A Randomized Controlled Trial of the Effect of Hydrocortisone on Survival Without Bronchopulmonary Dysplasia and on Neurodevelopmental Outcomes at 22 - 26 Months of Age in Intubated Infants < 30 Weeks Gestation Age

Brief Summary

Detailed Description

Bronchopulmonary dysplasia (BPD) remains a leading morbidity of the extremely preterm infant, and prolonged mechanical ventilation is associated with increased risk for BPD. Dexamethasone has been used previously to facilitate extubation and decrease the incidence of BPD; however, due to adverse effects on neurodevelopmental outcomes, the use of this drug has decreased. One cohort study suggests that hydrocortisone (HC) may facilitate extubation. HC has thus far not been associated with adverse neurodevelopmental outcomes in either cohort studies or randomized controlled trials. A recent meta-analysis of postnatal corticosteroid therapy begun after the first week of life suggested that "late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes," although the methodological quality of some of the follow-up was acknowledged to be limited. This is a randomized controlled trial to study the efficacy and safety of a 10-day tapering course of hydrocortisone treatment for infants \<30 weeks estimated gestational age at birth who remain intubated at 14 - 28 days postnatal age. Based on previous Network data these criteria define a population with a risk of death or BPD at 36 weeks postmenstrual age of approximately 65 - 75%. The primary outcome for this study will incorporate both (1) survival without moderate to severe BPD by Network physiologic definition and (2) survival without moderate or severe NDI at 18 - 22 months corrected age. Therefore, the results of this study will be reported only when follow-up data are available unless (1) the trial is stopped early by the DSMC because of strong evidence of benefit or harm, or (2) at the time all subjects have completed treatment the DCC finds a substantial survival benefit favoring hydrocortisone (p\<0.001). Individual study assignment will remain masked until the follow-up is completed. Secondary outcomes will include short term measures such as respiratory morbidities and growth at 36 weeks postmenstrual age and long term measures including growth and other outcomes at 22 - 26 months corrected age. Secondary studies include: 1. Effect of Hydrocortisone on the Cardiac mass of Premature Intubated Infants - will determine left ventricular mass index at 36 weeks postmenstrual age (or prior to discharge/transfer if after 34 weeks) in infants enrolled in the hydrocortisone for BPD RCT, and compare HC-treated infants to placebo-treated infants. It will similarly assess and compare the incidence of pulmonary hypertension in these patients. 2. Extended follow-up: Subjects will be seen for a follow-up visit at 5-6 years corrected age to assess functional developmental and respiratory outcomes at early school age. In a subset of five Neonatal Research Network Clinical Centers, impulse oscillometry (IOS), which is the optimal direct measure of lung capacity and function, will be performed to validate the 6-minute walk test and International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire as functional measures of pulmonary status. Also at these five Centers, the six minute walk test, ISAAAC questionnaire, and IOS will be administered as part of (1) the Healthy Lungs sub-study, which will recruit 120 TOP 5 study participants who had minimal lung disease when they were infants to define normative ranges in healthy, preterm-born children, and (2) the Healthy Lungs Two sub-study, which will recruit 120 healthy, term-born children without history of lung disease to characterize functional and mechanical respiratory outcomes at 5-7 years of age.

Primary Outcomes

Secondary Outcomes

• Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade at 36 Weeks Postmenstrual Age(At 36 weeks postmenstrual age)
• Number of Participants With Moderate-severe Cerebral Palsy(At 22-26 months corrected age)
• Number of Participants With no/Some Functional Vision(At 22-26 months corrected age)
• Number of Participants With Successful Extubation(From day of randomization to day 14 post randomization)
• Total Deaths Before Discharge(From day of randomization to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With Dexamethasone Given Before 36 Weeks Postmenstrual Age (PMA)(From birth to 36 weeks postmenstrual age)
• Head Circumference Growth Measure Following Extremely Preterm Birth(At 36 weeks post-menstrual age)
• Number of Participants Who Received Other Systemic Glucocorticoids During Study Period(From randomization to day 14 post randomization)
• Number of Participants Diagnosed With Necrotizing Enterocolitis (NEC)(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With Periventricular Leukomalacia(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Days of Mechanical Ventilation to 36 Weeks Postmenstrual Age (PMA)(From birth to 36 weeks postmenstrual age)
• Follow-up Head Circumference Growth Measure Following Extremely Preterm Birth(At 22-26 months corrected age)
• Duration of Oxygen Supplementation Among Survivors to 36 Weeks(From birth to 36 weeks postmenstrual age)
• Duration of Invasive Positive Pressure Ventilation (PPV) After Postnatal Day 14(From postnatal day 15 to 36 weeks post menstrual age or Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With Patent Ductus Arteriosus (PDA) Treated With Medication or Surgery(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 70(At 22-26 months corrected age)
• Duration of Oxygen Supplementation up to Status(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Length of Hospital Stay in Days Among Survivors to Discharge(From birth up to one year)
• Number of Participants With Gross Motor Function Greater Than or Equal to Level 2(At 22-26 months corrected age)
• Number of Participants With Severe Hearing Impairment (by Report)(At 22-26 months corrected age)
• Weight Growth Measure Following Extremely Preterm Birth(At 36 weeks post-menstrual age)
• Follow-up Length Growth Measure Following Extremely Preterm Birth(At 22-26 months corrected age)
• Duration of Non-invasive Positive Pressure Ventilation (PPV) (Nasal IPPV/CPAP) After Postnatal Day 14(From postnatal day 15 to 36 weeks post menstrual age or Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants Who Received Inhaled Glucocorticoids During Study Period(From randomization to day 14 post randomization)
• Number of Participants With Normal/Mild, Moderate or Severe/Profound NDI(At 22-26 months corrected age)
• Length Growth Measure Following Extremely Preterm Birth(At 36 weeks post-menstrual age)
• Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade 40 Weeks Postmenstrual Age(At 40 weeks post menstrual age)
• Follow-up Weight Growth Measure Following Extremely Preterm Birth(At 22-26 months corrected age)
• Days of Mechanical Ventilation up to Status(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants Receiving Therapy for Retinopathy of Prematurity (ROP)(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With Severe Intraventricular Hemorrhage (IVH)(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 70(At 22-26 months corrected age)
• Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 85(At 22-26 months corrected age)
• Number of Days Dexamethasone Given Before 36 Weeks PMA(From birth to 36 weeks postmenstrual age)
• Number of Participants With Retinopathy of Prematurity (ROP) Stage 3 or Worse(From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth)
• Number of Participants With Neurodevelopmental Impairment (NDI)(At 22-26 months corrected age)
• Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 85(At 22-26 months corrected age)
• Number of Participants With Any Cerebral Palsy(At 22-26 months corrected age)