanoC.Randomizedtrialof laryngealmaskairwayversusendotrachealintubationfor sur-factantdelivery.JPerinatol.2016;36:196---201.
10.Dargaville PA, AiyappanA, DePaoli AG,Kuschel CA, Kamlin CO,CarlinJB,etal.Minimally-invasivesurfactanttherapyin preterminfantsoncontinuouspositiveairwaypressure.Arch DisChildFetalNeonatalEd.2013;98:F122---6.
11.AttridgeJT,StewartC,StukenborgGJ,KattwinkelJ. Adminis-trationofrescuesurfactantbylaryngealmaskairway:lessons fromapilottrial.AmJPerinatol.2013;30:201---6.
12.RobertsKD,FinerNN,RudserKD,BrownR,LamplandAL,Leone TA,etal.Laryngealmaskairwayforsurfactantadministration inneonates.PASAbstracts.2016:4470.2.
13.GöpelW, KribsA,ZieglerA, LauxR, HoehnT, WiegC,etal. Avoidanceofmechanicalventilationbysurfactanttreatmentof spontaneouslybreathingpreterminfants(AMV):anopen-label, randomised,controlledtrial.Lancet.2011;378:1627---34.
14.DargavillePA,KamlinCO,DePaoliAG,CarlinJB,OrsiniF,Soll RF,etal.TheOPTIMIST-Atrial:evaluationofminimally-invasive surfactanttherapyinpreterminfants25-28 weeksgestation. BMCPediatr.2014;14:213.
15.Schmölzer GM, Agarwal M,Kamlin CO,Davis PG. Supraglot-ticairwaydevicesduringneonatalresuscitation:anhistorical perspective,systematicreviewandmeta-analysisofavailable clinicaltrials.Resuscitation.2013;84:722---30.
16.WyckoffMH,AzizK,EscobedoMB,Kapadia VS,KattwinkelJ, PerlmanJM,etal.Part13:NeonatalResuscitation:2015 Amer-icanHeartAssociationguidelinesupdateforcardiopulmonary resuscitationandemergencycardiovascularcare.Circulation. 2015;132:S543---60.
17.DargavillePA,GerberA,JohanssonS,DePaoliAG,KamlinCO, OrsiniF,etal.IncidenceandoutcomeofCPAPfailureinpreterm infants.Pediatrics.2016:138,pii:e20153985.
18.Roberts KD, Leone TA, Edwards WH, Rich WD, Finer NN. Premedication for nonemergent neonatalintubations: a ran-domized, controlled trial comparing atropine and fentanyl to atropine,fentanyl,and mivacurium.Pediatrics. 2006;118: 1583---91.
19.Trevisanuto D, Grazzina N, Ferrarese P, Micaglio M, Vergh-eseC, Zanardo V.Laryngealmask airway usedasa delivery conduitfortheadministrationofsurfactanttopreterminfants with respiratory distress syndrome. Biol Neonate. 2005;87: 217---20.
316 DargavillePA
21.Kribs A, RollC,Göpel W, WiegC,Groneck P,Laux R,et al. Nonintubatedsurfactantapplicationvs.conventionaltherapy inextremelypreterminfants:arandomizedclinicaltrial.JAMA Pediatr.2015;169:723---30.
22.KribsA.Minimallyinvasivesurfactanttherapyandnoninvasive respiratorysupport.ClinPerinatol.2016;43:755---71.
23.van der Burg PS, de Jongh FH, Miedema M, Frerichs I, van Kaam AH.Effect ofminimallyinvasivesurfactanttherapyon lung volume and ventilation in preterm infants. J Pediatr. 2016;170:67---72.
24.Bohlin K, Bouhafs RK, Jarstrand C, Curstedt T, Blennow M, Robertson B. Spontaneous breathing or mechanical ven-tilation alters lung compliance and tissue association of exogenoussurfactantinpretermnewbornrabbits.PediatrRes. 2005;57:624---30.
