1. 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

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

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

4. 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

5. Do Clinical Markers of Barotrauma and Oxygen Toxicity Explain Interhospital Variation in Rates of CLD? %
Compared practices and outcomes in 452 infants g at birth from 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

6. (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

7. (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?

8. 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

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

10. 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

11. 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

12. 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

13. 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

14. Very Early Surfactant Without Mandatory Ventilation in Premature Infants Rx With Early CPAP: A RCTNS
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

15. 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

16. 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

17. 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

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

19. 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

20. 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

21. Randomized Trial Comparing 3 Approaches to the Initial Respiratory Management of Preterm Neonates (VON Delivery Room Management Study) %
Dunn. Pediatrics. 2011

22. 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

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

24. 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

25. Intubation/Ventilation vs. InSurE%
VON DR Trial

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

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

28. 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

29. 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

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

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

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

33. 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
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

34. 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

35. 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
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

36. 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

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

38. LMA ProSeal
Standard LMA

39. 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 ( g)
RDS treated with nasal CPAP
Procedure:
Surfactant administered via LMA without sedation/analgesia
Trevisanuto. Biol Neonate. 2005

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

41. 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

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

43. 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

44. 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
FiO
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

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

46. Surfactant Aerosol Rx of RDS in Spontaneously Breathing Preterm Infants
Median gestation: 31 weeks (range 28-35)
Median birth weight: 1680g (range g)
On CPAP 1-7h of age
2 doses of surfactant over 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

47. 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

48. 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

49. 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

50. 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

51.  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 FiO
Randomized to:
Nebulized poractant alpha: 1-2 doses over 12h
CPAP without nebulized surfactant
Primary Outcome: Need for intubation
Minocchieri. PAS Abstract. 2013

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

53. 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

54. 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

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

56. MIST Study - Technique
Dargaville

57. Surfactant without Intubation in Preterm Infants with Respiratory Distress: First Multi-center Data
Observational data comparing “surfactant without intubation” with standard care from
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

58. 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

59. 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

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

61. 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

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

63. 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

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

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

66. 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

67. 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

68. 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

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

70. 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

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

72. Thank you!
Questions?