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

• ClinicalTrials.gov Identifier: NCT00005777
• Recruitment Status: Terminated
• First Posted: June 2, 2000
• Last Update Posted: June 8, 2015
• Sponsor: NICHD Neonatal Research Network
• Collaborator: National Center for Research Resources (NCRR)
• Information provided by: NICHD Neonatal Research Network

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Bronchopulmonary Dysplasia; Respiratory Distress Syndrome; Infant, Newborn; Infant, Low Birth Weight; Infant, Small for Gestational Age; Infant, Premature	Procedure: Minimal mechanical ventilation management; Procedure: Routine mechanical ventilation management; Drug: Dexamethasone; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 220 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Trial of Minimal Ventilator Support and Early Corticosteroid Therapy to Increase Survival Without Chronic Lung Disease in Extremely-Low-Birth-Weight Infants
• Study Start Date: February 1998
• Actual Primary Completion Date: September 1998
• Actual Study Completion Date: September 2002

Arms and Interventions

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 Name: Saline
Active Comparator: Routine ventilation with Dexamethasone	Procedure: Routine mechanical ventilation management; Partial pressure of carbon dioxide (PCO2) target <48 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.
Active Comparator: Routine ventilation without Dexamethasone	Procedure: Routine mechanical ventilation management; Partial pressure of carbon dioxide (PCO2) target <48 mm Hg); Drug: Placebo; The infants in the placebo groups received equal volumes of saline.; Other Name: Saline

Outcome Measures

Primary Outcome Measures :

1. Death or moderate to severe bronchopulmonary dysplasia [ Time Frame: 36 weeks postmenstrual age ]

Secondary Outcome Measures :

1. Death [ Time Frame: 36 weeks postmenstrual age ]
2. Mechanical ventilation [ Time Frame: 36 weeks postmenstrual age ]
3. Pulmonary interstitial emphysema [ Time Frame: 36 weeks postmenstrual age ]
4. Pneumothorax [ Time Frame: 36 weeks postmenstrual age ]
5. Open-label steroids [ Time Frame: 36 weeks postmenstrual age ]
6. Reintubation [ Time Frame: 36 weeks postmenstrual age ]
7. Intracranial hemorrhage (IVH) III or IV [ Time Frame: 36 weeks postmenstrual age ]
8. Periventricular leukomalacia [ Time Frame: 36 weeks postmenstrual age ]
9. Necrotizing enterocolitis [ Time Frame: 36 weeks postmenstrual age ]
10. Duration of oxygen supplementation [ Time Frame: 36 weeks postmenstrual age ]
11. Duration of ventilation [ Time Frame: 36 weeks postmenstrual age ]
12. Length of hospitalization [ Time Frame: Hospital discharge ]
13. Death or neurodevelopmental impairment [ Time Frame: 18-22 months corrected age ]
14. Death [ Time Frame: 18-22 months corrected age ]
15. Neurodevelopmental impairment [ Time Frame: 18-22 months corrected age ]
16. Cerebral palsy [ Time Frame: 18-22 months corrected age ]
17. Bilateral blindness [ Time Frame: 18-22 months corrected age ]
18. Deafness [ Time Frame: 18-22 months corrected age ]
19. Bayley Scales of Infant Development-Revised II Psychomotor Developmental Index (PDI) [ Time Frame: 18-22 months corrected age ]
20. Rehospitalizations [ Time Frame: 18-22 months corrected age ]

Eligibility Criteria

• Ages Eligible for Study: 5 Minutes to 10 Days (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

United States, California

Stanford University

Palo Alto, California, United States, 94304

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06504

United States, Florida

University of Miami

Miami, Florida, United States, 33136

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30303

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48201

United States, New Mexico

University of New Mexico

Albuquerque, New Mexico, United States, 87131

United States, North Carolina

RTI International

Durham, North Carolina, United States, 27705

United States, Ohio

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States, 45267

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States, 44106

United States, Rhode Island

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States, 02905

United States, Tennessee

University of Tennessee

Memphis, Tennessee, United States, 38163

United States, Texas

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75235

Sponsors and Collaborators

NICHD Neonatal Research Network

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
• Principal Investigator: Avroy A. Fanaroff, MD; Case Western Reserve University, Rainbow Babies & Children's Hospital
• Principal Investigator: Edward F. Donovan, MD; Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Barbara J. Stoll, MD; Emory University
• Principal Investigator: Charles R. Bauer, MD; University of Miami
• Study Director: Lu-Ann Papile, MD; University of New Mexico
• Principal Investigator: David K. Stevenson, MD; Stanford University
• Principal Investigator: Sheldon B. Korones, MD; University of Tennessee
• Principal Investigator: Jon E. Tyson, MD MPH; University of Texas Southwestern Medical Center
• Principal Investigator: Seetha Shankaran, MD; Wayne State University
• Principal Investigator: Richard A. Ehrenkranz, MD; Yale University
• Principal Investigator: W. Kenneth Poole, PhD; RTI International

More Information

Additional Information:

NICHD Neonatal Research Network 

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

Publications of Results:

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.

• Responsible Party: Waldemar A. Carlo, Lead Principal Investigator, University of Alabama - Birmingham
• ClinicalTrials.gov Identifier: NCT00005777
• Other Study ID Numbers: NICHD-NRN-0018; U10HD034216 ( U.S. NIH Grant/Contract ); U10HD034167 ( U.S. NIH Grant/Contract ); U10HD021397 ( U.S. NIH Grant/Contract ); U10HD027853 ( U.S. NIH Grant/Contract ); U10HD027871 ( U.S. NIH Grant/Contract ); U10HD021415 ( U.S. NIH Grant/Contract ); U10HD027904 ( U.S. NIH Grant/Contract ); U10HD027881 ( U.S. NIH Grant/Contract ); U10HD021385 ( U.S. NIH Grant/Contract ); U10HD027851 ( U.S. NIH Grant/Contract ); U10HD027880 ( U.S. NIH Grant/Contract ); U10HD021373 ( U.S. NIH Grant/Contract ); U01HD036790 ( U.S. NIH Grant/Contract ); M01RR008084 ( U.S. NIH Grant/Contract ); M01RR006022 ( U.S. NIH Grant/Contract ); M01RR000750 ( U.S. NIH Grant/Contract ); M01RR000997 ( U.S. NIH Grant/Contract ); M01RR000070 ( U.S. NIH Grant/Contract ); M01RR001032 ( U.S. NIH Grant/Contract )
• First Posted: June 2, 2000
• Last Update Posted: June 8, 2015
• Last Verified: June 2015

Keywords provided by NICHD Neonatal Research Network:

NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW); Prematurity; Chronic Lung Disease (CLD); Dexamethasone; Glucocorticoids; Respiration, Artificial; Mechanical ventilation; Respiratory Insufficiency

Additional relevant MeSH terms:

Lung Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Premature Birth; Birth Weight; Body Weight; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Ventilator-Induced Lung Injury; Lung Injury; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents