Evidence based perinatal lung protective strategies in newborns

1. Lung Protective Strategies In
Premature Newborn
Dr Dinesh Viruvanti
MBBS, MD(Pediatrics)

2. Learning Objectives
Introduction
• Etiology and Pathophysiology of lung
injuries
Antenatal Lung Protective Strategies-
evidence
• Antenatal corticosteroids
• Treatment of Chorioamnionitis
Delivery roomStrategies- evidence
• Resuscutation strategies
• Delivery room CPAP
Postnatal Strategies- evidence
1) CPAP
2) Surfactant
3) Caffeine
4) Target SO2
5) Corticosteroids
Optimal Ventilation strategies and Other
considerations
Summary

3. INTRODUCTION

4. Neonatal Lung And Airway Injury
Pulmonary
complications
associated with
assisted
ventilation in
newborn
BPD
Extraneous
air syndromes
Pulmonary
haemorrhage
Atelectasis
Pneumonia
Barotrauma: High Peak airway
pressures- Transfer of air from
airway to interstitium.
Volutrauma: Overdistension of
alveoli- Diffuse alveolar
damage, Pulmonary capillary
damage.
Atelectrauma: Low end
expiratory pressure, Surfactant
deficency- inadequate alveolar
recruitment.
Biotrauma: PPV,Intubation
activate inflammatory cascade

5. Bronchopulmonary Dysplasia
Etiological
implications of BPD
Antenatal:
1)Prematurity
of Lungs
2)Chorioamnio
nitis
Perinatal:
Lung injury dring
resuscitation
Postnatal:
1) O2 toxicity
2) Mechanical
Ventilation
3) Infection and
inflammation
4) Nutrional
inadequacy
5) PDA
6) Fluid Overload
Incidence of BPD : 50%, 8.1% and 2.3% among the babies with birth weight <1000 grams, 1000-1249 grams and
1250-1499 grams respectively. (Anil narang et al,PGIMER, Chandigarh,2002)

6. Extraneous Air Syndromes (Air leaks)
• Group of clinically recognizable
disorders initially produced by
alveolar rupture with
subsequent escape of air into
tissue in which air is not
normally present.
• All clinical variations of EAS
originate in overdistended
alveoli.
Alveolar
overdistension
Vigorous
ventilatory
resuscitation
high PEEP/PIP
ventilation
Air trapping in
presence of
ball-valve
mechanism

7. Antenatal Strategies

8. Antenatal Corticosteroids- Early studies
A Controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in
premature infants.
G.C. Liggins and R.N Howie, Auckland, New Zealand -1972

9. Antenatal Corticosteroids- Later studies
Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth-
Roberts D et al.
• Cochrane Review published in March 2017
• Meta analysis of 30 studies(7774 women and 8158 infants)
Reduction in
•Perinatal death (avg RR- 0.72,
95% CI 0.58 to 0.89)
•Neonatal death(avg RR- 0.69,
95% CI 0.59 to 0.81)
•RDS(avg RR- 0.66, 95% CI 0.56
to 0.77)
•IVH(avg RR- 0.55, 95% CI 0.40
to 0.76)
•NEC(avg RR- 0.50, 95% CI 0.32
to 0.78)
•Need for MV(avg RR- 0.68,
95% CI 0.56 to 0.84)
Didnot increase
the risk of
•Chorioamnionitis(avg RR-
0.83, 95% CI 0.66 to 1.06)
•Endometritis(avg RR- 1.20,
95% CI 0.87 to 1.63)
•Maternal deaths
No benefit for
•BPD(avg RR- 0.86, 95% CI 0.42
to 1.79)

10. Antenatal Corticosteroids- GOI Recommendations

11. Chorioamnionitis and BPD
• Prospective study conducted by Viscardi et al, June 1999 TO
June 2002
• Sample size: 276 infants with GA <33 wk and B.wt <1501 g.

12. Delivery room Strategies

13. Delivery Room Strategies
• NRP 2015 recommends starting FiO2 of 21-30% for resuscitation of preterm
(<35wk) and titrate according to the SPO2 recordings to meet the target
saturations.
• Use of blender allows FiO2 titration
• T-piece resuscitator allows monitoring of pressure and FiO2 being delivered
• Flow inflating bag allows FiO2 control.

14. Early CPAP Use In Delivery Room

15. Early CPAP Use In Delivery Room
EARLY CPAP USE- DECREASES THE NEED
FOR SURFACTANT.

16. Postnatal Strategies

17. Nasal CPAP or Intubation at Birth for Very Preterm
Infants. - Morlin CJ et al, 2008. (COIN trial)
Study details
•Design: RCT
•Inclusion criteria:
• 1) Infants with gestational
age at delivery b/w 25wks
0 days and 28wks 6days
• 2) No known condition
that might adversely affect
breathing apart from
prematurity
• 3) Ability to breathe
spontaneously at 5 min of
life but needing
respiratory support
because of increased
respiratory
effort,grunting or
cyanosis.
•Exclusion crieria:
• 1) If intubated before
randomisation
• 2) requiring no respiratory
support or oxygen
•Sample size: 610
infants
Method
• Randomization: into
CPAP group and
Intubation group.
• CPAP was started at 8cm
of water with single or
binasal prongs. Pressure
was later altered as
required.
• CPAP group infants were
intubated and
mechanically ventilated
if
• 1)Apnoea: &gt; 6
episodes requiring
stimulation in 6 hrs or
requiring &gt; 1 episode
of PPV
• 2) arterial blood pH &lt;
7.25 with PaCO2 &gt;
60mm Hg
• 3) metabolic acidosis not
responisive to treatment
• 4) Requiring &gt; 60%
FiO2
Analysis
• Primary outcome: Death
or BPD(need for O2
treatment at 36wk GA)

18. Nasal CPAP or Intubation at Birth for Very Preterm Infants. - Morlin CJ et al, 2008. - Results

19. Early CPAP versus Surfactant in Extremely Preterm Infants SUPPORT
Study Group of the Eunice Kennedy Shriver NICHD, Neonatal Research Network
• RCT
• Feb 2005 to Feb 2009
Study Design
• Death or BPD
• (BPD was defined according to the physiological defn)
Primary
objective
• GA of 24wk 0days to 27wk 6days
• No known malformations
Inclusion
criteria
• 1316 infants
Sample size

20. Early CPAP versus Surfactant in Extremely Preterm Infants
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD, Neonatal Research Network

21. Prophylactic versus selective use of surfactant in preventing morbidity
and mortality in preterm infants- Cochrane review 2012
Rojas-Reyes MX, Morley CJ, Soll R
Meta-analysis of 11 RCTS
•Dunn 1991, Kendig 1991, Merritt 1991, Egberts 1993, Walti 1995, Bevilacqua 1996,
Bevilacqua 1997, Iaru kova 1999,SUPPORT 2010, Dunn 2011
•SUPPORT 2010 and Dunn 2011used CPAP in &amp;apos;Rescue&amp;apos; group.
Objective
•To compare the effect of prophylactic surfactant administration to surfactant
treatment of established RDS in very preterm infants.
Primary outcomes of individual studies (1 or more of the following)
•Neonatal mortality
•Mortality prior to hospital discharge
•BPD or Death
•BPD

22. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants-
Cochrane review 2012 -RESULTS
Rojas-Reyes MX, Morley CJ, Soll R
If CPAP routinely used, no advantage
of prophylactic surfactant
.

23. Early versus delayed selective surfactant treatment for neonatal
respiratory distress syndrome- Cochrane review 2012
Bahadue FL, Soll R
Meta-analysis of 6 RCTS
•European study 1992, Konishi 1992,OSIRIS 1992, Gortner 1998, Plavka 2002 and
Lefort 2003.
Objective
•To compare the effect of prophylactic surfactant administration to surfactant
treatment of established RDS in very preterm infants.
Primary outcomes of individual studies (1 or more of the following)
•Neonatal mortality
•Mortality prior to hospital discharge
•BPD or Death
•BPD

24. Early versus delayed selective surfactant treatment for neonatal
respiratory distress syndrome- Cochrane review 2012-RESULTS
Bahadue FL, Soll R

25. Early versus delayed selective surfactant treatment for neonatal
respiratory distress syndrome- Cochrane review 2012-RESULTS
Bahadue FL, Soll R
Early selective surfactant has better
outcome compared to delayed
administration.

26. Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and
treatment of RDS- Cochrane review 2015
Ardell S, Pfister RH, Soll R

27. Animal derived surfactant extract versus protein free synthetic surfactant for the
prevention and treatment of RDS- Cochrane review 2015
Ardell S, Pfister RH, Soll R

28. Minimally Invasive Surfactant Therapy(MIST)/ Less
Invasive Surfactant Administration(LISA)
• Nasopharyngeal instillation, Laryngeal msk placement,
Aerosolisation : Not ready for clinical application on a wide scale
at present.
• Intratracheal surfactant instillation in a spontaneiusly breathing
infant.(Hobart method)
• 2 prospective randomized clinical trials: AMV and Take Care
• AMV study: infants who received LISA were less frequently
intubated, had fewer days of mechanical ventilation, and needed
less oxygen at 28 days.
• The Take Care investigators observed significantly less BPD in the
group of infants who received LISA compared with surfactant
administration via short intubation.
• In both studies, infants were relatively mature (mean GA, 28
weeks).
• A large multicentered RCT, OPTIMIST trial is underway. Results
yet to be published.

29. Bayesian network meta-analysis of 7
ventilation strategies to reduce death/BPD
Isayama, JAMA, 2016: 4987 infants, 21 trials

30. Caffeine Therapy for Apnea of Prematurity(CAP Trial)
Schmidt B et al
• RCT
• Oct 1999 to Oct 2004
Study Design
• Composite of death, CP, Cognitive delay, deafness
or blindness at a corrected age of 18 to 21 months
Primary
outcome
• Infants with birth weight of 500 to 1250 g in the
first 10days of life
Inclusion
criteria
• 2006 infants
Sample size

31. Caffeine Therapy for Apnea of Prematurity(CAP Trial)- Results
Schmidt B et al

32. Effects of targeting lower versus higher arterial oxygen saturations on
death or disability in preterm infants- Cochrane review 2017
Bahadue FL, Soll R
Meta-analysis of 5 RCTS
• Vaucher 2012, Schmidt 2013, BOOST NZ 2014,
BOOST-II UK 2016, BOOST-II Australia 2016
Objective
• What are the effects of targeting lower (85-
89%)vs higher(90-95%) O2 saturation ranges
on death or major morbidities or both in
extremely preterm infants(&lt;28wk GA)

33. Effects of targeting lower versus higher arterial oxygen saturations on
death or disability in preterm infants- Cochrane review 2017- RESULTS
Bahadue FL, Soll R

34. Postnatal corticosteroids- Early(<8 days)

35. Postnatal corticosteroids- Early(<8 days)

36. Postnatal corticosteroids- Late(>8 days)
Definite reduction of BPD with the use of Postnatal corticosteroids but at the
cost of increased risk of Abnormal neurological outcome.

37. Overview of Lung protective Mechanical
Ventilation Strategies- VTV vs PLV

39. Overview of Lung protective Mechanical
Ventilation Strategies- ACV/SIMV vs CMV

40. Overview of Lung protective Mechanical
Ventilation Strategies- SIMV/SIMV+PS vs HFOV

41. Other Considerations
1) Inhaled Nitric oxide:
• Multicentered RCTs demonstrated that iNO therapy reduces ECMO treatment TERM newborns.
• Useful in treatment of PPHN
• Subhedar et al reported no benefit in survival, CLD or ICH in preterms.
• Van Meurs et al(RCT with 420 infants weighing 401 g to 1500 g) found no difference in the incidence of death or
BPD.
• Post-hoc analysis of this study showed reduction in BPD/death in >1000g group
• But in <1000g group, there was increase in the risk of ICH/PVL
• Needs further larger studies

43. Summary
• Decrease in Perinatal death, Neonatal death, RDS,IVH, Need for MV
Antenatal
Corticosteroids
• Decrease in Days on Ventilator and Pneumothorax (compared to
Early Intubation.)
• Decreased need for Mech.Vent (compared to Surfactant only)
Early CPAP use
• Prophylactic vs Rescue(CPAP supported): Increase in BPD incidence
• Early vs Delayed: Decrease in mortality, CLD, air leaks.
• Animal derived vs Synthetic: Less mortality and Pneumothorax , More NEC
Surfactant
• Decrease in BPD
Caffeine
• More deaths at 18-20mo in Lower SO2 group
• More NEC
• Less BPD and ROP
Lower vs Higher target
SO2

44. Summary
• Less BPD
• More GI bleed, HTN, Hyperglycemia, GI bleed,
Abnormal neurological development, CP.
Postnatal
Corticosteroids
• Less BPD and Pneumothorax in VTV compared to PLV
• CMV compared to SIMV: No difference in BPD,
pneumothorax
• HFOV vs SIMV: Less BPD, Less Deaths
Mechanical
Ventilation

45. 1. Use antenatal steroids in mothers at risk of preterm delivery
2. Do not use prophylactic surfactant
3. Start CPAP early and combine with INSURE rather than starting with IMV or waiting for
CPAP failure to give surfactant
4. If intubation unavoidable, use volume targeted ventilation over pressure controlled
ventilation
5. Can consider high frequency ventilation (marginal benefit)
6. In IMV, use PEEP liberally, PIP miserly, allow PCO2 to rise
7. Start caffeine, preferably within 3 days of life

46. THANK YOU
1. Use antenatal steroids in mothers at risk of preterm delivery
2. Do not use prophylactic surfactant
3. Start CPAP early and combine with INSURE rather than starting with IMV or waiting for CPAP failure to give surfactant
4. If intubation unavoidable, use volume targeted ventilation over pressure controlled ventilation
5. Can consider high frequency ventilation (marginal benefit)
6. In IMV, use PEEP liberally, PIP miserly, allow PCO2 to rise
7. Start caffeine, preferably within 3 days of life