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

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

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.

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.

• Bronchopulmonary Dysplasia
• Respiratory Distress Syndrome
• Infant, Newborn
• Infant, Low Birth Weight
• Infant, Small for Gestational Age
• Infant, Premature

• Procedure: Minimal mechanical ventilation management
  Partial pressure of carbon dioxide (PCO2) target (>52 mm Hg)
• 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.
• Drug: Placebo
  The infants in the placebo groups received equal volumes of saline.
  Other Name: Saline

• Experimental: Minimal ventilation with Dexamethasone
  Minimal ventilator support strategy (permissive hypercapnia) and early stress dose dexamethasone therapy
  Interventions:

  • Procedure: Minimal mechanical ventilation management
  • Drug: Dexamethasone
• Experimental: Minimal Ventilation without Dexamethasone
  Minimal ventilator support strategy (permissive hypercapnia) and no dexamethasone therapy
  Interventions:

  • Procedure: Minimal mechanical ventilation management
  • Drug: Placebo
• Active Comparator: Routine ventilation with Dexamethasone
  Interventions:

  • Procedure: Routine mechanical ventilation management
  • Drug: Dexamethasone
• Active Comparator: Routine ventilation without Dexamethasone
  Interventions:

  • Procedure: Routine mechanical ventilation management
  • Drug: Placebo

• 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.
• 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 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.

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