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Novel Surfactant Administration Strategies in NeonatesAlan de Klerk, MBChBDivision of NeonatologyNemours Childrens HospitalNemours Childrens Hospital Grand RoundsJune 10th, 20151Alan de Klerk, MBChBDivision of NeonatologyNemours Childrens HospitalFINANCIAL DISCLOSURE:

Nothing to disclose

2Recent large RCTsNovel approaches to surfactant administration:CPAP/NIV With Less Invasive Surfactant AdministrationOutline3 Is Chronic Lung Disease in Low Birth Weight Infants Preventable? A Survey of Eight CentersAvery. Pediatrics. 1987Center (3 = Columbia, NY)%4Do Clinical Markers of Barotrauma and Oxygen Toxicity Explain Interhospital Variation in Rates of CLD?Van Marter. Pediatrics . 2000Conclusion: NICU-specific risk of CLD was predominantly associated with the decision to use mechanical ventilation%5Compared practices and outcomes in 452 infants 500-1500g at birth from 1991-1993 at Columbia NY with two Boston hospitals100 from Columbia341 from BostonConclusions:NICU-specific risk of CLD was predominantly associated with the decision to use mechanical ventilationAmong those receiving mechanical ventilation, high inspired oxygen concentrations, high ventilator PIPs, and hypercarbia during the first postnatal week were associated with increased CLD risk

(Debatable) Generalizations!Avoiding/limiting invasive ventilation (within reason) is desirableEven when appropriately or optimally used, all forms of respiratory support are necessary evilsInappropriately used they become unnecessary evils6Non-invasive respiratory support of the neonate is not benign respiratory supportCPAP:Nasal trauma, pneumothoracesNIPPV:Bowel perforationsHHHFNC:Infections, perforated eardrumLFNC:Mucosal trauma, infections

Should we be thinking less invasive respiratory support of the neonate? (Debatable) Generalizations!7Early surfactant with extubation to NCPAP vs. later selective surfactant and ongoing MV is associated with less MV, BPD, and air leakSurfactant by transient intubation using a low treatment threshold is preferable to later surfactant therapy using a higher threshold or at the time of respiratory failure/MVEarly Surfactant Administration with Brief Ventilation vs. Selective Surfactant and Continued Mechanical Ventilation for Preterm Infants with Or at Risk for RDSCochrane Neonatal Reviews. 20078Recent large RCTsNovel approaches to surfactant administration:CPAP With Less Invasive Surfactant AdministrationOutline9610 infantsGestational age 25+0 to 28+6 weeksBreathing spontaneously at 5 minutes after birth, needing respiratory supportRandomized to:CPAPIntubation and ventilationNasal CPAP or Intubation at Birth for Very Preterm Infants (COIN Trial)Morley. N Engl J Med. 2008Nasal CPAP or Intubation at Birth for Very Preterm Infants (COIN Trial)OR (95% CI)0.63 (0.46, 0.88)P = 0.006P < 0.001%Morley. N Engl J Med. 2008NS11Nasal CPAP or Intubation at Birth for Very Preterm Infants (COIN Trial)Morley. N Engl J Med. 2008P < 0.001%P = 0.001NSNS12279 infantsGestational age 27+0 to 31+6 weeks15-60 minutes of ageEvidence of respiratory distress and Rx with O2 in the delivery roomRandomized to:Intubation, surfactant, extubation to NCPAPCPAP alone/selective intubation and surfactantVery Early Surfactant Without MandatoryVentilation in Premature Infants Rx With Early CPAP: A RCTRojas. Pediatrics. 2009RR (95% CI)0.69 (0.49, 0.97)P 0.05Rojas. Pediatrics. 2009RR (95% CI)0.25 (0.07, 0.85)P 0.05NSVery Early Surfactant Without MandatoryVentilation in Premature Infants Rx With Early CPAP: A RCTP = 0.039%14208 inborn infantsGestational age 25+0 to 28+6 weeksNot intubated at birthRandomized within 30 minutes of birth to:Prophylactic surfactant, then extubated to nCPAP within 1 hournCPAP with selective surfactant administrationProphylactic or Early Selective Surfactant Combined with nCPAP in Very Preterm Infants (CURPAP Trial)Sandri. Pediatrics. 201015Need for MV within 5 Days%Sandri. Pediatrics. 2010Prophylactic or Early Selective Surfactant Combined with nCPAP in Very Preterm Infants (CURPAP Trial)RR (95% CI)6.82 (0.86, 53.75)GA:161316 infantsGestational age 24+0 to 27+6 weeksRandomized to:Early CPAP/limited ventilationEarly intubation/surfactant administrationEarly CPAP versus Surfactant in ExtremelyPreterm Infants (SUPPORT Study)Finer. N Engl J Med. 201017%P = 0.01P < 0.001P = 0.03Early CPAP versus Surfactant in ExtremelyPreterm Infants (SUPPORT Study)Finer. N Engl J Med. 201018%RR (95% CI)0.74 (0.57 to 0.98) P = 0.03RR (95% CI)0.68 (0.5 to 0.92) P = 0.01Early CPAP versus Surfactant in ExtremelyPreterm Infants (SUPPORT Study)Finer. N Engl J Med. 201019648 infantsGestational age 26+0 to 29+6 weeksTreatment Groups:PS Group: Intubation, surfactant, ventilationISX Group: Intubation, surfactant, extubation to NCPAPNCPAP Group: NCPAP with selective intubation and surfactantRandomized Trial Comparing 3 Approaches to the Initial Respiratory Management of Preterm Neonates(VON Delivery Room Management Study)Dunn. Pediatrics. 2011%Randomized Trial Comparing 3 Approaches to the Initial Respiratory Management of Preterm Neonates(VON Delivery Room Management Study)Dunn. Pediatrics. 20112126-27 weeks GA: 36 weeks PMARandomized Trial Comparing 3 Approaches to the Initial Respiratory Management of Preterm Neonates(VON Delivery Room Management Study)%Dunn. Pediatrics. 201122Intubation/Ventilation vs. CPAPDeath or BPD at 36 Weeks% 23Intubation/Ventilation vs. CPAPRisk of Death or BPD at 36 WeeksRRCOIN0.87 (0.70, 1.07)SUPPORT0.90 (0.81, 1.00)VON0.84 (0.64, 1.10)Total0.89 (0.81, 0.97)Finer. Hot Topics in Neonatology. 201024VON DR TrialIntubation/Ventilation vs. InSurE%25InSurE vs. CPAPNeed for Mechanical VentilationRR (95% CI)0.69 (0.49, 0.97)P 0.05%NSNSNS26Death or BPD at 36 Weeks% BPD at 36 WeeksInSurE vs. CPAP27InSurE vs. CPAPRRCURPAP1.03 (0.61, 1.72)Rojas0.86 (0.70, 1.05)VON0.94 (0.70, 1.25)Total (+ 3 studies)0.88 (0.76, 1.02)Risk of Death or BPD at 36 WeeksIsayama. JAMA Pediatr. 2015Similar findings for death and air leak 28ConclusionsNon-invasive support (CPAP or InSurE) is at least as effective as invasive supportInSurE is not consistently superior to CPAP aloneLong term outcomes are neededHypothesisWould even less invasive surfactant administration to a spontaneously breathing neonate improve outcomes further?CPAP With Less Invasive Surfactant AdministrationIntrapartum/pharyngeal administrationAdministration via laryngeal mask airway (LMA)Aerosolized surfactantThin catheter administrationIntrapartum/pharyngeal administrationAdministration via laryngeal mask airway (LMA)Aerosolized surfactantThin catheter administrationCPAP With Less Invasive Surfactant AdministrationTen Centre Trial of Artificial Surfactant (Artificial Lung Expanding Compound) in Very Premature BabiesRCT of 328 preterm infants25 - 29 weeks gestation

Procedure:Pharyngeal ALEC or normal saline at birthUp to 3 more doses if intubated DOL #1Ten Centre Study Group. BMJ. 198733Ten Centre Trial of Artificial Surfactant (Artificial Lung Expanding Compound) in Very Premature BabiesTen Centre Study Group. BMJ. 1987%P < 0.02P < 0.0334Technique for Intrapartum Administration of Surfactant without Requirement for an ETTNon-randomized feasibility study23 preterm infants27 - 30 weeks gestation, 560 1804gProcedure:Nasopharyngeal airway suctionedInfasurf instilled into nasopharynx before delivery of shouldersCPAP by mask as breathing initiated, then maintained on CPAP for 48+ hoursKattwinkel. J Perinatol. 200435Technique for Intrapartum Administration of Surfactant without Requirement for an ETTResults:13 of 15 vaginally delivered babies weaned quickly to room air with no further surfactant or intubation5 of 8 C-section babies required intubation, 2 received surfactantConclusion:NP surfactant at birth appears relatively safe and simple, especially for vaginal birthsKattwinkel. J Perinatol. 200436Intrapartum/pharyngeal administrationAdministration via laryngeal mask airway (LMA)Aerosolized surfactantThin catheter administrationCPAP With Less Invasive Surfactant Administration

LMA ProSeal

Standard LMALMA Used as a Delivery Conduit for the Administration of Surfactant to Preterm Infants with RDSFeasibility trial of 8 infantsMedian GA:31 weeks (28-35 weeks)Median BW:1700g (880-2520g)RDS treated with nasal CPAPProcedure:Surfactant administered via LMA without sedation/analgesiaTrevisanuto. Biol Neonate. 200539LMA Used as a Delivery Conduit for the Administration of Surfactant to Preterm Infants with RDSTrevisanuto. Biol Neonate. 2005

P < 0.0140RCT of newborn piglets with lung injury induced by normal saline surfactant washoutOn CPAP via short binasal prongsRandomized to:Surfactant via ETT(n = 8)Surfactant via LMA(n = 8)LMA, no surfactant(n = 8)Returned to CPAP after 5 minutesLaryngeal Mask Airway for Surfactant Administration in a Newborn Animal ModelRoberts. Ped Research. 2010

Laryngeal Mask Airway for Surfactant Administration in a Newborn Animal ModelRoberts. Ped Research. 2010

RCT of 26 preterm neonates (183 planned)> 1200g and < 72 hours of ageOn CPAP for RDS in 30-60% O2Randomized to:Calfactant via LMA, then ongoing CPAPCPAP onlyNo difference in need for MV within 96hReduced FiO2 requirement for 12 hoursAdministration of Rescue Surfactant by Laryngeal Mask Airway: Lessons from a Pilot TrialAttridge. Am J Perinatol. 2013Surfactant via LMA: Studies in ProgressPinheiroRobertsn130144Gestation27-36 weeks28-35 weeksWeight> 800g-Postnatal Age2-48 hours 36 hoursCPAP Criteria 5 cmH2OFiO2 0.3-0.66 cmH2OFiO2 0.3Study ArmsSurfactant via ETT

Surfactant via LMACPAP + surfactant/LMA

CPAPPrimary OutcomeAvoiding mechanical ventilationIntubation/MV in 1st 7 daysEstimated CompletionAugust 2017Dec 201644Intrapartum/pharyngeal administrationAdministration via laryngeal mask airway (LMA)Aerosolized surfactantThin catheter administrationCPAP With Less Invasive Surfactant AdministrationSurfactant Aerosol Rx of RDS in Spontaneously Breathing Preterm Infants20 preterm infantsMedian gestation:31 weeks (range 28-35)Median birth weight:1680g (range 1150-2500g)On CPAP 1-7h of age2 doses of surfactant over 20-50 minutes at 2-9h of age via jet nebulizer/nasopharyngeal tubeResults:Compared to 2 hours of CPAP alone, showed decreases in:Alveolar-arterial oxygen gradientSilverman scorePaCO2Jorch. Pediatr Pulm. 199746Inhalation of Aerosolized Surfactant (Exosurf) to Neonates Treated with Nasal CPAP22 preterm infants23-36 weeks gestation< 3 days old1, 2, 4 or 8 vials of Exosurf via jet nebulizerNo controlsResults:No adverse effectsNo improvement in clinical variables or a/A-ratioArroe. Prenat Neonat Med. 199847Pilot Study of Nebulized Surfactant Therapy for Neonatal Respiratory Distress Syndrome32 preterm infants with RDS on CPAP27-34 weeks gestation< 2 hours oldRandomized to:Jet nebulized poractant alfa plus CPAPCPAP aloneResults:No side effects notedNo beneficial effects notedBerggren. Acta Paediatr. 200048An Open Label, Pilot Study of Aerosurf Combined with NCPAP to Prevent RDS in Preterm NeonatesFeasibility and safety studyUsed KL4-containing synthetic surfactant17 preterm infants28-32 weeks gestationOn CPAP within 15 minutes of birthGiven lucinactant over 3h by vibrating membrane nebulizer at 1L/minRandomized to:Up to 3 re-treatments in 48h separated by at least 3hUp to 3 re-treatments in 48h separated by at least 1hFiner. Jnl Aerosol Med. 201049An Open Label, Pilot Study of Aerosurf Combined with NCPAP to Prevent RDS in Preterm NeonatesResults:Well tolerated aside from transient desaturationsVariable output rates/dispensed drug volumesMean FiO2 decreased from 0.4 baseline to 0.32 at 4hFiner. Jnl Aerosol Med. 201050Nebulized Surfactant for Treatment of Respiratory Distress in the First Hours of Life: The CureNeb Study64 preterm infants29+0 to 33+6 gestational ageAge: 0-4hRDS on CPAP with FiO2 0.22-0.30Randomized to:Nebulized poractant alpha: 1-2 doses over 12hCPAP without nebulized surfactantPrimary Outcome: Need for intubationMinocchieri. PAS Abstract. 201351Nebulized Surfactant for Treatment of Respiratory Distress in the First Hours of Life: The CureNeb StudyMinocchieri. PAS Abstract. 2013

52Nebulized Surfactant: Studies in ProgressSoodSegaln12048Gestation24-36 weeks29-34 weeksPostnatal Age< 24 hours 21 hoursSupport CriteriaRDS on NIVFiO2 0.25CPAPModerate FiO2Study ArmsSurvanta 100 mg/kg

Survanta 200 mg/kgCPAP + Lucinactant (3 doses)

CPAPPrimary OutcomeSafetyNeed for intubationSafetyTolerabilityEstimated CompletionOctober 2017March 201553NebulizerType:Ultrasonic vs. Jet vs. Vibrating membraneFlowMass median aerodynamic diameter (MMAD)Patient interfacePatient factorsRespiratory mechanics/performanceSurfactantType:Effects of nebulizationDose:Fixed vs. weight basedTiming:Early vs. established RDS

Aerosolized Surfactant: Key QuestionsIntrapartum/pharyngeal administrationAdministration via laryngeal mask airway (LMA)Aerosolized surfactantThin catheter administrationCPAP With Less Invasive Surfactant AdministrationMIST Study - TechniqueDargaville

Surfactant without Intubation in Preterm Infants with Respiratory Distress: First Multi-center DataObservational data comparing surfactant without intubation with standard care from 2003 - 20071542 preterm infants < 1500g and 30 weeks GAProcedure:Performed on nCPAPNo mandatory sedation/analgesiaSurfactant given over 1-5 minutes via thin catheter placed in trachea under direct laryngoscopyKribs. Klin Padiatr. 2010 Kribs. Klin Padiatr. 2010 P < 0.001P < 0.001P = 0.004P = 0.007P = 0.001Surfactant without Intubation in Preterm Infants with Respiratory Distress: First Multi-center Data%58Avoidance of Mechanical Ventilation by SurfactantTreatment of Spontaneously Breathing Preterm Infants(AMV Trial)220 infantsGestational age 26+0 to 28+6 weeks< 1500g birth weight< 12 hours of ageRDS on CPAP with FiO2 > 0.30Randomized to:Surfactant via thin ET catheter on CPAPCPAP with rescue intubation/surfactant if indicatedPrimary Outcome: Need for mechanical ventilation OR pCO2 > 65 or FiO2 > 0.6 for 2+ hoursGpel. Lancet. 2011P = 0.008Gpel. Lancet. 2011P < 0.0001P = 0.032Avoidance of Mechanical Ventilation by SurfactantTreatment of Spontaneously Breathing Preterm Infants(AMV Trial)60Minimally-Invasive Surfactant Therapy in Preterm Infants on CPAP61 neonatesGestational age 25+0 to 32+6 weeks< 24 hours of ageRDS on CPAP > 7 cmH2O with FiO2 > 0.30 0.35Study Groups:Surfactant via thin ET catheter on CPAP (MIST)Historical controls on CPAPDargaville. Arch Dis Child Fetal Neonatal Ed. 2012Minimally-Invasive Surfactant Therapy in Preterm Infants on CPAPDargaville. Arch Dis Child Fetal Neonatal Ed. 201225-28 Weeks29-32 WeeksP = 0.0011P = 0.025P = 0.0025P = 0.019%Surfactant Administration via Thin Catheter During Spontaneous Breathing (Take Care)Kanmaz. Pediatrics. 2013200 infantsGestational age < 32 weeksRDS on CPAP with FiO2 > 0.40 at 0-2 hoursRandomized to:Surfactant via 5F ET catheter on CPAPSurfactant via ETT, PPV x 30 secs, then CPAPPrimary Outcome: Need for mechanical ventilation in first 72 hours63Surfactant Administration via Thin Catheter During Spontaneous Breathing (Take Care)Kanmaz. Pediatrics. 2013P = 0.02P = 0.009%64Surfactant Administration via Thin Catheter During Spontaneous Breathing (Take Care)Kanmaz. Pediatrics. 2013P = 0.002P = 0.00665Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP)211 infantsGestational age 23+0 to 26+6 weeks< 1500g birth weight< 12 hours of ageRDS on CPAP with FiO2 > 0.30 or SS 5Randomized to:Surfactant via thin ET catheter on CPAPSurfactant via ETT on ventilatorPrimary Outcome: Rate of mechanical ventilation between 24 and 72 hoursKribs. JAMA Pediatr. 2015Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP)Kribs. JAMA Pediatr. 2015P < 0.01P = 0.02%Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP)Kribs. JAMA Pediatr. 2015P = 0.04P = 0.02%Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP)Kribs. JAMA Pediatr. 2015

Surfactant During Spontaneous Breathing: Studies in ProgressEl HelouDargaville (OPTIMIST-A)n40606Gestation (weeks)< 3025-28Postnatal Age< 36 hours< 6 hoursRespiratory CriteriaCPAP5-6 cmH2O/FiO2 0.357-8 cmH2O/FiO2 0.30CPAP/NIPPV5-8 cmH2OFiO2 0.3Study ArmsMISurf (thin catheter)CPAP + MISTInSurECPAPPrimary OutcomeProtocol ComplianceDeath/BPDEstimated CompletionDecember 20152019www.menzies.utas.edu.au/optimist-trials

70Non-Invasive Respiratory Support in the NICULMA SurfactantThin Catheter SurfactantAerosolized surfactantOscillation/HFV????CPAP??HHHFNCNIPPVLFNC/OtherInvasive Respiratory Support????????71Thank you!

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