Extreme Prematurity, Preterm Birth
Conditions
Keywords
Neonatal resuscitation, Extreme Low Gestational Age Newborn (ELGAN), Delivery Room, Continuous positive airway pressure (CPAP), Positive pressure ventilation (PPV), Sustained inflation
Brief summary
This study is a 2-arm randomized, controlled, multi-center clinical trial to determine which of two strategies at birth are best to optimally aerate the lung of preterm infants. Specifically we will determine in 600 infants of 23-26 weeks gestational age (GA) requiring respiratory support at birth which of two lung opening strategies - either a standard PEEP/CPAP of 5-7 cm H2O in the delivery room (DR), as compared to early lung recruitment using Sustained Inflation (SI) in the DR, will result in a lower rate of the combined endpoint of death or bronchopulmonary dysplasia (BPD) at 36 weeks gestational age. Hypotheses: 1. Early lung recruitment with SI superimposed upon standard PEEP/CPAP in the DR will reduce the need for mechanical ventilation in the first seven days of life, and reduce need for surfactant use; and 2. A policy of DR SI on standard PEEP/CPAP recruitment will confer better outcomes at 36 weeks post-menstrual age (PMA) than standard PEEP/CPAP
Detailed description
The SAIL trial aims to provide evidence for changing policy or standard of care. The context of this trial is an unacceptable rate of poor long-term outcomes of preterm infants born as Extremely Low Gestational Age Newborns (ELGAN) \<1000 g birthweight (BW), but especially for those born between 23-26 weeks' gestational age (GA). Such infants are the most vulnerable and immature in all organ systems, including the lungs and the brain. These infants are at high risk of death and bronchopulmonary dysplasia (BPD) during their initial hospitalization, neurodevelopmental impairment (NDI) and pulmonary problems in infancy and childhood. The SAIL trial focuses on facilitating the difficult transition of these most vulnerable infants from a liquid filled in-utero lung to an ex-utero air-filled lung. Sustained Inflation (SI) is a promising delivery room (DR) intervention, with evidence of short-term efficacy with minimal risk of additional harm beyond current standard accepted Newborn Resuscitation Program (NRP) Guidelines. This protocol proposes a fully informed consenting procedure. We propose to evaluate the impact of a SI in the DR on the need for mechanical ventilation in the first week of life which would also impact mortality rates and the incidence and severity of BPD.
Interventions
PROCEDURESustained Inflation
The first sustained inflation will use inflation pressure of 20 cm H20 for 15 seconds
PROCEDUREStandard of Care
Newborn Resuscitation Program (NRP) Guidelines using a standard PEEP/CPAP of 5-7 cm H2O as compared to the Sustained Inflation intervention
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
23 Weeks to 26 Weeks
Healthy volunteers
No
Inclusion criteria
* Gestational age (GA) at least 23 weeks but less than 27 completed weeks by best obstetrical estimate * Requiring resuscitation/respiratory intervention at birth -apneic, labored breathing, gasping (as defined in NRP 2011 AAP 6th Edition p.45)
Exclusion criteria
* Considered non-viable by the attending neonatologist * Refusal of antenatal informed consent * Known major anomalies, pulmonary hypoplasia * Mothers who are unable to consent for their medical care and who do not have a surrogate guardian will not be approached for consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Outcome of Death or Bronchopulmonary Dysplasia | 36 weeks | To determine in infants born at 23-26 weeks gestational age requiring respiratory support at birth, which of two treatment strategies when compared, results in a lower rate of the combined endpoint of death or bronchopulmonary dysplasia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oxygen Profile With Highest FiO2 Level up to 48 Hours | 48 hours of life | Highest FiO2 level recorded during the first 48 hours post DR |
| Heart Rate in the Delivery Room (DR) | First 30 seconds of life in DR | Categorical variable with 3 levels: \<60, 60-100, \>100 |
| Detailed Status on Departure From the Delivery Room (DR) | Resuscitation time will vary - 1 to 30 minutes | Type of respiratory support (CPAP, PPV) and Fraction of Inspired Oxygen (FiO2) on departure from DR |
| Use of Inotropes on Arrival in NICU | First 48 hours of life | Circulatory support post-delivery room |
| Need for Intubation in Delivery Room | First 30 seconds to 24 hours of life | Need for intubation in delivery room during the first 30 seconds to 24 hours of age |
| Pressure-volume Characteristics in the Delivery Room (DR) | Expected average 30 minutes | Pressure-volume characteristics in the Delivery room (DR) expected within 30 minutes |
| Pneumothorax or New Chest Drains in the First 48 Hours of Life | First 48 hours of life | Chest x-ray reports showing pneumothorax or new chest drains in the first 48 hours of life |
| Duration of Any Chest Drain In-situ Post-DR | During hospitalization - up to 36 weeks Post Menstrual Age (PMA) | Duration of any chest drain in-situ post-DR during hospitalization - up to 36 weeks Post Menstrual Age (PMA) |
| Intraventricular Hemorrhage by All Grades | 48 hours to 10 days | Head ultrasound and/or MRI findings of intraventricular hemorrhage by all grades focusing on grades 3 and 4 by 48 hour and by day 10 |
| Chest X-ray Between Days 7-10 | First 7-10 days of life | Chest x-ray between the first 7-10 days of life |
| Oxygen Profile Over First 24 Hours | First 24 hours post delivery | Oxygen profile over first 24 hours post delivery room using hourly FiO2 records |
| Highest FiO2 and Area Under the FiO2 Curve for the First Week of Life | First 7 days of life | Highest FiO2 and Area under the FiO2 curve during the first 7 days of life |
| Pneumothorax and Pulmonary Interstitial Emphysema (PIE) | First 10 days of life | Pneumothorax and pulmonary interstitial emphysema (PIE) during the first 10 days of life |
| Survival to Discharge Home Without BPD, Retinopathy of Prematurity (Grades 3 & 4), or Significant Brain Abnormalities on Head Ultrasound | Expected discharge between 36 - 40 weeks PMA | Survival to discharge home without BPD, retinopathy of prematurity (grades 3 & 4), or significant brain abnormalities on head ultrasound with an expected discharge between 36-40 weeks PMA |
| Duration of Respiratory Support (Ventilation, CPAP, Supplemental Oxygen) | During hospitalization - up to 36 weeks Post Menstrual Age (PMA) | Duration of respiratory support (ventilation, CPAP, supplemental oxygen) during hospitalization upto 36 weeks Post Menstrual Age (PMA) |
| Death in Hospital | During expected hospitalization 23 - 40 weeks PMA | Death in hospital during expected hospitalization of 23-40 weeks PMA |
| Retinopathy of Prematurity (ROP) Stage 3 or Greater Requiring Treatment | 36 weeks | Retinopathy of prematurity (ROP) stage 3 or greater requiring treatment at 36 weeks |
| Use of Postnatal Steroids for Treatment of BPD | During hospitalization - up to 36 weeks Post Menstrual Age (PMA) | Use of postnatal steroids for treatment of BPD during hospitalization up to 36 weeks Post Menstrual Age (PMA) |
| Length of Hospital Stay | Average discharge between 36 - 40 weeks PMA | Length of hospital stay with average discharge between 36-40 weeks PMA |
| Neurodevelopmental and Respiratory Outcome at 22-26 Months Corrected Gestational Age | 22-26 months corrected gestational age | Neurodevelopmental and respiratory outcome at 22-26 months corrected gestational age |
| Death or Need for Positive Pressure Ventilation | First 7 days of life | Death or need for positive pressure ventilation during the first 7 days of life |
Countries
Australia, Austria, Canada, Germany, Italy, Netherlands, Singapore, South Korea, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Arm-Standard of Care Control Arm-Respiratory support using Standard of Care positive-end expiratory pressure/continuous positive airway pressure (PEEP/CPAP) of 5-7 cm H2O compared to Sustained Inflation intervention
Standard of Care: Newborn Resuscitation Program (NRP) Guidelines using a standard PEEP/CPAP of 5-7 cm H2O as compared to the Sustained Inflation intervention | 211 |
| Sustained Intervention Administer delivery room respiratory support using a Sustained Inflation (SI) intervention and expiratory pressure/continuous positive airway pressure (PEEP/CPAP) of 5-7 cm H2O
Sustained Inflation: The first sustained inflation will use inflation pressure of 20 cm H20 for 15 seconds | 215 |
| Total | 426 |
Baseline characteristics
| Characteristic | Control Arm-Standard of Care | Total | Sustained Intervention |
|---|---|---|---|
| Age, Customized 23-24 weeks GA | 75 Participants | 151 Participants | 76 Participants |
| Age, Customized 25-26 weeks GA | 136 Participants | 275 Participants | 139 Participants |
| Consent Type Antenatal | 113 participants | 235 participants | 122 participants |
| Consent Type Deferred | 98 participants | 191 participants | 93 participants |
| Maternal Age | 30.5 years | 30.9 years | 31.1 years |
| Race/Ethnicity, Customized Asian | 23 Participants | 41 Participants | 18 Participants |
| Race/Ethnicity, Customized Black | 50 Participants | 79 Participants | 29 Participants |
| Race/Ethnicity, Customized Other | 28 Participants | 48 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 110 Participants | 258 Participants | 148 Participants |
| Region of Enrollment Australia | 35 participants | 65 participants | 30 participants |
| Region of Enrollment Austria | 6 participants | 11 participants | 5 participants |
| Region of Enrollment Canada | 23 participants | 43 participants | 20 participants |
| Region of Enrollment Germany | 20 participants | 41 participants | 21 participants |
| Region of Enrollment Italy | 11 participants | 24 participants | 13 participants |
| Region of Enrollment Netherlands | 50 participants | 106 participants | 56 participants |
| Region of Enrollment Singapore | 0 participants | 1 participants | 1 participants |
| Region of Enrollment South Korea | 5 participants | 8 participants | 3 participants |
| Region of Enrollment United States | 61 participants | 127 participants | 66 participants |
| Sex: Female, Male Female | 108 Participants | 204 Participants | 96 Participants |
| Sex: Female, Male Male | 103 Participants | 222 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 35 / 211 | 48 / 215 |
| other Total, other adverse events | 146 / 211 | 157 / 215 |
| serious Total, serious adverse events | 51 / 211 | 45 / 215 |
Outcome results
Primary
Combined Outcome of Death or Bronchopulmonary Dysplasia
To determine in infants born at 23-26 weeks gestational age requiring respiratory support at birth, which of two treatment strategies when compared, results in a lower rate of the combined endpoint of death or bronchopulmonary dysplasia.
Time frame: 36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Arm-Standard of Care | Combined Outcome of Death or Bronchopulmonary Dysplasia | 125 Participants |
| Sustained Intervention | Combined Outcome of Death or Bronchopulmonary Dysplasia | 137 Participants |
Secondary
Chest X-ray Between Days 7-10
Chest x-ray between the first 7-10 days of life
Time frame: First 7-10 days of life
Secondary
Death in Hospital
Death in hospital during expected hospitalization of 23-40 weeks PMA
Time frame: During expected hospitalization 23 - 40 weeks PMA
Secondary
Death or Need for Positive Pressure Ventilation
Death or need for positive pressure ventilation during the first 7 days of life
Time frame: First 7 days of life
Secondary
Detailed Status on Departure From the Delivery Room (DR)
Type of respiratory support (CPAP, PPV) and Fraction of Inspired Oxygen (FiO2) on departure from DR
Time frame: Resuscitation time will vary - 1 to 30 minutes
Secondary
Duration of Any Chest Drain In-situ Post-DR
Duration of any chest drain in-situ post-DR during hospitalization - up to 36 weeks Post Menstrual Age (PMA)
Time frame: During hospitalization - up to 36 weeks Post Menstrual Age (PMA)
Secondary
Duration of Respiratory Support (Ventilation, CPAP, Supplemental Oxygen)
Duration of respiratory support (ventilation, CPAP, supplemental oxygen) during hospitalization upto 36 weeks Post Menstrual Age (PMA)
Time frame: During hospitalization - up to 36 weeks Post Menstrual Age (PMA)
Secondary
Heart Rate in the Delivery Room (DR)
Categorical variable with 3 levels: \<60, 60-100, \>100
Time frame: First 30 seconds of life in DR
Secondary
Highest FiO2 and Area Under the FiO2 Curve for the First Week of Life
Highest FiO2 and Area under the FiO2 curve during the first 7 days of life
Time frame: First 7 days of life
Secondary
Intraventricular Hemorrhage by All Grades
Head ultrasound and/or MRI findings of intraventricular hemorrhage by all grades focusing on grades 3 and 4 by 48 hour and by day 10
Time frame: 48 hours to 10 days
Secondary
Length of Hospital Stay
Length of hospital stay with average discharge between 36-40 weeks PMA
Time frame: Average discharge between 36 - 40 weeks PMA
Secondary
Need for Intubation in Delivery Room
Need for intubation in delivery room during the first 30 seconds to 24 hours of age
Time frame: First 30 seconds to 24 hours of life
Secondary
Neurodevelopmental and Respiratory Outcome at 22-26 Months Corrected Gestational Age
Neurodevelopmental and respiratory outcome at 22-26 months corrected gestational age
Time frame: 22-26 months corrected gestational age
Secondary
Oxygen Profile Over First 24 Hours
Oxygen profile over first 24 hours post delivery room using hourly FiO2 records
Time frame: First 24 hours post delivery
Secondary
Oxygen Profile With Highest FiO2 Level up to 48 Hours
Highest FiO2 level recorded during the first 48 hours post DR
Time frame: 48 hours of life
Secondary
Pneumothorax and Pulmonary Interstitial Emphysema (PIE)
Pneumothorax and pulmonary interstitial emphysema (PIE) during the first 10 days of life
Time frame: First 10 days of life
Secondary
Pneumothorax or New Chest Drains in the First 48 Hours of Life
Chest x-ray reports showing pneumothorax or new chest drains in the first 48 hours of life
Time frame: First 48 hours of life
Secondary
Pressure-volume Characteristics in the Delivery Room (DR)
Pressure-volume characteristics in the Delivery room (DR) expected within 30 minutes
Time frame: Expected average 30 minutes
Secondary
Retinopathy of Prematurity (ROP) Stage 3 or Greater Requiring Treatment
Retinopathy of prematurity (ROP) stage 3 or greater requiring treatment at 36 weeks
Time frame: 36 weeks
Secondary
Survival to Discharge Home Without BPD, Retinopathy of Prematurity (Grades 3 & 4), or Significant Brain Abnormalities on Head Ultrasound
Survival to discharge home without BPD, retinopathy of prematurity (grades 3 & 4), or significant brain abnormalities on head ultrasound with an expected discharge between 36-40 weeks PMA
Time frame: Expected discharge between 36 - 40 weeks PMA
Secondary
Use of Inotropes on Arrival in NICU
Circulatory support post-delivery room
Time frame: First 48 hours of life
Secondary
Use of Postnatal Steroids for Treatment of BPD
Use of postnatal steroids for treatment of BPD during hospitalization up to 36 weeks Post Menstrual Age (PMA)
Time frame: During hospitalization - up to 36 weeks Post Menstrual Age (PMA)