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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

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

Intervention / Treatment
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* Procedure: Minimal mechanical ventilation management
* Procedure: Routine mechanical ventilation management
* Drug: Dexamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Minutes
Maximum Age: 10 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Minimal ventilation with Dexamethasone<br>Minimal ventilator support strategy (permissive hypercapnia) and early stress dose dexamethasone therapy | Procedure: Minimal mechanical ventilation management<br>* Partial pressure of carbon dioxide (PCO2) target (>52 mm Hg)<br>Drug: Dexamethasone<br>* 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.<br>|
| Experimental: Minimal Ventilation without Dexamethasone<br>Minimal ventilator support strategy (permissive hypercapnia) and no dexamethasone therapy | Procedure: Minimal mechanical ventilation management<br>* Partial pressure of carbon dioxide (PCO2) target (>52 mm Hg)<br>Drug: Placebo<br>* The infants in the placebo groups received equal volumes of saline.<br>* Other names: Saline;|
| Active Comparator: Routine ventilation with Dexamethasone<br> | Procedure: Routine mechanical ventilation management<br>* Partial pressure of carbon dioxide (PCO2) target <48 mm Hg)<br>Drug: Dexamethasone<br>* 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.<br>|
| Active Comparator: Routine ventilation without Dexamethasone<br> | Procedure: Routine mechanical ventilation management<br>* Partial pressure of carbon dioxide (PCO2) target <48 mm Hg)<br>Drug: Placebo<br>* The infants in the placebo groups received equal volumes of saline.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Neurodevelopmental impairment |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NICHD Neonatal Research Network, Extremely Low Birth Weight (ELBW), Prematurity, Chronic Lung Disease (CLD), Dexamethasone, Glucocorticoids, Respiration, Artificial, Mechanical ventilation, Respiratory Insufficiency