Nemours Children’s Hospital Grand Rounds Novel Surfactant Administration Strategies in Neonates Nemours Children’s Hospital Grand Rounds June 10th, 2015 Alan de Klerk, MBChB Division of Neonatology Nemours Children’s Hospital

FINANCIAL DISCLOSURE: Nothing to disclose Alan de Klerk, MBChB Division of Neonatology Nemours Children’s Hospital

Outline Recent large RCTs Novel approaches to surfactant administration: CPAP/NIV With Less Invasive Surfactant Administration

Is Chronic Lung Disease in Low Birth Weight Infants Preventable Is Chronic Lung Disease in Low Birth Weight Infants Preventable? A Survey of Eight Centers % Center (3 = Columbia, NY) Avery. Pediatrics. 1987

Do Clinical Markers of Barotrauma and Oxygen Toxicity Explain Interhospital Variation in Rates of CLD? % Compared practices and outcomes in 452 infants 500-1500g at birth from 1991-1993 at Columbia NY with two Boston hospitals 100 from Columbia 341 from Boston Conclusions: NICU-specific risk of CLD was predominantly associated with the decision to use mechanical ventilation Among those receiving mechanical ventilation, high inspired oxygen concentrations, high ventilator PIPs, and hypercarbia during the first postnatal week were associated with increased CLD risk Conclusion: NICU-specific risk of CLD was predominantly associated with the decision to use mechanical ventilation Van Marter. Pediatrics . 2000

(Debatable) Generalizations! Avoiding/limiting invasive ventilation (within reason) is desirable Even when appropriately or optimally used, all forms of respiratory support are necessary evils Inappropriately used they become unnecessary evils

(Debatable) Generalizations! Non-invasive respiratory support of the neonate is not benign respiratory support CPAP: Nasal trauma, pneumothoraces NIPPV: Bowel perforations HHHFNC: Infections, perforated eardrum LFNC: Mucosal trauma, infections Should we be thinking less invasive respiratory support of the neonate?

Early Surfactant Administration with Brief Ventilation vs Early Surfactant Administration with Brief Ventilation vs. Selective Surfactant and Continued Mechanical Ventilation for Preterm Infants with Or at Risk for RDS Early surfactant with extubation to NCPAP vs. later selective surfactant and ongoing MV is associated with less MV, BPD, and air leak Surfactant 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/MV Cochrane Neonatal Reviews. 2007

Outline Recent large RCTs Novel approaches to surfactant administration: CPAP With Less Invasive Surfactant Administration

Gestational age 25+0 to 28+6 weeks Nasal CPAP or Intubation at Birth for Very Preterm Infants (COIN Trial) 610 infants Gestational age 25+0 to 28+6 weeks Breathing spontaneously at 5 minutes after birth, needing respiratory support Randomized to: CPAP Intubation and ventilation Morley. N Engl J Med. 2008

Nasal CPAP or Intubation at Birth for Very Preterm Infants (COIN Trial) OR (95% CI) 0.63 (0.46, 0.88) P = 0.006 P < 0.001 % NS Morley. N Engl J Med. 2008

Nasal CPAP or Intubation at Birth for Very Preterm Infants (COIN Trial) NS P < 0.001 NS P = 0.001 % Morley. N Engl J Med. 2008

Gestational age 27+0 to 31+6 weeks 15-60 minutes of age Very Early Surfactant Without Mandatory Ventilation in Premature Infants Rx With Early CPAP: A RCT 279 infants Gestational age 27+0 to 31+6 weeks 15-60 minutes of age Evidence of respiratory distress and Rx with O2 in the delivery room Randomized to: Intubation, surfactant, extubation to NCPAP CPAP alone/selective intubation and surfactant Rojas. Pediatrics. 2009

Very Early Surfactant Without Mandatory Ventilation in Premature Infants Rx With Early CPAP: A RCT NS RR (95% CI) 0.69 (0.49, 0.97) P ≤ 0.05 % P = 0.039 RR (95% CI) 0.25 (0.07, 0.85) P ≤ 0.05 Rojas. Pediatrics. 2009

Gestational age 25+0 to 28+6 weeks Not intubated at birth Prophylactic or Early Selective Surfactant Combined with nCPAP in Very Preterm Infants (CURPAP Trial) 208 inborn infants Gestational age 25+0 to 28+6 weeks Not intubated at birth Randomized within 30 minutes of birth to: Prophylactic surfactant, then extubated to nCPAP within 1 hour nCPAP with selective surfactant administration Sandri. Pediatrics. 2010

Prophylactic or Early Selective Surfactant Combined with nCPAP in Very Preterm Infants (CURPAP Trial) Need for MV within 5 Days RR (95% CI) 6.82 (0.86, 53.75) % GA: Sandri. Pediatrics. 2010

Gestational age 24+0 to 27+6 weeks Randomized to: Early CPAP versus Surfactant in Extremely Preterm Infants (SUPPORT Study) 1316 infants Gestational age 24+0 to 27+6 weeks Randomized to: Early CPAP/limited ventilation Early intubation/surfactant administration Finer. N Engl J Med. 2010

Early CPAP versus Surfactant in Extremely Preterm Infants (SUPPORT Study) % P < 0.001 Finer. N Engl J Med. 2010

Early CPAP versus Surfactant in Extremely Preterm Infants (SUPPORT Study) RR (95% CI) 0.74 (0.57 to 0.98) P = 0.03 RR (95% CI) 0.68 (0.5 to 0.92) P = 0.01 % Finer. N Engl J Med. 2010

Gestational age 26+0 to 29+6 weeks Treatment Groups: Randomized Trial Comparing 3 Approaches to the Initial Respiratory Management of Preterm Neonates (VON Delivery Room Management Study) 648 infants Gestational age 26+0 to 29+6 weeks Treatment Groups: PS Group: Intubation, surfactant, ventilation ISX Group: Intubation, surfactant, extubation to NCPAP NCPAP Group: NCPAP with selective intubation and surfactant Dunn. Pediatrics. 2011

Randomized 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) % 26-27 weeks GA: 36 weeks PMA Dunn. Pediatrics. 2011

Intubation/Ventilation vs. CPAP Death or BPD at 36 Weeks %

Intubation/Ventilation vs. CPAP Risk of Death or BPD at 36 Weeks RR COIN 0.87 (0.70, 1.07) SUPPORT 0.90 (0.81, 1.00) VON 0.84 (0.64, 1.10) Total 0.89 (0.81, 0.97) Finer. Hot Topics in Neonatology. 2010

Intubation/Ventilation vs. InSurE % VON DR Trial

InSurE vs. CPAP % Need for Mechanical Ventilation RR (95% CI) 0.69 (0.49, 0.97) P ≤ 0.05 NS NS %

InSurE vs. CPAP Death or BPD at 36 Weeks BPD at 36 Weeks %

InSurE vs. CPAP Risk of Death or BPD at 36 Weeks RR CURPAP 1.03 (0.61, 1.72) Rojas 0.86 (0.70, 1.05) VON 0.94 (0.70, 1.25) Total (+ 3 studies) 0.88 (0.76, 1.02) Similar findings for death and air leak Isayama. JAMA Pediatr. 2015

Conclusions Non-invasive support (CPAP or InSurE) is at least as effective as invasive support InSurE is not consistently superior to CPAP alone Long term outcomes are needed

Hypothesis Would even less invasive surfactant administration to a spontaneously breathing neonate improve outcomes further?

CPAP With Less Invasive Surfactant Administration Intrapartum/pharyngeal administration Administration via laryngeal mask airway (LMA) Aerosolized surfactant Thin catheter administration

CPAP With Less Invasive Surfactant Administration Intrapartum/pharyngeal administration Administration via laryngeal mask airway (LMA) Aerosolized surfactant Thin catheter administration

RCT of 328 preterm infants Procedure: Ten Centre Trial of Artificial Surfactant (Artificial Lung Expanding Compound) in Very Premature Babies RCT of 328 preterm infants 25 - 29 weeks gestation Procedure: Pharyngeal ALEC or normal saline at birth Up to 3 more doses if intubated DOL #1 Ten Centre Study Group. BMJ. 1987

Ten Centre Trial of Artificial Surfactant (Artificial Lung Expanding Compound) in Very Premature Babies P < 0.03 P < 0.02 % Ten Centre Study Group. BMJ. 1987

Non-randomized feasibility study 23 preterm infants Procedure: Technique for Intrapartum Administration of Surfactant without Requirement for an ETT Non-randomized feasibility study 23 preterm infants 27 - 30 weeks gestation, 560 – 1804g Procedure: Nasopharyngeal airway suctioned Infasurf instilled into nasopharynx before delivery of shoulders CPAP by mask as breathing initiated, then maintained on CPAP for 48+ hours Kattwinkel. J Perinatol. 2004

Technique for Intrapartum Administration of Surfactant without Requirement for an ETT Results: 13 of 15 vaginally delivered babies weaned quickly to room air with no further surfactant or intubation 5 of 8 C-section babies required intubation, 2 received surfactant Conclusion: NP surfactant at birth appears relatively safe and simple, especially for vaginal births Kattwinkel. J Perinatol. 2004

CPAP With Less Invasive Surfactant Administration Intrapartum/pharyngeal administration Administration via laryngeal mask airway (LMA) Aerosolized surfactant Thin catheter administration

LMA ProSeal Standard LMA

Feasibility trial of 8 infants LMA Used as a Delivery Conduit for the Administration of Surfactant to Preterm Infants with RDS Feasibility trial of 8 infants Median GA: 31 weeks (28-35 weeks) Median BW: 1700g (880-2520g) RDS treated with nasal CPAP Procedure: Surfactant administered via LMA without sedation/analgesia Trevisanuto. Biol Neonate. 2005

LMA Used as a Delivery Conduit for the Administration of Surfactant to Preterm Infants with RDS Trevisanuto. Biol Neonate. 2005

On CPAP via short binasal prongs Randomized to: Laryngeal Mask Airway for Surfactant Administration in a Newborn Animal Model RCT of newborn piglets with lung injury induced by normal saline surfactant washout On CPAP via short binasal prongs Randomized to: Surfactant via ETT (n = 8) Surfactant via LMA (n = 8) LMA, no surfactant (n = 8) Returned to CPAP after 5 minutes Roberts. Ped Research. 2010

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

RCT of 26 preterm neonates (183 planned) Administration of Rescue Surfactant by Laryngeal Mask Airway: Lessons from a Pilot Trial RCT of 26 preterm neonates (183 planned) > 1200g and < 72 hours of age On CPAP for RDS in 30-60% O2 Randomized to: Calfactant via LMA, then ongoing CPAP CPAP only No difference in need for MV within 96h Reduced FiO2 requirement for 12 hours Attridge. Am J Perinatol. 2013

Surfactant via LMA: Studies in Progress Pinheiro Roberts n 130 144 Gestation 27-36 weeks 28-35 weeks Weight > 800g - Postnatal Age 2-48 hours ≤ 36 hours CPAP Criteria ≥ 5 cmH2O FiO2 0.3-0.6 6 cmH2O FiO2 ≥ 0.3 Study Arms Surfactant via ETT Surfactant via LMA CPAP + surfactant/LMA CPAP Primary Outcome Avoiding mechanical ventilation Intubation/MV in 1st 7 days Estimated Completion August 2017 Dec 2016

CPAP With Less Invasive Surfactant Administration Intrapartum/pharyngeal administration Administration via laryngeal mask airway (LMA) Aerosolized surfactant Thin catheter administration

Surfactant Aerosol Rx of RDS in Spontaneously Breathing Preterm Infants Median gestation: 31 weeks (range 28-35) Median birth weight: 1680g (range 1150-2500g) On CPAP 1-7h of age 2 doses of surfactant over 20-50 minutes at 2-9h of age via jet nebulizer/nasopharyngeal tube Results: Compared to 2 hours of CPAP alone, showed decreases in: Alveolar-arterial oxygen gradient Silverman score PaCO2 Jorch. Pediatr Pulm. 1997

1, 2, 4 or 8 vials of Exosurf via jet nebulizer No controls Results: Inhalation of Aerosolized Surfactant (Exosurf) to Neonates Treated with Nasal CPAP 22 preterm infants 23-36 weeks gestation < 3 days old 1, 2, 4 or 8 vials of Exosurf via jet nebulizer No controls Results: No adverse effects No improvement in clinical variables or a/A-ratio Arroe. Prenat Neonat Med. 1998

32 preterm infants with RDS on CPAP Pilot Study of Nebulized Surfactant Therapy for Neonatal Respiratory Distress Syndrome 32 preterm infants with RDS on CPAP 27-34 weeks gestation < 2 hours old Randomized to: Jet nebulized poractant alfa plus CPAP CPAP alone Results: No side effects noted No beneficial effects noted Berggren. Acta Paediatr. 2000

Feasibility and safety study 17 preterm infants An Open Label, Pilot Study of Aerosurf Combined with NCPAP to Prevent RDS in Preterm Neonates Feasibility and safety study Used KL4-containing synthetic surfactant 17 preterm infants 28-32 weeks gestation On CPAP within 15 minutes of birth Given lucinactant over 3h by vibrating membrane nebulizer at 1L/min Randomized to: Up to 3 re-treatments in 48h separated by at least 3h Up to 3 re-treatments in 48h separated by at least 1h Finer. Jnl Aerosol Med. 2010

Results: Well tolerated aside from transient desaturations An Open Label, Pilot Study of Aerosurf Combined with NCPAP to Prevent RDS in Preterm Neonates Results: Well tolerated aside from transient desaturations Variable output rates/dispensed drug volumes Mean FiO2 decreased from 0.4 baseline to 0.32 at 4h Finer. Jnl Aerosol Med. 2010

 Nebulized Surfactant for Treatment of Respiratory Distress in the First Hours of Life: The CureNeb Study 64 preterm infants 29+0 to 33+6 gestational age Age: 0-4h RDS on CPAP with FiO2 0.22-0.30 Randomized to: Nebulized poractant alpha: 1-2 doses over 12h CPAP without nebulized surfactant Primary Outcome: Need for intubation Minocchieri. PAS Abstract. 2013

 Nebulized Surfactant for Treatment of Respiratory Distress in the First Hours of Life: The CureNeb Study Minocchieri. PAS Abstract. 2013

Nebulized Surfactant: Studies in Progress Sood Segal n 120 48 Gestation 24-36 weeks 29-34 weeks Postnatal Age < 24 hours ≤ 21 hours Support Criteria RDS on NIV FiO2 ≥ 0.25 CPAP Moderate FiO2 Study Arms Survanta 100 mg/kg Survanta 200 mg/kg CPAP + Lucinactant (3 doses) Primary Outcome Safety Need for intubation Tolerability Estimated Completion October 2017 March 2015

Aerosolized Surfactant: Key Questions Nebulizer Type: Ultrasonic vs. Jet vs. Vibrating membrane Flow Mass median aerodynamic diameter (MMAD) Patient interface Patient factors Respiratory mechanics/performance Surfactant Type: Effects of nebulization Dose: Fixed vs. weight based Timing: Early vs. established RDS

CPAP With Less Invasive Surfactant Administration Intrapartum/pharyngeal administration Administration via laryngeal mask airway (LMA) Aerosolized surfactant Thin catheter administration

MIST Study - Technique Dargaville

Surfactant without Intubation in Preterm Infants with Respiratory Distress: First Multi-center Data Observational data comparing “surfactant without intubation” with standard care from 2003 - 2007 1542 preterm infants < 1500g and ≤ 30 weeks GA Procedure: Performed on nCPAP No mandatory sedation/analgesia Surfactant given over 1-5 minutes via thin catheter placed in trachea under direct laryngoscopy Kribs. Klin Padiatr. 2010

Surfactant without Intubation in Preterm Infants with Respiratory Distress: First Multi-center Data % P = 0.004 P = 0.007 P = 0.001 Kribs. Klin Padiatr. 2010

220 infants Randomized to: Avoidance of Mechanical Ventilation by Surfactant Treatment of Spontaneously Breathing Preterm Infants (AMV Trial) 220 infants Gestational age 26+0 to 28+6 weeks < 1500g birth weight < 12 hours of age RDS on CPAP with FiO2 > 0.30 Randomized to: Surfactant via thin ET catheter on CPAP CPAP with rescue intubation/surfactant if indicated Primary Outcome: Need for mechanical ventilation OR pCO2 > 65 or FiO2 > 0.6 for 2+ hours Göpel. Lancet. 2011

Avoidance of Mechanical Ventilation by Surfactant Treatment of Spontaneously Breathing Preterm Infants (AMV Trial) P < 0.0001 P = 0.008 P = 0.032 Göpel. Lancet. 2011

Minimally-Invasive Surfactant Therapy in Preterm Infants on CPAP 61 neonates Gestational age 25+0 to 32+6 weeks < 24 hours of age RDS on CPAP > 7 cmH2O with FiO2 > 0.30 – 0.35 Study Groups: Surfactant via thin ET catheter on CPAP (MIST) Historical controls on CPAP Dargaville. Arch Dis Child Fetal Neonatal Ed. 2012

Minimally-Invasive Surfactant Therapy in Preterm Infants on CPAP 25-28 Weeks 29-32 Weeks P = 0.0011 P = 0.0025 % P = 0.025 P = 0.019 Dargaville. Arch Dis Child Fetal Neonatal Ed. 2012

Surfactant Administration via Thin Catheter During Spontaneous Breathing (Take Care) 200 infants Gestational age < 32 weeks RDS on CPAP with FiO2 > 0.40 at 0-2 hours Randomized to: Surfactant via 5F ET catheter on CPAP Surfactant via ETT, PPV x 30 secs, then CPAP Primary Outcome: Need for mechanical ventilation in first 72 hours Kanmaz. Pediatrics. 2013

Surfactant Administration via Thin Catheter During Spontaneous Breathing (Take Care) % P = 0.009 Kanmaz. Pediatrics. 2013

Surfactant Administration via Thin Catheter During Spontaneous Breathing (Take Care) Kanmaz. Pediatrics. 2013

211 infants Randomized to: Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP) 211 infants Gestational age 23+0 to 26+6 weeks < 1500g birth weight < 12 hours of age RDS on CPAP with FiO2 > 0.30 or SS ≥ 5 Randomized to: Surfactant via thin ET catheter on CPAP Surfactant via ETT on ventilator Primary Outcome: Rate of mechanical ventilation between 24 and 72 hours Kribs. JAMA Pediatr. 2015

Nonintubated Surfactant Application vs Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP) P < 0.01 P = 0.02 % Kribs. JAMA Pediatr. 2015

Nonintubated Surfactant Application vs Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP) P = 0.02 P = 0.04 % Kribs. JAMA Pediatr. 2015

Nonintubated Surfactant Application vs Nonintubated Surfactant Application vs. Conventional Therapy in Extremely Preterm Infants (NINSAPP) Kribs. JAMA Pediatr. 2015

Surfactant During Spontaneous Breathing: Studies in Progress El Helou Dargaville (OPTIMIST-A) n 40 606 Gestation (weeks) < 30 25-28 Postnatal Age < 36 hours < 6 hours Respiratory Criteria CPAP 5-6 cmH2O/FiO2 ≥ 0.35 7-8 cmH2O/FiO2 ≥ 0.30 CPAP/NIPPV 5-8 cmH2O FiO2 ≥ 0.3 Study Arms MISurf (thin catheter) CPAP + MIST InSurE Primary Outcome Protocol Compliance Death/BPD Estimated Completion December 2015 2019 www.menzies.utas.edu.au/optimist-trials

Non-Invasive Respiratory Support in the NICU LMA Surfactant ? ? ? Thin Catheter Surfactant ? NIPPV ? ? ? ? CPAP ? ? ? ? ? Aerosolized surfactant HHHFNC Oscillation/HFV ? LFNC/Other

Thank you! Questions?