Hydrocortisone for Term Hypotension

Cardiovascular insufficiency is common and potentially life-threatening in critically ill term and late preterm newborns admitted to the newborn intensive care unit (NICU) in the first few days of age.

This study proposes to conduct a multicenter, randomized, masked, placebo-controlled trial within the Neonatal Research Network (NRN). This trial will evaluate the effects of a 7-day course of hydrocortisone therapy on short-term morbidity, cardiovascular function, long-term neurodevelopment, and mortality in critically ill, term and late preterm infants diagnosed with cardiovascular insufficiency as defined by a need for inotrope therapy in the first 72 hours of age.

• Hydrocortisone (Drug): • 7 day course of hydrocortisone (hydrocortisone sodium succinate, plain; will not have benzyl alcohol) given through intravenous line or by intramuscular injection if no intravenous line). 1 mg/kg loading dose x 1; 0.5 mg/kg q 6 hours x 12 doses; 0.5 mg/kg q 12 hours x 4 doses; 0.5 mg/kg q day x 1 dose
• Placebo (Drug): 7 days of intravenous or intramuscular placebo (normal saline in equal volume) 1 mg/kg loading dose x 1; 0.5 mg/kg q 6 hours x 12 doses; 0.5 mg/kg q 12 hours x 4 doses; 0.5 mg/kg q day x 1 dose

Primary outcomes

• Death [Birth to 22-26 months corrected gestational age]: This is measured as Yes if an infant died between birth and 22-26 months corrected gestational age; Otherwise, No.
• Number of Participants With Neurodevelopmental Impairment [Birth to 22-26 months corrected gestational age]: This is measured as Yes if an any hearing impairment or visual impairment is noted, if non-normal gross motor function level is noted, any seizures have been noted, or if the cognitive, language, or motor scores of the Bayley III score are more than 1 standard deviation below the average; Otherwise, No.
• Number of Participants With Death or Neurodevelopmental Impairment [Birth to 22-26 months corrected gestational age]: A composite outcome that measures the occurrence of death or neurodevelomental impairment between birth and 22-26 months corrected gestational age.

Secondary outcomes

• Duration of Mechanical Ventilation [Birth to 60 days of life]: This is measured as the number of days between birth and 60 days of life of mechanical ventialtion of laryngeal intubation.
• Days to Full Feeds [Birth to 60 days of life]: The day of life at which full nipple feeds were reached between birth and 60 days of life. Full nipple feeds are defined as at least 120 mg/kg/day.
• Number of Participants With Need for Gastronomy Tube [Birth to 60 days of life]: This is measured as Yes if a gastronomy tube was placed anytime prior to final status between birth and 60 days of life; Otherwise, No
• Duration of Oxygen Requirement [Birth to 60 days of life]: This is measured as the number of days between birth and 60 days of life that an infant was on oxygen in the hospital.
• Number of Participants With Need for Home Oxygen [Birth to 60 days of life]: This is measured as Yes if an infant was discharged to home while on oxygen between birth and 60 days of life; Otherwise, No.
• Hospital Length of Stay [Birth to 60 days of life]: This is measured as the number of days between birth and 60 days of life that an infant was in the hospital. Infants who died or transferred to another care facility were not included.
• Number of Participants With Renal Insufficiency [Birth to 60 days of life]: This is measured as Yes if an infant had renal insufficieny between birth and 60 days of life; Otherwise, No. Renal insufficiency is defined as creatinine less than 2 during 7 days after first treatment
• Number of Participants With Necrotizing Enterocolitis [Birth to 60 days of life]: This is measured as Yes if an infant necrotizing enterocolitis (NEC) between birth and 60 days of life; Otherwise, No. NEC could be proven with or without surgery
• Number of Participants With Need for ECMO Therapy [Birth to 60 days of life]: This is measured as Yes if an infant received ECMO treatment anytime between birth and 60 days of life; Otherwise, No. Extracorporeal membrane oxygenation (ECMO) is a treatment that uses a pump to circulate blood through an artificial lung back into the bloodstream of a very ill baby.
• Number of Participants With Inotrope Exposure [24 hours prior to study drug administration through 3 days post study drug administration.]: This is measured as Yes if an infant was receiving inotropes on the specific day after the initiation of study drug.
• Inotrope Duration [24 hours prior to study drug administration through 3 days post study drug administration.]: This is calculated as the number of days on inotropes starting 24 hours prior to initiation of study drug, during the 7-day study drug administration period, and for 3 days after the study drug.
• Maximum Inotrope Dose [From start of study drug administration (7 days) through 3 days post study drug administration.]: This is calculated as the maximum dose of all inotropes in the 10 days following the initiation of study drug administration. For the purposes of this calculation, dopamine and dobutamine doses were considered equivalent and 0.01 mcg/kg/min of epinephrine was equal to 5 mcg/kg/min of dopamine.
• Oxygenation Index [Birth to 60 days of life]: This is calculated as fraction of inspired oxygen (FiO2), as a percentage, multiplied by the mean airway pressure divided by partial pressure of oxygen in arterial blood (PaO2), during study drug administration. A lower oxygenation index is better.
• Respiratory Severity [Birth to 60 days of life]: This is calculated as fraction of inspired oxygen (FiO2), as a percentage, multiplied by the mean airway pressure during study drug administration. Higher score means more severe.
• Number of Participants With Fluid Boluses Given [Birth to 60 days of life]: This is measured as Yes if an infant received fluid boluses anytime before or during study drug administration between birth and 60 days of life; Otherwise, No.
• Number of Boluses Given [Birth to 60 days of life]: The number of fluid boluses given per participant, if any, before or during study drug administration between birth and 60 days of life

Sex: All, ages: 34 Weeks to any

Inclusion Criteria:

* Gestational age greater than or equal to 34 weeks at birth
* Admitted to the center NICU by 48 hours of age
* Intubated and mechanically ventilated for a minimum of 2 hours before 72 hours postnatal age

Exclusion Criteria:

* Receiving ECMO
* Intubated for the sole purpose of anticipated surgery or airway anomalies
* Treatment will be limited based on poor prognosis
* Receiving dexamethasone or hydrocortisone
* Receiving ibuprofen or indomethacin
* Congenital heart disease
* Hypotension thought to result from specific, immediately remediable factors including placental hemorrhage, acute hemorrhage or tension pneumothorax
* Pituitary hypoplasia or congenital adrenal hyperplasia
* Any chromosomal disorder
* Hypertension in the absence of inotrope therapy as defined by mean arterial blood pressure > 95th percentile
* Initiation of whole body cooling for moderate or severe neonatal encephalopathy
* Brain disorders or any other known structural abnormality
* Major anomalies

Participant flow

Outcome results

• Death (Primary), Count of participants, Participants: Hydrocortisone 6; Placebo 6
• Number of Participants With Neurodevelopmental Impairment (Primary), Count of participants, Participants: Hydrocortisone 3; Placebo 3
• Number of Participants With Death or Neurodevelopmental Impairment (Primary), Count of participants, Participants: Hydrocortisone 3; Placebo 3
• Duration of Mechanical Ventilation (Secondary), Median, Days: Hydrocortisone 8 (3 to 10); Placebo 11 (3 to 19)
• Days to Full Feeds (Secondary), Median, Days: Hydrocortisone 16 (12 to 23); Placebo 18 (8 to 22)
• Number of Participants With Need for Gastronomy Tube (Secondary), Count of participants, Participants: Hydrocortisone 6; Placebo 6
• Duration of Oxygen Requirement (Secondary), Median, Days: Hydrocortisone 15.5 (3 to 33); Placebo 18 (5 to 25)
• Number of Participants With Need for Home Oxygen (Secondary), Count of participants, Participants: Hydrocortisone 5; Placebo 4
• Hospital Length of Stay (Secondary), Median, Days: Hydrocortisone 27 (14 to 60); Placebo 24 (14 to 38)
• Number of Participants With Renal Insufficiency (Secondary), Count of participants, Participants: Hydrocortisone 6; Placebo 6
• Number of Participants With Necrotizing Enterocolitis (Secondary), Count of participants, Participants: Hydrocortisone 5; Placebo 6
• Number of Participants With Need for ECMO Therapy (Secondary), Count of participants, Participants: Hydrocortisone 6; Placebo 6
• Number of Participants With Inotrope Exposure (Secondary), Count of participants, Participants: Hydrocortisone 4; Placebo 4
• Inotrope Duration (Secondary), Median, days: Hydrocortisone 3 (1 to 8); Placebo 3 (1 to 8)
• Maximum Inotrope Dose (Secondary), Mean, mcg/kg/min: Hydrocortisone 9.5 +/- 2.9; Placebo 14.7 +/- 12.6
• Oxygenation Index (Secondary), Mean, Oxygenation Index: Hydrocortisone 10.7 +/- 6.1; Placebo 14.5 +/- 8.6
• Respiratory Severity (Secondary), Mean, Percentage of inspired oxygen * cmH2O: Hydrocortisone 726.8 +/- 371; Placebo 1184.7 +/- 518.7
• Number of Participants With Fluid Boluses Given (Secondary), Count of participants, Participants: Hydrocortisone 2; Placebo 2
• Number of Boluses Given (Secondary), Median, Boluses: Hydrocortisone 3 (1 to 7); Placebo 3 (2 to 8)

Adverse events

Time frame: 10 days

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The study was closed to enrollment after 12 participants due to slow recruitment.

• Study Protocol and Statistical Analysis Plan (PDF, 2014-04-02)

• Michele C Walsh, MD, Principal investigator, Case Western Reserve University, Rainbow Babies and Children's Hospital
• Seetha Shankaran, MD, Principal investigator, Wayne State University
• Abbot R Laptook, MD, Principal investigator, Brown University, Women & Infants Hospital of Rhode Island
• Ron N Goldberg, MD, Principal investigator, Duke University
• Barbara J Stoll, MD, Principal investigator, Emory University
• Brenda B Poindexter, MD, MS, Principal investigator, Indiana University
• Abhik Das, PhD, Principal investigator, RTI International
• Krisa P Van Meurs, MD, Principal investigator, Stanford University
• Kurt Schibler, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati
• Waldemar Carlo, MD, Principal investigator, University of Alabama at Birmingham
• Edward F Bell, MD, Principal investigator, Michele C Walsh, MD Study Principal Investigator Case Western Reserve University, Rainbow Babies and Children's Hospital Seetha Shankaran, MD Study Principal Investigator Wayne State University Abbot R Laptook, MD Study Principal Investigator Brown Un
• Erika Fernandez, MD, Study chair, University of New Mexico
• Myra Wycoff, MD, Principal investigator, University of Texas, Southwestern Medical Center at Dallas
• Kathleen A Kennedy, MD, MPH, Principal investigator, The University of Texas Health Science Center, Houston
• Barbara Schmidt, MD, Principal investigator, University of Pennsylvania
• Carl T D'Angio, MD, Principal investigator, University of Rochester
• Uday Devaskar, MD, Principal investigator, University of California, Los Angeles
• Leif Nelin, MD, Principal investigator, Research Institute at Nationwide Children's Hospital
• William Truog, MD, Principal investigator, Children's Mercy Hospital Kansas City

NIH grants: U10HD021364, U10HD040689, U10HD021385, U10HD027851, U10HD027853, U10HD027856, U10HD027904, U10HD027880, U10HD034216, U10HD021373, U10HD040492, U10HD053109, U10HD040461, U10HD068244, U10HD068263, U10HD068270, U10HD068278, U10HD068284, U10HD036790