Respiratory Distress Syndrome in Premature Infants, Very Low Birth Weight Baby
Conditions
Keywords
Prematurity, Oxygen exposure, Nitric Oxide
Brief summary
This study hopes to determine whether nitric oxide along with oxygen during the first 20 minutes of life in infants needing help with breathing will reduce the percentage and total exposure to oxygen during that time frame. Although the use of oxygen in management of breathing is an important part of supporting baby immediately after delivery, there is more evidence that too much exposure to oxygen may lead to potential problems for your baby later. Oxygen exposure can be harmful to premature babies developing lungs.
Detailed description
Current Neonatal Resuscitation Program (NRP) guidelines suggest the use of supplemental oxygen up to fraction of inspired oxygen of 1.0 during neonatal resuscitation for both term and preterm newborns. Exposure to supplemental oxygen in preterm babies has been shown to have significant toxicity. Even minimal exposure in the first hours of life has been shown to be associated with morbidity including later onset of cancer. The transition from fetal circulation to neonatal circulation is a complex process requiring lung inflation and decrease in pulmonary vascular resistance. Endogenous nitric oxide, along with oxygen, plays a major role in facilitating this transition by decreasing pulmonary vascular resistance. It is not known whether exogenous nitric oxide would facilitate this transition. In this study, we propose a novel approach to resuscitation of preterm infants where inhaled nitric oxide (iNO) will be used as an adjunct to oxygen with the primary goal of reducing supplemental oxygen exposure. This study is designed to be a double-blind, randomized, -placebo- controlled pilot trial with strict monitoring of parameters during transition in the delivery room.
Interventions
DRUGiNO
Immediately after birth, subjects will be randomized to receive iNO (20ppm) or nitrogen (placebo gas) with blended oxygen (starting with 0.3). Fraction of inspired oxygen will be adjusted by 0.1 increments every 15 seconds targeting pre-ductal oxygen saturation of 70-85% in the first 2 minutes of life, and then 85-93% until the end of the study period while requiring supplemental oxygen.
OTHERNitrogen
Subjects will be randomized to receive iNO (20ppm) or nitrogen (placebo gas) with blended oxygen (starting with 0.3). Fraction of inspired oxygen will be adjusted by 0.1 increments every 15 seconds targeting pre-ductal oxygen saturation of 70-85% in the first 2 minutes of life, and then 85-93% until the end of the study period while requiring supplemental oxygen.
Sponsors
Mallinckrodt
University of Oklahoma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Minutes to 2 Minutes
Healthy volunteers
No
Inclusion criteria
* Infants that are 25 0/7 - 31 6/7 weeks gestation * Infants who require Continuous Positive Airway Pressure (CPAP) or Positive Pressure Ventilation ( PPV) during delivery room resuscitation.
Exclusion criteria
* Refusal of consent * Known complex congenital anomalies of the heart or lungs * Known major genetic defects * Hydrops fetalis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Hyperoxia | 20 minutes | FiO2 \>60% at any 5 second increment during the study period of 20 minutes for each infant in each arm. |
| Maximum Factional Inspired Oxygen Percent (FiO2) | 20 minutes | To investigate whether iNO decreases the supplemental oxygen exposure in the preterm infants who require continuous positive airway pressure (CPAP) or positive pressure ventilation (PPV) during resuscitation as per Neonatal Resuscitation Program (NRP) protocol. |
| Pre and Postductal Saturation Levels | at 20 minutes (end of study) | Oxygen saturations as described as preductal (right hand) as well as post ductal (either foot) and measured as percent of saturated hemoglobin by pulse oximetry. |
| Heart Rate During Resuscitation | 5, 10 and 20 minutes on study | Measured and recorded heart rates every 5 seconds on study as described as beats per minute (BPM) |
| Need for Intubation | by end of study, 20 minutes | Infants requiring placement of endotracheal tube as part of the Neonatal Resuscitation Program algorithm for airway management. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intraventricular Hemorrhage > Grade 2 | Hospital Discharge | Intraventricular Hemorrhage (IVH) \> Gr 2 as described by radiographic scale as described in Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm., Papile L A; Burstein J; Burstein R; Koffler H, The Journal of pediatrics, (1978 Apr) Vol. 92, No. 4, pp. 529-34. Journal code: 0375410. ISSN: 0022-3476. L-ISSN: 0022-3476. IVH classification systems Papile system Grade I Subependymal hemorrhage Grade II IVH without ventricular dilation Grade III IVH with ventricular dilation Grade IV Extensive IVH with parenchymal involvement |
| Late Onset Sepsis | at any time during study period | Late Onset Sepsis as described as infection after day 5 of life. This would include all patients who survived to day of life 5. |
| Infants With Patent Ductus Arteriosus (PDA) Requiring Treatment | Prior to infant discharge from the hospital | Count of patients requiring either pharmacologic or surgical treatment for persistent PDA |
| Retinopathy of Prematurity (ROP)> Stage 2 | Prior to infant discharge from the hospital | Staging of any retinal disease as described by the standard screening by the American Association for Pediatric Ophthalmology and Strabismus. Only infants who survived to obtain retinal imaging are included (12 in Placebo arm and 11 in INO arm) |
| Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | Prior to infant discharge from the hospital | endotracheal or other airway placement and mechanical ventilation in days, days of non-invasive ventilation as described as nasal ventilation, CPAP, high flow and low flow oxygen as counted in days. Only infants who survived to discharge were included in this analysis. |
| Bronchopulmonary Dysplasia | at 36 weeks adjusted gestational age of participant | Bronchopulmonary Dysplasia as described as oxygen need at 36 weeks adjusted gestational age. Only infants who survived to 36 weeks gestation were included in this analysis. |
Countries
United States
Participant flow
Recruitment details
Women admitted in preterm labor with gestational ages of 25 0/7 to 31 6/7 weeks gestation were approached for prenatal consent. 171 mothers were identified, 95 mothers consented
Pre-assignment details
64 consented mothers or infants met subsequent exclusion criteria. Of those, only 33 were enrolled at time of delivery. Most common exclusion was aging out of gestational age limit, precipitous delivery, or no team available.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 20ppm Nitrogen at 20 ppm at the beginning of study start with gradual taper at 10 minutes of the study and completely off by 17 minutes of the study
Nitrogen: Subjects will be randomized to receive iNO (20ppm) or nitrogen (placebo gas) with blended oxygen (starting with 0.3). Fraction of inspired oxygen will be adjusted by 0.1 increments every 15 seconds targeting pre-ductal oxygen saturation of 70-85% in the first 2 minutes of life, and then 85-93% until the end of the study period while requiring supplemental oxygen. | 14 |
| iNO 20 Ppm Nitric Oxide 20 ppm at the beginning of study start with gradual taper at 10 minutes of the study and completely off by 17 minutes of the study
iNO: Immediately after birth, subjects will be randomized to receive iNO (20ppm) or nitrogen (placebo gas) with blended oxygen (starting with 0.3). Fraction of inspired oxygen will be adjusted by 0.1 increments every 15 seconds targeting pre-ductal oxygen saturation of 70-85% in the first 2 minutes of life, and then 85-93% until the end of the study period while requiring supplemental oxygen. | 14 |
| Total | 28 |
Baseline characteristics
| Characteristic | Total | Placebo 20ppm | iNO 20 Ppm |
|---|---|---|---|
| Age, Continuous | 28.4 Weeks | 28.1 Weeks | 28.6 Weeks |
| Any Antenatal Steroid | 17 Participants | 8 Participants | 9 Participants |
| Apgar Score at 5 minutes | 7.5 units on a scale | 8 units on a scale | 7 units on a scale |
| Apgar Score at one minute | 4 units on a scale | 5 units on a scale | 4 units on a scale |
| Birthweight | 1105 Grams | 1105 Grams | 1145 Grams |
| Chorioamnionitis | 5 Participants | 2 Participants | 3 Participants |
| Maternal Preeclampsia | 9 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized African American | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 20 Participants | 10 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Native American | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other Race | 1 Participants | 0 Participants | 1 Participants |
| Rupture of Membranes (ROM) greater than 18 hours | 6 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 18 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 14 | 2 / 14 |
| other Total, other adverse events | 0 / 13 | 0 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
Heart Rate During Resuscitation
Measured and recorded heart rates every 5 seconds on study as described as beats per minute (BPM)
Time frame: 5, 10 and 20 minutes on study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo 20ppm | Heart Rate During Resuscitation | BPM at 5 minutes | 139 BPM | Standard Deviation 53 |
| Placebo 20ppm | Heart Rate During Resuscitation | BPM at 10 minutes | 161 BPM | Standard Deviation 53 |
| Placebo 20ppm | Heart Rate During Resuscitation | BPM at 20 minutes | 168 BPM | Standard Deviation 53 |
| iNO 20 Ppm | Heart Rate During Resuscitation | BPM at 5 minutes | 130 BPM | Standard Deviation 46 |
| iNO 20 Ppm | Heart Rate During Resuscitation | BPM at 10 minutes | 149 BPM | Standard Deviation 46 |
| iNO 20 Ppm | Heart Rate During Resuscitation | BPM at 20 minutes | 158 BPM | Standard Deviation 46 |
Primary
Maximum Factional Inspired Oxygen Percent (FiO2)
To investigate whether iNO decreases the supplemental oxygen exposure in the preterm infants who require continuous positive airway pressure (CPAP) or positive pressure ventilation (PPV) during resuscitation as per Neonatal Resuscitation Program (NRP) protocol.
Time frame: 20 minutes
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo 20ppm | Maximum Factional Inspired Oxygen Percent (FiO2) | 48 percentage of Inspired Oxygen |
| iNO 20 Ppm | Maximum Factional Inspired Oxygen Percent (FiO2) | 39 percentage of Inspired Oxygen |
p-value: 0.0012t-test, 2 sided
Primary
Need for Intubation
Infants requiring placement of endotracheal tube as part of the Neonatal Resuscitation Program algorithm for airway management.
Time frame: by end of study, 20 minutes
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo 20ppm | Need for Intubation | 4 Participants |
| iNO 20 Ppm | Need for Intubation | 4 Participants |
Primary
Pre and Postductal Saturation Levels
Oxygen saturations as described as preductal (right hand) as well as post ductal (either foot) and measured as percent of saturated hemoglobin by pulse oximetry.
Time frame: at 20 minutes (end of study)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo 20ppm | Pre and Postductal Saturation Levels | Preductal Saturation | 90.5 Percent Saturation | Standard Deviation 5.7 |
| Placebo 20ppm | Pre and Postductal Saturation Levels | Postductal Saturation | 79.9 Percent Saturation | Standard Deviation 25.8 |
| iNO 20 Ppm | Pre and Postductal Saturation Levels | Preductal Saturation | 82.8 Percent Saturation | Standard Deviation 13.8 |
| iNO 20 Ppm | Pre and Postductal Saturation Levels | Postductal Saturation | 78.2 Percent Saturation | Standard Deviation 20 |
Primary
Rate of Hyperoxia
FiO2 \>60% at any 5 second increment during the study period of 20 minutes for each infant in each arm.
Time frame: 20 minutes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo 20ppm | Rate of Hyperoxia | 708 Observations on >60% FiO2 |
| iNO 20 Ppm | Rate of Hyperoxia | 370 Observations on >60% FiO2 |
p-value: <0.000195% CI: [1.68, 2.18]Poisson
Secondary
Bronchopulmonary Dysplasia
Bronchopulmonary Dysplasia as described as oxygen need at 36 weeks adjusted gestational age. Only infants who survived to 36 weeks gestation were included in this analysis.
Time frame: at 36 weeks adjusted gestational age of participant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo 20ppm | Bronchopulmonary Dysplasia | 5 Participants |
| iNO 20 Ppm | Bronchopulmonary Dysplasia | 5 Participants |
Secondary
Infants With Patent Ductus Arteriosus (PDA) Requiring Treatment
Count of patients requiring either pharmacologic or surgical treatment for persistent PDA
Time frame: Prior to infant discharge from the hospital
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo 20ppm | Infants With Patent Ductus Arteriosus (PDA) Requiring Treatment | 4 Participants |
| iNO 20 Ppm | Infants With Patent Ductus Arteriosus (PDA) Requiring Treatment | 1 Participants |
Secondary
Intraventricular Hemorrhage > Grade 2
Intraventricular Hemorrhage (IVH) \> Gr 2 as described by radiographic scale as described in Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm., Papile L A; Burstein J; Burstein R; Koffler H, The Journal of pediatrics, (1978 Apr) Vol. 92, No. 4, pp. 529-34. Journal code: 0375410. ISSN: 0022-3476. L-ISSN: 0022-3476. IVH classification systems Papile system Grade I Subependymal hemorrhage Grade II IVH without ventricular dilation Grade III IVH with ventricular dilation Grade IV Extensive IVH with parenchymal involvement
Time frame: Hospital Discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo 20ppm | Intraventricular Hemorrhage > Grade 2 | 2 Participants |
| iNO 20 Ppm | Intraventricular Hemorrhage > Grade 2 | 0 Participants |
Secondary
Late Onset Sepsis
Late Onset Sepsis as described as infection after day 5 of life. This would include all patients who survived to day of life 5.
Time frame: at any time during study period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo 20ppm | Late Onset Sepsis | 2 Participants |
| iNO 20 Ppm | Late Onset Sepsis | 0 Participants |
Secondary
Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS)
endotracheal or other airway placement and mechanical ventilation in days, days of non-invasive ventilation as described as nasal ventilation, CPAP, high flow and low flow oxygen as counted in days. Only infants who survived to discharge were included in this analysis.
Time frame: Prior to infant discharge from the hospital
Population: 2 of the 14 patients in the placebo arm died were not included in the analysis, 1 of the 14 patients in the INO Group was excluded for pulmonary hypoplasia..
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo 20ppm | Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | Mechanical Ventilation | 14 Days |
| Placebo 20ppm | Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | NIV | 15 Days |
| Placebo 20ppm | Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | LOS | 52 Days |
| iNO 20 Ppm | Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | Mechanical Ventilation | 8.5 Days |
| iNO 20 Ppm | Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | NIV | 20.5 Days |
| iNO 20 Ppm | Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay in Days (LOS) | LOS | 70.5 Days |
Secondary
Retinopathy of Prematurity (ROP)> Stage 2
Staging of any retinal disease as described by the standard screening by the American Association for Pediatric Ophthalmology and Strabismus. Only infants who survived to obtain retinal imaging are included (12 in Placebo arm and 11 in INO arm)
Time frame: Prior to infant discharge from the hospital
Population: 2 of the 14 patients in the placebo arm died and had no ROP exam, 3 of the 14 patients in the INO Group died and had no ROP exam.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo 20ppm | Retinopathy of Prematurity (ROP)> Stage 2 | 4 Participants |
| iNO 20 Ppm | Retinopathy of Prematurity (ROP)> Stage 2 | 1 Participants |