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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

MCH Research Roundtable:Early Cortisol Replacement to Prevent BPD

Grant MCJ - 420633

Kristi L. Watterberg, M.D.


Outline of presentation
Outline of Presentation

  • Introduction to bronchopulmonary dysplasia

  • Previous use of steroids for BPD

  • A new paradigm: adrenal insufficiency & BPD

  • Intervention: cortisol replacement pilot study


Bronchopulmonary dysplasia
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


Bpd a risk factor for
BPD - a risk factor for:

  • Prolonged hospitalization & rehospitalization

  • Future lung disease

  • Poor growth

  • Impaired neurodevelopmental outcome


Oxygen

Ventilation

Chronic lung disease

Endotracheal tube

Suctioning

Pneumonia


Inflammation and bpd
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


Dexamethasone early studies
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)


Prevention multicenter trials
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)


Dex a few side effects
Dex: a few side effects

  • Hyperglycemia

  • Hypertension, cardiac hypertrophy

  • Proteolysis, muscle wasting, osteopenia

  • Sepsis

  • Adrenal suppression

  • GI perforation

  • Growth failure

  • Neurodevelopmental impairment


Steroids are stress hormones
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?


Why dexamethasone
Why dexamethasone?

  • Very long half-life, compared to cortisol

  • Very high blood levels achieved

  • Pharmacokinetics almost unknown

  • May have unique toxic properties


Why this dose
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


Oxygen

Ventilation

Chronic lung disease

Endotracheal tube

Suctioning

Pneumonia



Oxygen

Repair & Resolution

Ventilation

Host response

Chorioamnionitis

Suctioning

Chronic lung disease

Pneumonia


Cortisol and the host response
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


Early gestation
Early Gestation

Mother Placenta Fetus

Cortisol Cortisol

(fetal ACTH)

(fetal cortisol)


Later gestation
Later Gestation

Mother Placenta Fetus

Cortisol 11 HSD (maternal cortisol)

Cortisone  ACTH

 Fetal Cortisol


Extremely premature infant
Extremely Premature Infant

Mother Placenta Fetus

Cortisol Cortisol

(11HSD)

Cortisone(fetal ACTH)

(fetal cortisol)


Relative adrenal insufficiency
‘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


Evidence linking early adrenal insufficiency with cld
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


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


Background
Background Chronic Lung Disease in Premature Infants

  • 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


Background1
Background Chronic Lung Disease in Premature Infants

  • Many premature infants show biochemical evidence of adrenal insufficiency

  • Infants who develop BPD have a decreased cortisol response to ACTH early in life


Hypothesis
Hypothesis Chronic Lung Disease in Premature Infants

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


Study design population
Study Design: Population Chronic Lung Disease in Premature Infants

  • 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


Study design steroid dose
Study Design: Steroid Dose Chronic Lung Disease in Premature Infants

  • 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)


Study design outcomes
Study Design: Outcomes Chronic Lung Disease in Premature Infants

  • “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


Results population characteristics
Results: Chronic Lung Disease in Premature Infants 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)


Results primary outcome
Results: Primary Outcome Chronic Lung Disease in Premature Infants

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.


Results other respiratory outcomes
Results: Chronic Lung Disease in Premature InfantsOther 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)


Results adverse effects
Results: Adverse Effects Chronic Lung Disease in Premature Infants

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%


Results adverse outcomes
Results: Adverse Outcomes Chronic Lung Disease in Premature Infants

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%)


Chronic Lung Disease in Premature Infants HC  Placebo


Chronic Lung Disease in Premature Infants HC  Placebo


Chronic Lung Disease in Premature Infants HC  Placebo


Chronic Lung Disease in Premature Infants HC  Placebo


Chronic Lung Disease in Premature Infants HC  Placebo


Chronic Lung Disease in Premature Infants HC  Placebo


Conclusions
Conclusions Chronic Lung Disease in Premature Infants

  • 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%).


Conclusions1
Conclusions Chronic Lung Disease in Premature Infants

  • 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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