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MCH Research Roundtable: Early Cortisol Replacement to Prevent BPD

MCH Research Roundtable: Early Cortisol Replacement to Prevent BPD. Grant MCJ - 420633 Kristi L. Watterberg, M.D. Outline of Presentation. Introduction to bronchopulmonary dysplasia Previous use of steroids for BPD A new paradigm: adrenal insufficiency & BPD

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MCH Research Roundtable: Early Cortisol Replacement to Prevent BPD

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  1. MCH Research Roundtable:Early Cortisol Replacement to Prevent BPD Grant MCJ - 420633 Kristi L. Watterberg, M.D.

  2. Outline of Presentation • Introduction to bronchopulmonary dysplasia • Previous use of steroids for BPD • A new paradigm: adrenal insufficiency & BPD • Intervention: cortisol replacement pilot study

  3. Bronchopulmonary Dysplasia • Chronic lung disease following acute neonatal lung injury • Oxygen at 28 days of life or 36 weeks gestation • Usually occurs in premature infants • Affects about 15,000 infants/year • Affects about half of the infants < 1000 g BW

  4. BPD - a risk factor for: • Prolonged hospitalization & rehospitalization • Future lung disease • Poor growth • Impaired neurodevelopmental outcome

  5. Oxygen Ventilation Chronic lung disease Endotracheal tube Suctioning Pneumonia

  6. Inflammation and BPD • Broad, early increases in lung inflammation • neutrophils and neutrophil elastase • cytokines (interleukin 1, interleukins 6 and 8) • protein leakage into airspaces •  inflammation after dexamethasone treatment

  7. Dexamethasone: Early Studies • Abstracts: early anecdotes (‘78, ‘80, ‘81) • ‘hastened weaning from ventilator’ (Mammel et al, 6 infants; Lancet, 1983) • ‘striking short-term improvement’ (Avery et al, 16 infants; Pediatrics, 1985) • faster weaning from IMV and O2 (Cummings et al, 36 infants; NEJM, 1989)

  8. Prevention: Multicenter Trials • Dex works (Yeh et al, Pediatrics 1997) • Or it doesn’t(Sinkin et al, Pediatrics 2000) • Dex works, but dose  for adverse effect (Garland et al, Pediatrics 1999) • Study stopped for lack of efficacy and/or safety concerns (Vermont-Oxford Network, abstract, 1999) (NICHD Neonatal Network, abstract, 1999)

  9. Dex: a few side effects • Hyperglycemia • Hypertension, cardiac hypertrophy • Proteolysis, muscle wasting, osteopenia • Sepsis • Adrenal suppression • GI perforation • Growth failure • Neurodevelopmental impairment

  10. Steroids are stress hormones Short-termLong-term Mobilize energyProtein wasting  CV tone BP, hypertrophy Suppress: -digestionGI ulceration, perforation -immune response Immune suppression -growthShort stature  alveolar surface area? brain growth?

  11. Why dexamethasone? • Very long half-life, compared to cortisol • Very high blood levels achieved • Pharmacokinetics almost unknown • May have unique toxic properties

  12. Why this dose? • Endogenous cortisol production: 7.5mg/m2/d (0.75mg/kg for 1 kg baby) • 0.5 mg/kg/day of dex = 12.5 - 20 mg/kg/d of hydrocortisone, or . . . •  15 - 30x endogenous cortisol production

  13. Oxygen Ventilation Chronic lung disease Endotracheal tube Suctioning Pneumonia

  14. Why do some infants get BPD, while others do not?

  15. Oxygen Repair & Resolution Ventilation Host response Chorioamnionitis Suctioning Chronic lung disease Pneumonia

  16. Cortisol and the host response • Injury produces inflammation • Cortisol is central to the resolution of inflammation •  production during stress/injury • Fetal cortisol production is suppressed until late in gestation

  17. Early Gestation Mother Placenta Fetus Cortisol Cortisol (fetal ACTH) (fetal cortisol)

  18. Later Gestation Mother Placenta Fetus Cortisol 11 HSD (maternal cortisol) Cortisone  ACTH  Fetal Cortisol

  19. Extremely Premature Infant Mother Placenta Fetus Cortisol Cortisol (11HSD) Cortisone(fetal ACTH) (fetal cortisol)

  20. ‘Relative’ Adrenal Insufficiency • Described in adult patients in ICUs • Associated with cardiovascular instability and increased mortality • May have ‘normal’ basal cortisol values • Unable to respond to stress/illness

  21. Evidence linking early adrenal insufficiency with CLD •  cortisol and  response to ACTH • cortisol precursors • cortisol in infants with PDA • Inverse correlation of cortisol with lung inflammation and protein leak • Direct correlation of cortisol with enteral nutrition

  22. Prophylaxis Against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants Kristi L. Watterberg, M.D. Jeffrey S. Gerdes, M.D. Kathleen L. Gifford, R.N. Hung-Mo Lin, Ph.D. Pennsylvania State University University of Pennsylvania

  23. Background • Infants who develop chronic lung disease (BPD) have increased lung inflammation • Cortisol plays a central role in attenuating the body’s response to inflammatory stimuli

  24. Background • Many premature infants show biochemical evidence of adrenal insufficiency • Infants who develop BPD have a decreased cortisol response to ACTH early in life

  25. Hypothesis Prevention of early adrenal insufficiency will decrease the incidence of BPD in extremely low birth weight infants.

  26. Study Design: Population • Prospective, randomized, double-blind, placebo-controlled pilot study at 2 centers • Population: 500 - 999 grams birth weight • Intubated beyond 12 hours of life • Enrolled before 48 hours of life • Exclusions: SGA, congenital sepsis, major congenital anomaly, maternal diabetes

  27. Study Design: Steroid Dose • Hydrocortisone (HC) given for 12 days: 1 mg/kg/day x 9 days (~8-10 mg/m2/day), then 0.5 mg/kg/day x 3 days • Equivalent to 5% - 8% of the commonly used dexamethasone dose of 0.5mg/kg/day • Equivalent dexamethasone dose would be ~0.025 - 0.04 mg/kg/day (~25-40x potency)

  28. Study Design: Outcomes • “Success” = Survival without CLD at 36 weeks postmenstrual age • 1997 Vermont-Oxford data: 39% ‘success’ for 500 - 999g infants (73% survival, 47% CLD in survivors) • Secondary outcomes: CLD in survivors, other clinical outcome measures, and adverse events

  29. Results: Population Characteristics Treatment (20) Placebo (20) BW (g) 732135* 770135 GA (wks) 25.21.3 25.41.5 Steroids 17 (85%) 17 (85%) FiO2 (12o) 0.38.22 0.39.13 MAP (12o) 8.43.1 7.61.3 *(mean SD)

  30. Results: Primary Outcome Survival without CLD: Infants treated with hydrocortisone had significantly better success rate: 60% versus 35% in placebo group *p=0.02, odds ratio 12.3 (1.8 - 151.5) Significant adverse factors included lower birth weight, chorioamnionitis, and preeclampsia.

  31. Results:Other respiratory outcomes Outcome HC (20) Placebo (20) ‘p’ CLD (survivors) 5 (29%) 10 (59%) .17/.04* O2 at discharge 4 (24%) 8 (47%) .09/.04 Days on: Ventilator 25(14-34)† 32 (11-45) .13/.03 >40% O2 7 (3-18) 28 (10-51) .006/.006 Oxygen 48(32-64) 69 (34-75) .11/.02 * analyzed by univariate analysis / multiple regression † median (25-75%ile)

  32. Results: Adverse Effects Treatment Placebo Adverse effect Days (280) Days (269) Hyperglycemia 8% 9% (Glucose>180) Hypertension 8% 6% (MAP 50) Dopamine Rx 9% 18% Insulin Rx 2% 0%

  33. Results: Adverse Outcomes Treatment (20) Placebo (20) • Died 3 (15%) 3 (15%) • Sepsis 5 (25%) 6 (30%) • PDA 8 (40%) 13 (65%) • NEC 2 (10%) 2 (10%) • GI Perf. 1 ( 5%) 1 ( 5%) • Withdrawn 1 ( 5%) 1 ( 5%)

  34.  HC  Placebo

  35.  HC  Placebo

  36.  HC  Placebo

  37.  HC  Placebo

  38.  HC  Placebo

  39.  HC  Placebo

  40. Conclusions • Hydrocortisone therapy in adrenal replacement doses - far below currently used dexamethasone doses - resulted in improved respiratory outcome. • Although the success rate was low in the placebo group (35%), it was similar to that extrapolated from the 1997 Vermont Oxford database (39%).

  41. Conclusions • Benefit was particularly apparent in patients with chorioamnionitis • No increased adverse effects were seen; however, this trial was not powerful enough to rule out a Type II error. • A multicenter trial is warranted, to further assess benefits and risks.

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