BPD and Steroids

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

2. Stages of BPD

3. 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)

4. “Old” BPD

5. 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

6. 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

7. “New” BPD

8. Anatomic Development of the Lung

9. Contributors to BPD

10. Development of BPD

11. Development of BPD

12. BPD Lung

13. 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)

14. IncidenceNICHD: Surviving VLBW 1987-1988

15. 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

16. 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

17. BPD and Steroids • Prenatal • Early Post Natal • Late Post Natal

18. 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

19. 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

20. BPD and SteroidsPostnatal Steroids:Late (³1 wk)

21. BPD and SteroidsPostnatal Steroids (<1 wk)

22. 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)

23. 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

24. BPD and SteroidsLong Term Issues • 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.

25. BPD and SteroidsLong Term Issues • 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

26. 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.

27. Steroids and BPD No 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)

28. DART trial(2006)

29. DART trial

30. Mortality/BPD and Dex.(Favors Dex.) Early Late

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

32. 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

33. 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

34. 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.

35. 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

36. So what do I do??

37. Steroids Comparison

38. Goal of Steroid Use

39. 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 • 10day course - Wean over 10 days • +/- Prednisone if rebound (???)