bpd and steroids

BPD AND STEROIDSJohn L. Stefano MD

Professor of PediatricsJefferson Medical College

Section Chief, CCHS Division of Neonatology

Stages of BPD

BPD: Definitions 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)

“Old” BPD

Newer Definitions (>2000 )Physiologic Test for Diagnosis of BPD 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

The “New BPD” Hallmark- Arrest in lung development Hazy lungs, minimal cystic changes Persistent O2 requirement that slowly

resolves Less airway reactivity Less pulmonary hypertension

“New” BPD

Anatomic Development of the Lung

Contributors to BPD

Development of BPD

BPD Lung

Incidence 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)

IncidenceNICHD: Surviving VLBW 1987-1988

BirthWeight

% O2 @ 28dPNA (range)

%O2 @ 36wksPCA (no. pts)

501-750g 79%(67%-100%)

26.3%(31/118)

751-1001g 42%(21%-68%)

13.1%(33/252)

1001-1500 13%(5%-23%)

4.5%(42/933)

All 26%(13%-38%)

8.1%(106/1303)

Incidence

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

Incidence - “New BPD” Using “Physiologic test for BPD” NICHD –

2004 17 NICU’s in NICHD network. Incidence

decreased from decreased from 35% to 25% of infants with birth weights < 1250 grams

BPD and Steroids Prenatal Early Post Natal Late Post Natal

BPD and SteroidsPrenatal Steroids

NIH Concensus Statement 1995 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

BPD and SteroidsPostnatal Steroids

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

BPD and SteroidsPostnatal Steroids:Late (³1 wk)

Study Age/Duration

Group No. IMVduration

O2duration

LOS

Avery et al1985

>14d for>30d tx

PlDex

88

0/7 Ext7/7 Ext*

--

62d86d

Harkavy etal 1989

>30d for> 14d tx

PlDex

129

57.2d39.4d*

95.5d74.9d

119d111d

Cummingset al 1989

>14d18d or 42dtx

PlDex 18Dex 42

111213

84d73d29d*

136d190d 65d**

---

Kazzi et al1990

21-28d17d tx

PlDex/HC

1112

3/11 Ext8/12 Ext*

75d79d

76d87d

Collaborat.Dex Trial1991

~21d7d tx9d optional

PlDex

142143

17.5d11d *

O2>60d38%33%

>100d27%22%

Ohlsson etal 1992

21-35d9d tx

PlDex

1312

2/13 Ext8/12 Ext*

--

--

Brozanski etal 1995

7d3d q 10d

PlDex

3939

74d49d

209d150d *

140d115d

Durand et al1995

7-14d7d tx

PlDex

2023

35d20d *

O2@28d68%32% *

85d69d *

BPD and SteroidsPostnatal Steroids (<1 wk)

Study Age/ Duration

Group No. IMV Duration

O2 Duration

O2@ ????

Yeh et al 1990

Dex 1mg/k/dx3d taper x12d

Pl Dex

29 28

Ext @2wk 28% 57% *

32d 27d

O2>40% 20d 8d

Sanders et al 1994

Dex .5mg/k q 12h for 1 day

Pl Dex

21 19

47d 35d

73d 44d

no BPD 43% 68%

Suske et al 1996

Dex .5 mg/k/d x 5d

Pl Dex

12 14

14.2d 6.6d *

12.5d 4.1d *

O2>28d 25% 7%

Shinwell et al 1996

Dex .25mg/k q12 x3d

Pl Dex

116 132

11d 9d

19d 20d

O2>40% 10d 8d

Rastogi et al 1996

Dex .5mg/k/d taper x 12d

Pl Dex

34 36

23.4d 8.4d

42.2d 12.2d *

O2>40% 10.5d 1.5d *

Tapia et Dex O2>36w

Postnatal Steroids: Short Term Side Effects

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)

BPD and SteroidsLong Term Issues

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


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.


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

First AAP Statement (2002)

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.

Steroids and BPDNo good at all???

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)

DART trial(2006)

DART trial

Mortality/BPD and Dex.(Favors Dex.)

Early

Late

Dex. and N/D outcome(no effect on CP or MDI)

Early

Late

Hydrocortisone and BPD 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

BPD and SteroidsInhaled steroids

Less side effects than systemic steroids Problems with delivery of medication to

distal airways: Arnon et al 1992 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

Inhaled Steroids and BPD 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 side-effects.

Most recent AAP statement2010

Dexamethasone High dose-do not recommend Low dose-may facilitate extubation and

reduce short and long term issues seen with high dose Dex

Hydrocortisone Early hydrocortisone treatment may be

beneficial in a specific population of infants. Inhaled Corticosteroids

No efficacy. No change from previous statement

So what do I do??

Steroids ComparisonGlucocorticoid

Approximate Equivalent Dose (mg)

Routes of Administration

Relative

Anti-inflammatory

Potency

Relative Mineralocortic

oid Potency

Protein Binding

(%)

Half-life Plasma

(min)

Short-Acting Cortisone 25 P.O., I.M. 0.8 0.8 90 30Hydrocortisone 20 I.M., I.V. 1 1 90 90

Intermediate-Acting MethylPREDNISolone1 4 P.O., I.M., I.V. 5 0 — 180

PrednisoLONE 5P.O., I.M., I.V., intra-articular,

intradermal, soft tissue injection

4 0.8 90-95 200

PredniSONE 5 P.O. 4 0.8 70 60

Triamcinolone1 4

I.M., intra-articular,

intradermal, intrasynovial,

soft tissue injection

5 0 — 300

Long-Acting

Betamethasone 0.75

P.O., I.M., intra-articular,

intradermal, intrasynovial,

soft tissue injection

25 0 64 100-300

Dexamethasone 0.75

P.O., I.M., I.V., intra-articular,

intradermal, soft tissue injection

25-30 0 — 100-300

Mineralocorticoids Fludrocortisone — P.O. 10 125 42 200

Goal of Steroid Use

CCHS guidelines for steroid use for BPD

Early: 2-3 weeks post-natal with evolving BPD, ventilated and requiring > 80% FiO2 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 DART treatment – Decadron

Start Decadron 0.15 mg/kg/day 10 day course - Wean over 10 days +/- Prednisone if rebound (???)

bpd and steroids

Documents