Minimal Breathing Support and Early Steroids to Prevent Chronic Lung Disease in Extremely Premature Infants (SAVE) (SAVE)

Randomized Trial of Minimal Ventilator Support and Early Corticosteroid Therapy to Increase Survival Without Chronic Lung Disease in Extremely-Low-Birth-Weight Infants

This multicenter clinical trial tested whether minimal ventilation decreases death or BPD. Infants with birth weight 501g to 1000g and mechanically ventilated before 12 hours were randomly assigned to minimal ventilation (partial pressure of carbon dioxide [PCO(2)] target >52 mm Hg) or routine ventilation (PCO(2) target <48 mm Hg) and a tapered dexamethasone course or saline placebo for 10 days, using a 2 x 2 factorial design. The primary outcome was death or BPD at 36 weeks' postmenstrual age. Blood gases, ventilator settings, and FiO2 were recorded for 10 days; complications and outcomes were monitored to discharge. The infants' neurodevelopment was evaluated at 18-22 months corrected age.

Study Overview

• Status: Terminated
• Conditions: Respiratory Distress Syndrome; Bronchopulmonary Dysplasia; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Procedure: Minimal mechanical ventilation management; Drug: Dexamethasone; Drug: Placebo; Procedure: Routine mechanical ventilation management

Detailed Description

Chronic lung disease (CLD), also known as bronchopulmonary dysplasia (BPD), in very premature infants has been associated with mechanical ventilation and relative adrenal insufficiency.

This multicenter clinical trial tested whether minimal ventilation decreases death or BPD. Infants with birth weight 501g to 1000g and mechanically ventilated before 12 hours were randomly assigned to minimal ventilation (partial pressure of carbon dioxide [PCO(2)] target >52 mm Hg) or routine ventilation (PCO(2) target <48 mm Hg) and a tapered dexamethasone course or saline placebo for 10 days, using a 2 x 2 factorial design. The primary outcome was death or BPD at 36 weeks' postmenstrual age. Blood gases, ventilator settings, and FiO2 were recorded for 10 days; complications and outcomes were monitored to discharge.

The trial was terminated by the Steering Committee when the interim analysis for the Data Safety and Monitoring Committee showed a higher rate of spontaneous gastrointestinal perforations in the dexamethasone-treated infants.

Neurodevelopment was assessed at 18-22 months postmenstrual age.

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 minutes to 1 week (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Greater than 12 hrs of age and less than 10 days chronologic age
• 501-1000 gm
• Intubated and mechanically ventilated before 12 hrs
• Indwelling vascular catheter
• Infants 751-100 gm must be receiving FiO2 greater than 0.30 and have received at least 1 dose of surfactant at randomization
• Parental consent

Exclusion Criteria:

• Major congenital anomaly
• Symptomatic non-bacterial infection
• Permanent neuromuscular conditions that affect respiration
• Terminal illness (defined as pH values less than 6.8 for more than 2 hours or persistent bradycardia associated with hypoxia for more than 2 hours)
• Use of postnatal corticosteroids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Minimal ventilation with Dexamethasone; Minimal ventilator support strategy (permissive hypercapnia) and early stress dose dexamethasone therapy	Procedure: Minimal mechanical ventilation management; Partial pressure of carbon dioxide (PCO2) target (>52 mm Hg); Drug: Dexamethasone; Treatment with the study medication was initiated within 24 hours after birth. The dexamethasone-treated infants received a 10-day tapered course (0.15 mg of dexamethasone per kilogram per day for three days, followed by 0.10 mg per kilogram for three days, 0.05 mg per kilogram for two days, and 0.02 mg per kilogram for two days), with the daily dose divided in half and given at 12-hour intervals intravenously or orally, if an intravenous catheter was no longer in place.
Experimental: Minimal Ventilation without Dexamethasone; Minimal ventilator support strategy (permissive hypercapnia) and no dexamethasone therapy	Procedure: Minimal mechanical ventilation management; Partial pressure of carbon dioxide (PCO2) target (>52 mm Hg); Drug: Placebo; The infants in the placebo groups received equal volumes of saline.; Other Names: Saline
Active Comparator: Routine ventilation with Dexamethasone	Drug: Dexamethasone; Treatment with the study medication was initiated within 24 hours after birth. The dexamethasone-treated infants received a 10-day tapered course (0.15 mg of dexamethasone per kilogram per day for three days, followed by 0.10 mg per kilogram for three days, 0.05 mg per kilogram for two days, and 0.02 mg per kilogram for two days), with the daily dose divided in half and given at 12-hour intervals intravenously or orally, if an intravenous catheter was no longer in place.; Procedure: Routine mechanical ventilation management; Partial pressure of carbon dioxide (PCO2) target <48 mm Hg)
Active Comparator: Routine ventilation without Dexamethasone	Drug: Placebo; The infants in the placebo groups received equal volumes of saline.; Other Names: Saline; Procedure: Routine mechanical ventilation management; Partial pressure of carbon dioxide (PCO2) target <48 mm Hg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Death or moderate to severe bronchopulmonary dysplasia	36 weeks postmenstrual age

Secondary Outcome Measures

Outcome Measure	Time Frame
Neurodevelopmental impairment	18-22 months corrected age
Death	36 weeks postmenstrual age
Mechanical ventilation	36 weeks postmenstrual age
Pulmonary interstitial emphysema	36 weeks postmenstrual age
Pneumothorax	36 weeks postmenstrual age
Open-label steroids	36 weeks postmenstrual age
Reintubation	36 weeks postmenstrual age
Intracranial hemorrhage (IVH) III or IV	36 weeks postmenstrual age
Periventricular leukomalacia	36 weeks postmenstrual age
Necrotizing enterocolitis	36 weeks postmenstrual age
Duration of oxygen supplementation	36 weeks postmenstrual age
Duration of ventilation	36 weeks postmenstrual age
Length of hospitalization	Hospital discharge
Death or neurodevelopmental impairment	18-22 months corrected age
Death	18-22 months corrected age
Cerebral palsy	18-22 months corrected age
Bilateral blindness	18-22 months corrected age
Deafness	18-22 months corrected age
Bayley Scales of Infant Development-Revised II Psychomotor Developmental Index (PDI)	18-22 months corrected age
Rehospitalizations	18-22 months corrected age

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Center for Research Resources (NCRR)
• Investigators: Study Director: Waldemar A. Carlo, MD, University of Alabama at Birmingham; Study Director: Ann R. Stark, MD, Brigham and Women's Hospital; Principal Investigator: William Oh, MD, Brown University, Women & Infants Hospital; Study Director: Lu-Ann Papile, MD, University of New Mexico

Publications and helpful links

General Publications

• Carlo WA, Stark AR, Wright LL, Tyson JE, Papile LA, Shankaran S, Donovan EF, Oh W, Bauer CR, Saha S, Poole WK, Stoll B. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr. 2002 Sep;141(3):370-4. doi: 10.1067/mpd.2002.127507.
• Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, Donovan EF, Oh W, Bauer CR, Saha S, Poole WK, Stoll BJ; National Institute of Child Health and Human Development Neonatal Research Network. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 2001 Jan 11;344(2):95-101. doi: 10.1056/NEJM200101113440203.

Helpful Links

• NICHD Neonatal Research Network
• Cochrane meta-analysis: "Postnatal corticosteroids in preterm infants with chronic lung disease: late treatment (> 3 weeks)."

Study record dates

Study Major Dates

• Study Start: February 1, 1998
• Primary Completion (Actual): September 1, 1998
• Study Completion (Actual): September 1, 2002

Study Registration Dates

• First Submitted: June 1, 2000
• First Submitted That Met QC Criteria: June 1, 2000
• First Posted (Estimate): June 2, 2000

Study Record Updates

• Last Update Posted (Estimate): June 8, 2015
• Last Update Submitted That Met QC Criteria: June 3, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Dexamethasone; Glucocorticoids; Prematurity; Respiratory Insufficiency; Mechanical ventilation; Respiration, Artificial; NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW); Chronic Lung Disease (CLD)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Infant, Newborn, Diseases; Body Weight; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Lung Diseases; Premature Birth; Birth Weight; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: NICHD-NRN-0018; U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD021415 (U.S. NIH Grant/Contract); U10HD027881 (U.S. NIH Grant/Contract); M01RR008084 (U.S. NIH Grant/Contract); M01RR006022 (U.S. NIH Grant/Contract); M01RR000750 (U.S. NIH Grant/Contract); M01RR000070 (U.S. NIH Grant/Contract); M01RR000997 (U.S. NIH Grant/Contract); U10HD021397 (U.S. NIH Grant/Contract); U10HD034167 (U.S. NIH Grant/Contract); M01RR001032 (U.S. NIH Grant/Contract); U01HD036790 (U.S. NIH Grant/Contract)