John L. Stefano MD Professor of Pediatrics Jefferson Medical College Section Chief, CCHS Division of Neonatology

   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  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

     Hallmark- Arrest in lung development Hazy lungs, minimal cystic changes Persistent O2 requirement that slowly resolves Less airway reactivity Less pulmonary hypertension

  Problem: Incidence/Frequency data depend on which definition is used to comprise the numerator (eg 28d O 2 vs O 2 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)

Birth Weight

501-750g 751-1001g 1001-1500 All

% O2 @ 28d PNA (range)

79% (67%-100%) 42% (21%-68%) 13% (5%-23%) 26% (13%-38%)

%O2 @ 36wks PCA (no. pts)

26.3% (31/118) 13.1% (33/252) 4.5% (42/933) 8.1% (106/1303)

   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

 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

   Prenatal Early Post Natal Late Post Natal

  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

      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 Age/ Duration

Avery et al 1985 Harkavy et al 1989 Cummings et al 1989 Kazzi et al 1990 Collaborat.

Dex Trial 1991 Ohlsson et al 1992 Brozanski et al 1995 >14d for >30d tx >30d for > 14d tx >14d 18d or 42d tx 21-28d 17d tx ~21d 7d tx 9d optional 21-35d 9d tx 7d 3d q 10d Durand et al 1995 7-14d 7d tx

Group No. IMV duration O2 duration LOS

Pl Dex Pl Dex Pl Dex 18 Dex 42 Pl Dex/HC 8 8 12 9 11 12 13 11 12 Pl Dex Pl Dex Pl Dex Pl Dex 142 143 13 12 39 39 20 23 0/7 Ext 7/7 Ext* 57.2d

39.4d* 84d 73d 29d* 3/11 Ext 8/12 Ext* 17.5d

11d * 2/13 Ext 8/12 Ext* 74d 49d 35d 20d * 95.5d

74.9d

136d 190d 65d** 75d 79d O2>60d 38% 33% 209d 150d * O2@28d 68% 32% * 62d 86d 119d 111d 76d 87d >100d 27% 22% 140d 115d 85d 69d *

Study Yeh et al 1990 Age/ Duration Dex 1mg/k/dx3d taper x12d Group No. IMV Duration Pl Dex 29 28 Ext @2wk 28% 57% * Sanders Dex et al 1994 .5mg/k q Suske et al 1996 12h for 1 day Dex .5 mg/k/d x 5d Shinwell et al 1996 Dex .25mg/k q12 x3d Pl Dex Pl Dex Pl Dex Rastogi Dex et al 1996 .5mg/k/d taper x 12d Pl Dex Tapia et Dex 21 19 47d 35d 12 14 116 132 14.2d 6.6d * 11d 9d 34 36 23.4d 8.4d O2 O2@ Duration ???? 32d 27d 73d 44d O2>40 % 20d 8d no BPD 43% 68% 12.5d 4.1d * 19d 20d 42.2d 12.2d * O2>28d 25% 7% O2>40 % 10d 8d O2>40 % 10.5d 1.5d * O2>36w

         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)

   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 cryotherapy for ROP  less

 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

   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.

     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

   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

   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

    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 systemic steroids. standard treatment for ventilated preterm infants. There was no evidence of difference in effectiveness or side-effect profiles for inhaled versus A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side effects.

  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

Glucocorticoid Approximate Equivalent Dose (mg) Routes of Administration Relative Anti-inflammatory Potency Relative Mineralocorticoid Potency Protein Binding (%) Half-life Plasma (min) Cortisone Hydrocortisone MethylPREDNISo lone 1 PrednisoLONE PredniSONE Triamcinolone Betamethasone 1 Dexamethasone Fludrocortisone

25 20 4 5 5 4 0.75

0.75

— P.O., I.M.

I.M., I.V.

Short-Acting

0.8

1

Intermediate-Acting

5 P.O., I.M., I.V.

P.O., I.M., I.V., intra-articular, intradermal, soft tissue injection P.O.

I.M., intra-articular, intradermal, intrasynovial, soft tissue injection 4 4 5

Long-Acting

P.O., I.M., intra articular, intradermal, intrasynovial, soft tissue injection P.O., I.M., I.V., intra-articular, intradermal, soft tissue injection P.O.

25 25-30

Mineralocorticoids

10 0.8

1 0 0.8

0.8

0 0 0 125 90 90 — 90-95 70 — 64 — 42 30 90 180 200 60 300 100-300 100-300 200

  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 (???)