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The Future of the VLBW-BPD Lung
Alan H. Jobe, MD, PhD
Cincinnati Childrens Hospital
University of Cincinnati
Cincinnati, Ohio
A Brief Summary of the Clinical
Landscape for Infants with GA <29 wks*
Most infants survive 72%
Many infants have BPD - 68%
Mild (28d oxygen requirement) 27%
Moderate oxygen requirement at 36 wks 23%
Severe oxygen + respiratory support
at 36 wks 18%
*Stoll, et al., Pediatr., 2010
But what is BPD?
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The New BPD
28 weeks GA infant with BPD lung
biopsy at 8 months of age
Normal term infant + 5 months
Coalson, Sem in Neonatology, 8:73, 2003
PECAM-1 Immunohistochemistry
Normal Lung BPD Lung
Bhatt, et al., AJRCCM, 164:1971, 2001
Anatomy of decreased alveolarization and
microvascular development is for worse
cases they died.
Most infants survive about 20% are
discharged on home oxygen (Rayatta, 2012).
Few infants have severe airway reactivity
at initial discharge.
Few infants have signicant pulmonary
hypertension.
!"#
Alveolar Stage
Saccular Stage
Canalicular Stage
Months After Term
40
Postnatal Age (years)
1 2
0
1
2
3
4
5
6
0
20
40
60
80
100
32 Wks
Term
2 4 6 8 10 12 14 16 18 %

A
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N
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A
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%

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20 25 30 35
Term
Gestational Age (weeks)
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Term
%

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2 4 6 8 10 12 14 16 18
32 wks
Months After Term
BPD with 33% of alveoli at term and normal accumulation rate
Normal increase in alveolar number
BPD with 33% of alveoli at term and normal accumulation
0
20
40
60
80
100
Normal
BPD with 33% of alveoli at term and normal accumulation
BPD with 33% of alveoli at term and an arrest in
alveolarization
Light Microscopy of Normal Rat Lungs
Burri, Biol Neonate, 89:313, 2006
1d Rat Lung 21d Rat Lung
Scanning EM of Normal Rat Lung
Burri, Biol Neonate, 89:313, 2006
1d Rat Lung 21d Rat Lung
Schittny, et al., A.J. Physiol., 294, 2008
Developmental and Late Alveolarization Formation of
Alveoli and Microvasculature During Development
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Developmental and Late Alveolarization
Schittny, et al., A.J. Physiol., 294, 2008
Adult Mice Lose Alveoli with Starvation and
Regenerate Alveoli with Re-feeding
Ad Libitum Feeding 15d Calorie Restriction Calorie Restriction
+ 3d Re-feeding
Massaro, et al., A.J. Physiol-Lung, 286:L896, 2004
Alveolar Volume and Diffusion of CO Indicate Increased Alveolar Number
for Infants 3 to 23 Months of Age
Balinotti, et al., AJRCCM, 179, 2009
Alveolar Volume and DLCO Indicate Decreased Diffusing
Capacity in Infants with BPD
Balinotti, et al., AJRCCM, 2010
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Alveoli continue to form in
healthy children from 7-21
years by measurements of
peripheral airspace
dimensions using
3
HeMR
Alveoli number increased
proportionate to increase in
FRC by 1.9 fold
Naraanan, et al., AJRCCM, 2012
The Science and the Clinical Reality
have Come Together
BPD lungs must grow throughout
childhood for survival.
BPD infants get better not worse.
Stages of BPD for Infants with
Moderate to Severe BPD
Early Injury Acute BPD Chronic BPD
Resolution of
BPD
23-28
Weeks
?-years
28-36
Weeks
36 Weeks
to months
Clinical Outcomes of Infants
with BPD
Reports indicate airway disease,
increased asthma, decreased
exercise tolerance.
A perspective problem
Most reports are for children who had
severe BPD
What is normal enough given the
normal large reserve of lung function?
!"#$"#%
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Consensus Conference Denition of BPD Predicts
18-22 Month Pulmonary and Developmental Outcomes
BPD
Controls Mild Moderate Severe
Number followed
Birth Weight (kg)
Gestational Age (wk)
876
867
27.8
1186
791
25.7
1143
766
25.7
643
798
25.6
Ehrenkranz, et al., Pediatr., 2005
Consensus Conference Denition of BPD Predicts 18-22
Month Pulmonary and Developmental Outcomes
BPD
Controls Mild Moderate Severe
Pulmonary Medications - %
Re-hospitalization-Lung- %
%MDI<70
27.2
23.9
21
29.7
26.7
25.6
40.8
33.5
35.1
46.6
39.4
49.8
Ehrenkranz, et al., Pediatr., 2005
Respiratory Outcomes at 6yrs for
Infants with GA # 25wks (EPICure)
No
BPD
Term
Comparison
Signicant
Number
Wheezing in past yr
Bronchodilators last 12mos
Steroids last 12mos
Peak Exp. Flow (l/min)
56
20%
16%
12%
154
148
13%
11%
9%
182
NS
NS
NS
*
Hennessy, et al., Arch Dis Child, 1037,2008
Respiratory Outcomes at 6yrs for
Infants with GA # 25wks (EPICure)
BPD No BPD Signicant
Number
Wheezing in past yr
Bronchodilators last 12mos
Steroids last 12mos
Peak Exp. Flow (l/min)
163
36%
28%
24%
133
56
20%
16%
12%
154
*
*
*
*
Hennessy, et al., Arch Dis Child, 1037,2008
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Exhaled NO is Decreased in Infants with BPD
Baraldi, et al., AJRCCM, 171:68, 2005
Lung Function at 11 Years for Children Born at
<26
o
Weeks GA in UK - 1995
Fawke, et al., AJRCCM, 2010
BPD No Term BPD No Term
BPD BPD
Thin-section a) inspiratory and b) expiratory computed tomography scans of a 25-yr-old nonsmoking
male, born weighing 1,100 g at 29 weeks gestation, dependent upon supplementary oxygen until 60
days post-partum. The forced expiratory volume in one second z-score was -4.75. There was
moderate-to-severe emphysema (arrows; voxel index 46.7%).
Wong, et al., Eur Respir J, 321, 2008
Patterns of Clinical Decision-Making for
the Treatment of BPD
The clinician who believes commonly
used drug therapies work.
The clinician who thinks most
therapies do not work and may cause
toxicity - the therapeutic nihilist.
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Variance about the Mean
Clinical course of BPD is variable and
chronic
Weeks

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The Clinician who Believes Lasix, Albuterol and Aerosolized

Steroids Work for BPD - Initiating Therapy
Result: Infant on Lasix, Albuterol, Steroids
Start
Lasix
Start
Albuterol
Start
Steroids

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Weeks
The Clinician who Thinks Drugs Cause Complications -
comes on Service to Manage Chronic BPD Treated with
Lasix, Albuterol, Steroids
Result: Infant unchanged and off drugs
Do
Nothing
Do
Nothing
Do
Nothing
Stop
Steroids
Stop
Lasix
Stop
Albuterol
Weeks

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Suggestions for Drug Treatment of BPD

Suspect that all drugs have adverse effects
Anticipate that a drug may have no effect (no
studies showing efcacy of drugs for chronic
BPD)
If you start a drug, be willing to stop it
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Summary
Lungs of infants with BPD improve
during childhood.
Early years require the most care
Minimal information on effective
therapies.
Very long term lung outcomes aging
are unknown.