John L. Stefano MD
Professor of Pediatrics
Jefferson Medical College
Section Chief, CCHS Division of Neonatology
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Northway definition: Radiographic
History of RDS, PPV x 3d, radiographic
changes plus Oxygen dependency at 28 days
PNA (Bancalari 1979)or...
History of RDS, radiographic changes plus
Oxygen dependency at 36 weeks PCA
(Shennen 1988)
Physiologic Test for Diagnosis of BPD
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Infants at 35 to 37 weeks PMA receiving mechanical
ventilation, continuous positive airway pressure, or
>30% O2 with saturation of <96% have BPD
Infants receiving <30% O2 or 30% O2 with saturation
of >96% tested for O2 need —O2 progressively
decreased gradually to room air —No BPD if
saturation is >90% in room air for 30 min
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Hallmark- Arrest in lung development
Hazy lungs, minimal cystic changes
Persistent O2 requirement that slowly resolves
Less airway reactivity
Less pulmonary hypertension
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Problem: Incidence/Frequency data
depend on which definition is used to
comprise the numerator (eg 28d O2 vs O2 at
36 wks PCA, physiologic definition)
Problem: Incidence/Frequency data
depend on patient population comprising
the denominator (eg NICU
admissions/survivors, ventilated infants,
surfactant treated infants, ELBW etc)
B irth
W eight
% O 2 @ 28d
P N A (range)
% O 2 @ 36w ks
P C A (no. pts)
501-750g
79%
(67% -100% )
42%
(21% -68% )
13%
(5% -23% )
26%
(13% -38% )
26.3%
(31/118)
13.1%
(33/252)
4.5%
(42/933)
8.1%
(106/1303)
751-1001g
1001-1500
A ll
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Since 1980, the incidence of BPD has
increased or decreased depending on the
data reported
Increased incidence-Parker et al, 1992:
 1976-1980---10.6%
 1981-1985---21.7%
 1986-1990---32.9%
However, 72% of this increase was
attributed to increased survival
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Using “Physiologic test for BPD” NICHD –
2004
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17 NICU’s in NICHD network. Incidence decreased
from decreased from 35% to 25% of infants with
birth weights < 1250 grams
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Prenatal
Early Post Natal
Late Post Natal
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NIH Concensus Statement 1995
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Reduction in RDS ~ 50% reduction
Reduction in mortality~ 60% reduction
Reduction in IVH~ 50% reduction
Extrapolate that RDS reduction will result in a
lower BPD rate however no published data
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Many questions, few answers
Timing of steroids: early vs. late
Route: systemic vs. inhaled
Dosing, duration of therapy, pulse vs. daily
Tapering; rebound
Side effects
Study
A ge/
D uration
G roup
N o.
IM V
O2
LOS
duration duration
>14d for
>30d tx
>30d for
> 14d tx
>14d
18d or 42d
tx
K azzi et al
21-28d
1990
17d tx
C ollaborat. ~21d
D ex T rial
7d tx
1991
9d optional
O hlsson et
21-35d
al 1992
9d tx
B rozanski et 7d
al 1995
3d q 10d
Pl
D ex
Pl
D ex
Pl
D ex 18
D ex 42
Pl
D ex/H C
8
8
12
9
11
12
13
11
12
0/7 E xt
7/7 E xt*
57.2d
39.4d*
84d
73d
29d*
3/11 E xt
8/12 E xt*
Pl
D ex
Pl
D ex
Pl
D ex
142
143
13
12
39
39
D urand et al 7-14d
1995
7d tx
Pl
D ex
20
23
A very et al
1985
H arkavy et
al 1989
C um m ings
et al 1989
95.5d
74.9d
136d
190d
65d**
75d
79d
O 2>60d
17.5d
38%
11d *
33%
2/13 E xt 8/12 E xt* 74d
209d
49d
150d *
O 2@ 28d
35d
68%
20d *
32% *
62d
86d
119d
111d
76d
87d
>100d
27%
22%
140d
115d
85d
69d *
Study
Age/
Duration
Group No. IMV
Duration
Yeh et al Dex
1990
1mg/k/dx3d Pl
taper x12d Dex
Sanders Dex
et al 1994 .5mg/k q
12h for 1
day
Suske et Dex
al 1996
.5 mg/k/d x
5d
Shinwell Dex
et al 1996 .25mg/k q12
x3d
Pl
Dex
Dex
29
28
Ext @2wk
28%
57% *
32d
27d
21
19
47d
35d
73d
44d
Pl
Dex
12
14
14.2d
6.6d *
12.5d
4.1d *
Pl
Dex
116
132
11d
9d
19d
20d
34
36
23.4d
8.4d
42.2d
12.2d *
Rastogi Dex
et al 1996 .5mg/k/d
Pl
taper x 12d Dex
Tapia et
O2
O2@
Duration ????
O2>40
%
20d
8d
no BPD
43%
68%
O2>28d
25%
7%
O2>40
%
10d
8d
O2>40
%
10.5d
1.5d *
O2>36w
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Hyperglycemia
Immune suppression & sepsis
Hypertension
Hypertrophic cardiomyopathy
Leukocytosis
Azotemia (catabolic state)
Poor growth (brain, lung, osteopenia)
Adrenal suppression
Gastric Perforation (especially if used with Indocin)
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Animal studies have shown negative
effects on cell growth (brain and lung)
Cummings et al 1989: better Bayley scores
in the 42d treated group (low n; low rate of
IVH in study group)
Sobel et al 1992: Dex>24d  less
cryotherapy for ROP
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In the mid-90’s long term studies start to show concern
for N/D outcome and/or brain growth
 O’Shea TM et al 1993:no difference in growth, CP or
Bayley scores
 Jones R et al 1995: Multi-centered European Study;
no difference in growth, CP, special schooling needs
 NICHD 1996; early vs late Dex; decreased growth
parameters, especially HC in early Dex.
 NICHD 2001; early Dex vs. placebo; less likely to be
O2 dependent at 28 days but lower weight gain and
smaller HC.
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Vermont Oxford Network: (Pediatrics 2001) Early Dex.
No decrease in BPD or death, had fewer days in
supplemental O2, increase risk of GI perforation,
decrease weight gain, trend to have more PVL
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AAP statement on Steroid use to treat or
prevent BPD-suggested moratorium on all
postnatal steroid use for BPD
The statement included a moratorium on the
use of inhaled steroids as well
If considering use of steroids strongly
recommended informed parental consent.
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Wrong steroid?? Why Dexamethasone?
Dex. Has sulfites in preservative---CNS
toxin
Wrong dose of Dex.??- most studies
used 0.5mg/kg/day and then taper.
Dose 10x that needed to saturate
receptors.
Length of therapy?? Rebound?
When to start (early, late, really late)
Early
Late
Early
Late
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Hydrocortisone as an alternative to Dex.
Watterberg et al (Pediatrics 2004) Early
prophylaxis with low dose HC; no difference in
BPD except infants with h/o of
chorioamnionitis; HC and Indocin together—
gastrointestinal perforations (largest study:
n=360)
However, other smaller studies show favorable
effect of low dose hydrocortisone
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Less side effects than systemic steroids
Problems with delivery of medication to
distal airways: Arnon et al 1992
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only .02% of dose with nebulizer
14.2% of dose with metered inhaler
Only a few small studies (n=13-20 infants)
short term improvement in PFT’s, possibly
enhance early extubation; virtually no side
effects
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Cochrane review: inhaled versus systemic
corticosteroids 2003
The review found no evidence that inhaled
corticosteroids confer net advantages over systemic
corticosteroids in the management of ventilator
dependent preterm infants.
Neither inhaled steroids, nor systemic steroids, can be
recommended as standard treatment for ventilated
preterm infants. There was no evidence of difference in
effectiveness or side-effect profiles for inhaled versus
systemic steroids.
A better delivery system guaranteeing selective
delivery of inhaled steroids to the alveoli might result
in beneficial clinical effects without increasing sideeffects.
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Dexamethasone
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Hydrocortisone
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High dose-do not recommend
Low dose-may facilitate extubation and reduce short
and long term issues seen with high dose Dex
Early hydrocortisone treatment may be beneficial in
a specific population of infants.
Inhaled Corticosteroids
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No efficacy. No change from previous statement
Relative
Protein Binding
Half-life Plasma
(%)
(min)
0.8
1
90
90
30
90
5
0
—
180
4
0.8
90-95
200
4
0.8
70
60
5
0
—
300
25
0
64
100-300
25-30
0
—
100-300
Mineralocorticoids
10
125
42
200
Approximate
Equivalent Dose
(mg)
Routes of
Administration
Cortisone
Hydrocortisone
25
20
P.O., I.M.
I.M., I.V.
Short-Acting
0.8
1
Intermediate-Acting
MethylPREDNISo
lone1
4
P.O., I.M., I.V.
Glucocorticoid
PrednisoLONE
5
PredniSONE
5
Triamcinolone1
4
Relative
Mineralocorticoid
Anti-inflammatory
Potency
Potency
P.O., I.M., I.V.,
intra-articular,
intradermal, soft
tissue injection
P.O.
I.M., intra-articular,
intradermal,
intrasynovial, soft
tissue injection
Long-Acting
Betamethasone
0.75
Dexamethasone
0.75
Fludrocortisone
—
P.O., I.M., intraarticular,
intradermal,
intrasynovial, soft
tissue injection
P.O., I.M., I.V.,
intra-articular,
intradermal, soft
tissue injection
P.O.
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Early: 2-3 weeks post-natal with evolving BPD,
ventilated and requiring > 80% FiO2
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Consider Hydrocortisone starting dose of 5 mg/kg/day
No clinical response – decrease in respiratory support – after
second or third day, discontinue
Positive clinical response treat for 24-48 hours then taper over a
period of 7-10 days
Late: 36 weeks PCA with BPD/CLD, FiO2 35-40% or
greater and continued need for ventilation ; X-ray
changes of BPD
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DART treatment – Decadron
 Start Decadron 0.15 mg/kg/day
 10 day course - Wean over 10 days
 +/- Prednisone if rebound (???)