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 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)

 Since 1980, the incidence of BPD has increased or decreased depending on the data reported  Increased incidence-Parker et al, 1992:  %  %  %  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

 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  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

 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 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.

 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) Short-Acting Cortisone 25P.O., I.M Hydrocortisone 20I.M., I.V.1190 Intermediate-Acting MethylPREDNISo lone 1 4P.O., I.M., I.V.50—180 PrednisoLONE 5 P.O., I.M., I.V., intra-articular, intradermal, soft tissue injection PredniSONE 5P.O Triamcinolone 1 4 I.M., intra-articular, intradermal, intrasynovial, soft tissue injection 50—300 Long-Acting Betamethasone 0.75 P.O., I.M., intra- articular, intradermal, intrasynovial, soft tissue injection Dexamethasone 0.75 P.O., I.M., I.V., intra-articular, intradermal, soft tissue injection — Mineralocorticoids Fludrocortisone —P.O

 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 hours then taper over a period of 7-10 days  Late: 36 weeks PCA with BPD/CLD, FiO % 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 (???)