Randomized Trial of Hydrocortisone in Very Preterm High-Risk Infants
Condition: Bronchopulmonary Dysplasia; Encephalomalacia; Premature Birth
MeSH terms: Bronchopulmonary Dysplasia; Encephalomalacia; Premature Birth
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether treatment of very preterm infants at
      high-risk for lung and brain injury with low dose hydrocortisone results in improved
      pulmonary and neurologic outcomes.
    

Detailed description: 
      Hypothesis: Among extremely low birth weight infants (ELBW; BW ≤ 1000 g) at high risk for
      bronchopulmonary dysplasia (BPD) and neurologic impairments, those infants randomized to
      seven days of hydrocortisone will demonstrate increased total cerebral tissue volumes as
      compared to infants randomized to placebo.

      Specific Aims: 1) To perform a pilot blinded randomized controlled trial of a 7-day regimen
      of low dose hydrocortisone in ELBW infants at high risk for BPD and neurosensory impairments
      and assess its effect on cerebral tissue volumes. 2) Evaluate and report 2 year
      neurodevelopmental outcomes.

      Background and Significance: Bronchopulmonary dysplasia is a disease of arrested lung
      development and lung inflammation. It is primarily seen in ELBW infants. Neurological delay,
      including cerebral palsy and mental retardation, affect up to 40%-50% of surviving ELBW
      infants. BPD is an important risk factor for such neurological delay. Postnatal
      administration of corticosteroids to ventilated preterm neonates results in a reduced risk of
      developing BPD. Postnatal corticosteroids however have shown harmful effects on the brain and
      can lead to increased rates of cerebral palsy and learning problems. This effect has
      primarily been seen with dexamethasone when high doses were given in the first week of life.
      Beyond the first week of life, there is insufficient information on the effects of steroids
      on the brain. Steroids other than dexamethasone, in much lower doses have been shown to
      improve short term lung function with minimal short-term side effects. A review study of all
      steroid trials for BPD shows that when given to a high risk group of infants (> 50% risk of
      BPD) steroids protect the brain and reduce rates of cerebral palsy. The American and Canadian
      Pediatric societies and respected researchers have commented on the urgent need for more
      trials of other corticosteroids at lower doses started after the first week of life to
      evaluate their short and long-term pulmonary and neurological benefits and risks.

      Research Design and Methods:

        1. Inclusion & Exclusion Criteria: See below.

        2. Procedures: Consented eligible patients will be randomly assigned to receive
           hydrocortisone in a tapering schedule over 7 days or placebo (comparison group). Study
           drug will be given every 12 hours IV with only study pharmacist aware of assignment. The
           patient's anatomic brain MRI (routinely done on all ELBW infants at 38 weeks
           post-menstrual age) will be further processed by the masked study investigators to
           derive total and regional brain volumes. Administration of indomethacin or dexamethasone
           to enrolled infants will be closely monitored and regulated throughout the trial period.
           Indomethacin use during study period is contraindicated. Dexamethasone (or other
           steroid) use will be restricted to ELBW infants on high ventilator settings (RIS > 10)
           after 28 days of life. All other procedures will be per routine care. Blinded
           developmental follow-up at two years, already currently performed for all ELBW infants
           at MHCH, will be analyzed and reported for all study infants.
    

Intervention name(s): Hydrocortisone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Hydrocortisone 3 mg/kg/d divided q 12h IV/PO tapered over 7 days; Saline
Intervention MeSH terms: Hydrocortisone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Bronchopulmonary Dysplasia; Encephalomalacia; Brain injury; Neurosensory impairment; Corticosteroids; Anti-Inflammatory Agents; Extremely Low Birth Weight (ELBW) infants; Premature Birth; Magnetic Resonance Imaging