Dexamethasone Therapy in VLBW Infants at Risk of CLD

Overview

Infants who are on breathing support are often treated with steroids (dexamethasone); however, the best timing of therapy is not known. This trial looked at the benefits and hazards of starting dexamethasone therapy at two weeks of age and four weeks of age in premature infants.

Full Title of Study: “Randomized Clinical Trial of Dexamethasone Therapy in Very-Low-Birth-Weight Infants at Risk for Chronic Lung Disease (CLD)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: January 1994

Detailed Description

Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown. We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 grams) who had respiratory-index scores (mean airway pressure x the fraction of inspired oxygen) of greater than or equal 2.4 at two weeks of age. The primary outcome was the number of days from randomization to extubation not requiring reintubation (extubation score or death). The secondary outcomes were death before discharge from the hospital; the duration of assisted ventilation, supplementary oxygen therapy and hospital stay; the incidence of chronic lung disease (defined as the need for supplemental oxygen at 36 weeks postconceptional age by best obstetrical estimate) and rates of morbidity and mortality from respiratory causes during the first year. Additional secondary endpoints were hyperglycemia, hypertension, growth, bacteremia, necrotizing enterocolitis and upper GI bleeding. The sample size of 370 was based on a 0.60 probability that the extubation score of late treatment was greater than early treatment, a 5% two-sided type 1 error, 85% power, and 10% treatment noncompliance. Infants were randomized to either receive dexamethasone for two weeks followed by saline placebo for two weeks, or saline placebo for two weeks followed by either dexamethasone or additional placebo for two weeks (if they still met entry criteria). Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose then tapered. The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head growth (P less than 0.001) in both groups. Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of age.

Interventions

  • Drug: Dexamethasone Early
    • Tapering course of dexamethasone in doses given twice a day (0.25 mg per kilogram of body weight per dose for five days, then 0.15 mg, 0.07 mg, and 0.03 mg per kilogram per dose for three days each), followed by two weeks of saline.
  • Drug: Dexamethasone Late
    • Saline for two weeks, followed by either the same tapering two-week course of dexamethasone given to the first group, if the respiratory-index score was >=2.4 on treatment day 14, or an additional two weeks of saline

Arms, Groups and Cohorts

  • Active Comparator: Dexamethasone
    • Dexamethasone
  • Placebo Comparator: Placebo
    • Saline

Clinical Trial Outcome Measures

Primary Measures

  • Number of days from randomization to ventilator independence, defined as extubation not requiring reintubation, or extubation followed by elective reintubation for seven days or less so that the infant could undergo a surgical procedure
    • Time Frame: At hospital discharge

Secondary Measures

  • Death before discharge from the hospital
    • Time Frame: At hospital discharge
  • Duration of assisted ventilation
    • Time Frame: At hospital discharge
  • Duration of supplemental oxygen therapy
    • Time Frame: At hospital discharge
  • Duration of hospital stay
    • Time Frame: At hospital discharge
  • Incidence of chronic lung disease
    • Time Frame: At hospital discharge
  • Morbidity and mortality from respiratory causes during the first year
    • Time Frame: 12 months of age

Participating in This Clinical Trial

Inclusion Criteria

  • 501 to 1500 grams – 13 to 15 days old – Respiratory-index score of greater than or equal to 2.4 that had been increasing or minimally decreasing during the previous 48 hours or a score of greater than or equal to 4.0 even if there had been improvement during the preceding 48 hours Exclusion criteria:

  • Received glucocorticoid treatment after birth – Had evidence or suspicious signs of sepsis as judged by the treating physician – Major congenital anomaly of the cardiovascular, pulmonary, or central nervous system

Gender Eligibility: All

Minimum Age: 13 Days

Maximum Age: 15 Days

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • NICHD Neonatal Research Network
  • Collaborator
    • National Center for Research Resources (NCRR)
  • Provider of Information About this Clinical Study
    • Lu-Ann Papile/ Lead Principal Investigator, University of New Mexico
  • Overall Official(s)
    • Lu-Ann Papile, MD, Principal Investigator, University of New Mexico
    • Jon E. Tyson, MD MPH, Principal Investigator, University of Texas Southwestern Medical Center
    • Barbara J. Stoll, MD, Principal Investigator, Emory University
    • Edward F. Donovan, MD, Principal Investigator, Children’s Hospital Medical Center, Cincinnati
    • Charles R. Bauer, MD, Principal Investigator, University of Miami
    • Sheldon B. Korones, MD, Principal Investigator, University of Tennessee Health Science Center
    • James A. Lemons, MD, Principal Investigator, Indiana University School of Medicine
    • Avroy A. Fanaroff, MD, Principal Investigator, Rainbow Babies & Children’s Hospital, Case Western Reserve University
    • David K. Stevenson, MD, Principal Investigator, Stanford University
    • Seetha Shankaran, MD, Principal Investigator, Wayne State University
    • William Oh, MD, Principal Investigator, Women & Infants’ Hospital, Brown University
    • Richard A. Ehrenkranz, MD, Principal Investigator, Yale University

Citations Reporting on Results

Papile LA, Tyson JE, Stoll BJ, Wright LL, Donovan EF, Bauer CR, Krause-Steinrauf H, Verter J, Korones SB, Lemons JA, Fanaroff AA, Stevenson DK. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med. 1998 Apr 16;338(16):1112-8.

Leitch CA, Ahlrichs J, Karn C, Denne SC. Energy expenditure and energy intake during dexamethasone therapy for chronic lung disease. Pediatr Res. 1999 Jul;46(1):109-13.

Stoll BJ, Temprosa M, Tyson JE, Papile LA, Wright LL, Bauer CR, Donovan EF, Korones SB, Lemons JA, Fanaroff AA, Stevenson DK, Oh W, Ehrenkranz RA, Shankaran S, Verter J. Dexamethasone therapy increases infection in very low birth weight infants. Pediatrics. 1999 Nov;104(5):e63.

Lee BH, Stoll BJ, McDonald SA, Higgins RD; National Institute of Child Health and Human Development Neonatal Research Network. Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics. 2006 May;117(5):1503-10.

Lee BH, Stoll BJ, McDonald SA, Higgins RD; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to dexamethasone versus betamethasone. Pediatrics. 2008 Feb;121(2):289-96. doi: 10.1542/peds.2007-1103.

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