Bpd,nnf kerala,march 2019 - Dr Karthik Nagesh

1. {
PHO
TO
NAME : DR. N. KARTHIK NAGESH MD,FRCPCH ( UK),FNNF
DESIGNATION: CHAIRMAN-HOD,NEONATOLOGY & NICUS ,
MANIPAL HOSPITALS
GROUP, INDIA
CITY: BANGALORE
AFFILIATIONS:
PROFESSOR OF NEONATOLOGY, MANIPAL UNIVERSITY,
PAST PRESIDENT , NATIONAL NEONATOLOGY FORUM – KARNATAKA
PAST PRESIDENT, INDIAN ACADEMY OF PEDIATRICS,BANGALORE,
EXAMINER-RCPCH ( UK),
TECHNICAL ADVISOR-NEONATAL RESUSCITATION DEVICES,
WHO –GENEVA
DNB-NEONATOLOGY TEACHER,INSPECTOR,EXAMINER
& PROGRAM COORDINATOR
AWARDS:
LIFETIME ACHIEVEMENT AWARD OF NATIONAL NEONATOLOGY FORUM ,KARNATAKA
ORATION AWARD - NATIONAL NEONATOLOGY FORUM-KARNATAKA
FELLOWSHIP OF THE NATIONAL NEONATOLOGY FORUM
FELLOWSHIP OF THE ROYAL COLLEGE OF PAEDIATRICS AND CHILD HEALTH (UK)
DR V BALAGOPA RAJU AWARD FOR PAEDIATRIC RESEARCH-INDIAN ACADEMY OF PAEDIATRICS
PUBLICATIONS: 82 PAPERS/ABSTRACTS; 17 CHAPTERS IN BOOKS
SPECIAL INTERESTS: NEONATAL INTENSIVE CARE/RESPIRATORY DISORDERS

2. CURRENT
STRATEGIES IN
MANAGEMENT OF BPD
DR KARHIK NAGESH N

3. NICU, Manipal hospital, Bangalore

4. BPD
 Bronchopulmonary dysplasia is characterized by alveolar
simplification , arrest in lung growth, impaired vascular
development and abnormal pulmonary function
 As per NICHD, BPD is defined as oxygen use and/or
respiratory support at 36 weeks PMA(or 56 days of age for
infants at >32 weeks GA)*
 Optimal definition of BPD -controversial, since oxygen use at
36 weeks have failed to predict long term respiratory
morbidities.
 Update on strategies for the prevention and management of
BPD
* Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care
Med. 2001;163:1723–1729

5. 28 Weeks POG…Stormy Course! 1993
• Baby S, outborn -28 weeks, 1.1kg.
• No Surfactant
• RDS from Birth: blow by oxygen given
and shifted
• Intubated at our NICU. Hypoxia,
acidosis
• Ventilated,(Pressure Mode,IMV)
for severe RDS for
4weeksSignificant PDA ligated
in OT > weaned off IMV
• Sepsis with DIC
• NEC perforated  Resection >
colostomy > re-anastamosis
• ROP CryoSurgery done in OT.
• Day 86 discharged home
• CLD
RDS (HMD)
RDS (HMD)
Pressure Limited Time Cycled Ventilators

6. BPD-STG.II
Fallout of MV
…2000, Severe CLD
• 24-28 Weeks POG
• APH
• Antenatal Steroids
• Severe RDS
• IPPV with AMBU
Bag at Birth…T-
Piece
• High Ventilatory
Requirements
• Surfactant…Bovine
• CLD…Ventilated…Months
O2 Dependent… 8 months

7. ELBW---25 Weeks POG
2016
(IVF-Donor Ovum) by LSCS
(REDF) at 25 weeks.
Antenatal steroids given
At birth, intubation/IPPV
through T-Piece resuscitotor.
Birth weight 460gm
Early rescue Surfactant
(Porcine) given and extubated
after 12 hours to CPAP
(INSURE).
Aggressive TPN nutrition
program instituted-Day1
Apnoea needing continued
CPAP/HHHFNC (21% FiO2)
Stable in Room Air …by 10
days
GERD….Full OG Feeds at 2
weeks , KMC

9. How do Antenatal Steroids Work?
Science
• Accelerate development of pneumocytes, thus improving lung
mechanics (maximal lung volume, compliance) and gas
exchange
• Increases surfactant production
• Induction of surfactant release, absorption of alveolar fluid,
increase lung antioxidant enzymes
Reduction in RDS, moderate to severe RDS
Reduction in Intraventricular hemmorhage, Necrotising
enterocolitis, mortality, systemic sepsis

10. Capillary leak
A syndrome of
inflammation
Diffuse
alveolar
epithelial
damage
Breakdown of
endothelial
barrier
Interstitial
edema
Proteinaceous
alveolar
flooding
Type 2 cell
Apoptotic
Type 1 cell
Pathophysiology of Acute Lung Injury in HMD
Acute Lung Injury in
Preterms

11. Complications of Invasive ventilation
Pressure
VILI
Volume Trauma
Barotrauma
Atelectotrauma
“Inappropriate Ventilation Of A Neonate
Can Be More Harmful Than The Disease
Itself ”

12. COIN* Trial
• 610 infants, 25 to 28 weeks
• Distress at 5 minutes of life
• CPAP or Ventilation
• Surfactant only if intubation and criteria for this
not pre-specified
• In CPAP group
– Only 46% required intubation in first 5 days
– Nearly 50% escaped surfactant
Early Rescue CPAP
*CPAP or Intubation and Ventilation without surfactant (CPAP
or Intubation (COIN Trial)) ,Morley CJ et al,2008
Grade A

13. CPAP is an alternative to intubation and surfactant in
preterm infants (Grade A)
• 1316 infants, 24 to 27 weeks
• CPAP vs. Intubation and
Surfactant at birth
• For CPAP group surfactant
was given
– If intubated at birth
– Failed CPAP i.e. FiO2>50%
• In CPAP group
– 33% did not receive
surfactant
– 83% got intubated
– Lesser need for
ventilation in first 7
days
• Prophylactic CPAP
“SUPPORT” trial,NEJM,2010

14. Both SUPPORT and COIN trials support
CPAP alone a safe alternative to
intubation and surfactant
Primary outcome was Death or BPD
•Intubation rates of 83% and 46% Only
• 33% and 50% lesser need of surfactant

15. IN-SU-RE technique
Stevens et al. Cochrane 2007
Reduction in mechanical ventilation,
BPD, mortality
Always combine with early CPAP
Grade A
Grade A

16. Volume Targetted Ventilation
Uses Lesser PIP once
Lungs Improve
• Relatively constant Tidal
Volumes
• Prevention of
Overdistension and
Volume Trauma- Sudden
changes in Compliance
• Automatic-Weaning
• Compensation for
Variable Respiratory
Drive
Grade A ( Cochrane,2011)

17. How does NIV work?
CPAP
• ↑FRC
• Stabilization of the
chest wall
• ↓in airway
resistance
• Improvement in lung
volume and
oxygenation
NIPPV
• ↑in MAP allowing
better recruitment
of alveoli
• ↓work of breathing
• ↑in Vt and minute
volume
• Improving the
respiratory drive

18. Minimally Invasive Surfactant Therapy
• These techniques have included administration of
exogenous surfactant by
• Brief tracheal catheterization,
• Aerosolization, and laryngeal mask.
• Of these, the methods involving brief tracheal
catheterization have been most extensively studied,
with surfactant administered by using both a
flexible feeding tube and a semi-rigid vascular
catheter

19. Less Invasive Surfactant Administration…The
Future
• Surfactant administration by minimally
invasive methods that allow for spontaneous
breathing might be safer and more effective
than administration with endotracheal
intubation and mechanical ventilation in
preterms ‘at risk’ or with RDS
American Academy of Pediatrics ,July 2014, VOLUME 15 / ISSUE

20. Management of early BPD
• Exogenous surfactant replacement therapy has been effective in
RDS , but has not decreased the incidence of BPD.
• Multicentre RCTs evaluating outcomes of infants who were on MV and
received late surfactant at 2 weeks did not show significant difference in the
outcome of severe BPD, but surfactant treated group had lesser respiratory
morbidity at 1 yr of age.*
• Cochrane review with meta-analysis of RCTs showed slight decrease in the
risk of BPD or mortality associated with use of animal derived versus synthetic
surfactant in preterm infants at risk of developing RDS*
• RCT is in progress comparing synthetic surfactant CHF5633 to Curosurf in
extremely preterm infants with BPD as one of the outcome
* Hascoet JM, Picaud JC, Ligi I, et al. Late Surfactant Administration in Very Preterm Neonates With Prolonged
Respiratory Distress and Pulmonary Outcome at 1 Year of Age: A Randomized Clinical Trial. JAMA pediatrics.
2016;170:365-372.
* Ardell S, Pfister RH, Soll R. Animal derived surfactant extract versus protein free synthetic surfactant for the
prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2015;8:CD000144
EARLY BPD

21. Surfactant Delivery And Ventilation Statergy
• Mode of surfactant delivery- Meta-analysis of 6 RCTs have
concluded that LISA decreases the risk of BPD, death
,early CPAP failure or invasive ventilation requirements.
• Meta analysis comparing prophylactic CPAP to assisted
ventilation with or without surfactant in preterm infants less
than 32 weeks gestation demonstrated reduction in the
incidence of BPD*
• No significant difference in the outcome of BPD was noted
with prophylactic INSURE vs CPAP.
• NIPPV is more effective than NCPAP in preventing BPD,
however as primary respiratory support no difference was seen
in incidence of BPD.
* Rigo V, Lefebvre C, Broux I. Surfactant instillation in spontaneously breathing preterm
infants: a systematic review and meta-analysis. European journal of
pediatrics.2016;175:1933-1942.
EARLY BPD

22. VENTILATION STATERGY
• Ventilation strategy- As lung compliance changes rapidly during RDS and
its treatment, volume targeted ventilation appears to be
appropriate.
• Cochrane review reported 21% reduction in death/BPD for VTV
compared to pressure limited MV.*
• Cochrane review on elective use of HFOV soon after intubation
showed significant reduction in death/BPD at 36-37 weeks PMA
or discharge and in BPD alone.*
EARLY BPD
* Klingenberg C, Wheeler KI, McCallion N, et al. Volume-targeted versus pressure limited
ventilation in neonates. Cochrane Database Syst Rev 2017;10:CD003666.
*Cools F, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus
conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane
Database Syst Rev 2015:CD000104

23. Steroids In BPD
• PREMILOC TRIAL- Large multicentre randomised placebo controlled
trial designed to look at the effect of early low dose hydrocortisone
on survival without BPD in extremely preterm infants with gestation
24 0/7 to 27 6/7 wks.*
• Hydrocortisone was administered at a dose of 1mg/kg/day
divided into two doses on days 1-7 followed by one dose 0.5
mg/kg/day for next 3 days.*
• 60% survived without BPD compared to 51% assigned to
placebo , Odds ratio -1.48* (p<0.04)
• Long term follow up results showed no significant difference in
neurodevelopmental outcomes between infants in the 2 groups at 2 year
follow up.*
EARLY BPD
Baud O, Maury L, Lebail F, et al. Effect of early low-dose hydrocortisone on survival
without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a
double-blind, placebo-controlled, multicentre, randomised trial. Lancet. 2016;387:1827

24. Inhaled Steroids In BPD
• NEUROSIS TRIAL-Inhaled budesonide vs placebo was administered to
extremely premature infants (23 0/7 to 27 6/7 weeks GA) starting within 24
hrs after birth.*
• Budesonide was administered at dose of 400 mcg every 12 hrs in the first
14 days of life and 200 mcg from day 15 until infants no longer need
respiratory support.*
• Infants who received budesonide had lower rate of BPD but higher death
rate (16.9 vs 13.6 %)*
• Meta-analysis of published trials have concluded that inhaled steroids
were associated with significant reduction in BPD, however long
term studies are needed before routine recommendation*
EARLY BPD
*Bassler D, Plavka R, Shinwell ES, et al. Early Inhaled Budesonide for the Prevention of
Bronchopulmonary Dysplasia. N Engl J Med. 2015;373:1497-1506

25. Surfactant With Steroids for BPD
• Meta-analysis of 2 RCTs demonstrated intratracheal
budesonide-surfactant mixture was associated with decreased
risk of BPD and composite outcome of death/BPD.
• In the above studies, very low birth weight infants with severe
RDS requiring mechanical ventilation and fractional inspired
concentration >0.5 were randomised to receive either
intratracheal budesonide combined with survanta or survanta
alone within four hours after birth.
• Intervention group had significantly lower incidence of
BPD/death with number needed to treat 4.1 95% CI
2.8-7.8*
EARLY BPD
*Yeh TF, Chen CM, Wu SY, et al. Intratracheal Administration of Budesonide/Surfactant
to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193:86-95

26. • Intra-tracheal administration of budesonide-
surfactant combination was associated with
decreased incidence of BPD alone or composite
outcome of death or BPD in VLBW
Intra-Tracheal Administration of Budesonide-Surfactant in
Prevention of Bronchopulmonary Dysplasia in Very LBWs:
A Systematic Review and Meta-Analysis.
Venkataraman , Kamaluddeen , Hasan SU, Robertson HL, Lodha A
Pediatr Pulmonol. 2017 Jul;52(7):968-975. doi: 10.1002/ppul.23680. Epub 2017 Feb 6.
EARLY BPD

27. AZITHROMYCIN AND BPD
 Meta-analysis support (12 RCTs) the association between ureaplasma
infection and development of chronic lung disease in preterm infants.
 Macrolide antibiotics has immunomodulatory effects suppressing lung
inflammation
 Treatment with azithromycin has been promising in a meta-analysis
demonstrating reduction in BPD in preterm infants when given
prophylactically.
 Studies combining use of all macrolides in ureaplasma colonised ventilated
preterm infants did not show reduction in BPD ,hence routine use for the
prevention of BPD is not recommended.*
EARLY BPD
*Nair V, Loganathan P, Soraisham AS. Azithromycin and other macrolides for
prevention of bronchopulmonary dysplasia: a systematic review and meta-analysis.
Neonatology. 2014;106:337–347

28. Nitric Oxide And BPD
 Infants with BPD are at increased risk for secondary pulmonary
hypertension due to intermittent episodes of hypoxia causing
pulmonary vasoconstriction.
 17 clinical RCTs - iNO was administered as either treatment during first
three days of life, routine use in preterm babies along with respiratory
support or later treatment for infants at increased risk for BPD .
 Cochrane systematic review showed no consistent long term
improvement in mortality or the incidence and severity of BPD when
using iNO in preterm infants as prevention or rescue strategy.*
EARLY BPD
* Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure
in preterm infants. Cochrane Database Syst Rev. 2017;12:CD000509.

29. • 22 RCTs were incorporated. Risk of BPD was significantly
lower in preterm infants supplemented with iNO (relative
risk [RR] = 0.88; P = 0.0007)

30. Proven Benefits in BPD!
 CAFFEINE- RCT of Caffeine for apnoea of prematurity (CAP) trial
provide unequivocal evidence in the reduction of BPD by 36 % in VLBW
infants. BPD was decreased by 52 % if caffeine was given on postnatal days 1-
3 compared to 23 % reduction if given after day 3.*
 Phase 4 trial is evaluating if administration of caffeine at earlier time (2 vs 12
hrs of life ) in infants born <32 weeks will have an effect on intubation rates*
 VITAMIN A- BPD rates was reduced by 13 % in infants <1000 gms
receiving Vit A( 3*5000 IU/week intramuscular over 4 weeks) compared with
placebo
 EXCLUSIVE BREAST MILK-Data from german neonatal network have
shown exclusively formula fed infants have 2.6 times increased risk of BPD
than breast milk fed infants*
EARLY BPD
*Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med
2006;354:2112–21.
*Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and shortand
long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev

31. Other Strategies in BPD…Promising!
 PENTOXIFYLLINE- It decreases production of inflammatory cytokines
and has significant immunomodulatory properties.
 Pilot study of 150 VLBW infants had shown nebulised pentoxifylline
reduced risk of BPD , however recent RCT in preterm infants in 81
preterm infants demonstrated nebulised pentoxifylline did not reduce
duration of oxygen supplementation*
 OMEGA 3 LONG CHAIN PUFA-Meta-analysis including 18 RCTs
showed that omega 3 LCPUFA supplementation was not associated with
decreased risk of BPD, but when considering RCTs less than 32 weeks of
gestation, authors found trend toward reduced BPD rates*
EARLY BPD
*Lauterbach R, Szymura-Oleksiak J, Pawlik D, Warchol J, Lisowska-Miszczyk I,
Rytlewski K. Nebulized pentoxifylline for prevention of bronchopulmonary dysplasia
in very low birth weight infants: a pilot clinical study. J Matern Fetal Neonatal Med.
2006;19:433–438.
*Zhang P, Lavoie PM, Lacaze-Masmonteil T, Rhainds M, Marc I. Omega-3 long-
chain polyunsaturated fatty acids for extremely preterm infants: a systematic
review. Pediatrics. 2014;134:120–134

32. Management in ‘EVOLVING
BPD’
 STOP-BPD TRIAL-Effect of hydrocortisone initiated between
7 and 14 days after birth on death/BPD in very preterm infants
 Preterm infants with gestational age of less than 30 weeks and/or
birth weight of less than 1250 g were randomly assigned to receive
22 day course of systemic hydrocortisone or placebo *
 Death or BPD occurred in 128 of 181(70.7%) infants randomised to
hydrocortisone and in 140 of 190(73.7%) infants randomised to
placebo.
 Among mechanically ventilated very preterm infants administration
of hydrocortisone between 7 and 14 days after birth, compared with
placebo did not improve the composite outcome of death or BPD
at 36 weeks postmenstrual age.
*Onland W et al. Effect of hydrocortisone therapy initiated 7-14days after birth on
mortality or bronchopulmonary dysplasia among very preterm infants receiving
mechanical ventillation. JAMA 2019; 321:354-363

33. Diuretics and BPD
 Premature infants with BPD develop interstitial and alveolar edema due to
iatrogenic fluid overload to maintain adequate hydration and nutrition ,
capillary leak due to pulmonary inflammation or patent ductus arteriosus
due to pulmonary over circulation.
 Diuretics improve pulmonary edema and lead to decreased pulmonary
vascular resistance and improved pulmonary compliance.
 However Cochrane meta-analysis revealed enteral administration of
furosemide in preterm infants at 3 weeks of age resulted in minimal
effect on BPD, whereas single dose of aerosolized furosemide in preterm
infants >3 weeks of age found transient improvement in pulmonary
function.
 Cochrane meta-analysis of six studies on the use of thiazides in preterm
infants demonstrated improvement in lung mechanics and decreased need
for supplemental furosemide boluses
*Brion et al. Aerolised diuretics for preterm infants with chronic lung disease.
Cochrane database systemic review.
EVOLVING BPD

34. Therapy in Established BPD
 DIURETICS-Thiazides and spironolactone comprise together most
commonly used diuretic in established BPD.
 In a randomised double blind crossover trial with sequential analysis, oral
diuretics improved pulmonary mechanics in 10 infants with BPD.
 Long term use of combination therapy for oxygen dependent BPD infants was
studied in randomised double blind placebo controlled study where infants
receiving spironolactone and hydrochlorothiazide had significant improvement in
lung mechanics, decrease in fraction of inspired oxygen compared to placebo.
 Large meta-analysis in preterm infants greater than 3 weeks of age with chronic
lung disease, acute and chronic administration of thiazide diuretics
showed improved pulmonary mechanics.
ESTABLISHED BPD
*Kao LC, Warburton D, Cheng MH, Cedeño C, Platzker AC, Keens TG. Effect of oral
diuretics on pulmonary mechanics in infants with chronic bronchopulmonary
dysplasia: results of a double-blind crossover sequential trial. Pediatrics 1984;74:37-
44.
* Kao LC, Durand DJ, McCrea RC, Birch M, Powers RJ, Nickerson BG. Randomized
trial of long term diuretic therapy for infants with oxygen dependent

35. Therapy in Established BPD
 INHALED STEROIDS-Infants with established BPD are
more likely to experience respiratory illness and episodes of
wheezing requiring hospitalisation during first 2 yrs of life.
 In randomised placebo controlled trial -30 infants CLD, who
received fluticasone or placebo via metered dose inhaler and
spacer starting at 36 wks reported no difference in respiratory
symptoms, duration of supplemental O2 use, respiratory
illness or need for hospitalization.
 Yuskel et al showed improvement in respiratory symptoms in
premature infants with chronic lung disease who received
beclomethasone compared to placebo
ESTABLISHED BPD
*Beresford MW, Primhak R, Subhedar NV, Shaw NJ. Randomised double
blind placebo
controlled trial of inhaled fluticasone propionate in infants with chronic lung
disease.

36. Therapy in Established BPD
 SYSTEMIC STEROIDS-No clear indication exists for use
for systemic steroids with established BPD
 Single center study showed the effect of oral prednisolone on
weaning oxygen in infants with established BPD (63 % of
patients were successfully weaned off supplemental oxygen
prior to hospital discharge).*
 Infants who were successfully weaned off supplemental
oxygen received oral prednisolone for single course, no
additional benefit was conferred with multiple courses.
ESTABLISHED BPD
* Bhandari A, Schramm CS, Kimble C, Pappagallo M, Hussain N. Effect of a short
course
of prednisolone in infants with oxygen-dependent bronchopulmonary dysplasia.
Pediatrics 2008;121:e344-349.

37. Therapy in Established BPD
 BRONCHODILATORS-Higher rates of airway reactivity exists in BPD
survivors, but eosinophilic inflammation doesn’t contribute to obstructive
lung disease in BPD.
 Structural abnormalities in the airways along with small airway caliber,
reduced elastic recoil increase airway narrowing with smooth muscle
contraction in BPD survivors.
 In clinical practice, BPD survivors who exhibit wheezing will respond to
albuterol even they don’t fit into asthma paradigm.
 No randomised trials evaluating effects of anticholinergic medications such
as ipratropium bromide in infants with established BPD.
ESTABLISHED BPD
* Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age
children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care
Med 2005;171:68-72.

38. BPD and pulmonary
hypertension
 Thresholds for initiating vasodilator therapy include Trjet velocity >3 /sec,
estimated RV/LV systolic pressure >0.5 and septal flattening in absence of
significant right to left shunt.
 Sildenafil PDE5 inhibitor commonly used first line therapy for BPD associated
PH ,is usually well tolerated. Large retrospective cohort study had identified 17 %
of the 598 infants diagnosed with BPD associated PH received sildenafil.
 Milrinone: PDE3 inhibitor increases cAMP levels in arterial smooth muscles
and myocardium resulting in decreased pulmonary vascular resistance and
increased cardiac contractility. Small series suggested that milrinone improved
biventricular output and reduced RV pressures in NO resistant preterm infants
with PH.
 Bosentan: Orally active non selective ETA and ETB receptor antagonist is
FDA approved for children 3yrs of age and above. Limited data exists for use in
PH.
* Backes CH, Reagan PB, Smith CV, Jadcherla SR, Slaughter JL. Sildenafil
Treatment of Infants With Bronchopulmonary Dysplasia-Associated Pulmonary
Hypertension. Hosp Pediatr. 2016;6(1):27- 33.

39. EMERGING THERAPIES for
BPD
 INOSITOL-Cochrane metanaysis showed significant reduction in death compared
with untreated controls, Phase 3 trial is currently in progress for prevention of
BPD.
 Recombinant Human Club Cell 10-Kilodalton protein-Levine et al in pilot
study of 22 VLBW ventilated preterm infants with RDS found no difference in the
BPD rates between rhCC treated and control infants. Phase 2 trial is in progress
evaluating survival in ELBW infants.
 Mesenchymal stem cell therapy-Five ongoing clinical trials are in progress,
however recent phase 1 clinical trial, nine preterm infants with Mean GA of 26
weeks at high risk for BPD were treated with intratracheal dose of Allogenic
umbilical cord derived MSCs and BPD appears to be lower compared
with controls.
*Chang YS, Ahn SY, Yoo HS, et al. Mesenchymal stem cells for bronchopulmonary
dysplasia: phase 1 dose-escalation clinical trial. J Pediatr. 2014;164:966.e6- 972.e6.
* Levine CR, Gewolb IH, Allen K, et al. Safety, pharmacokinetics, and antiinflammatory
effects of intratracheal recombinant human Clara cell protein in premature infants with
respiratory distress syndrome. Pediatr Res. 2005;58:15–21.

40. THANK YOU