Inhaled Nitric Oxide (iNO) as an Adjunct to Neonatal Resuscitation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Administration of Inhaled Nitric Oxide (iNO) as an Adjunct to Neonatal Resuscitation Protocol: A Pilot Trial

Conditions
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Respiratory Distress Syndrome in Premature Infants, Very Low Birth Weight Baby

Intervention / Treatment
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* Drug: iNO
* Other: Nitrogen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Minute
Maximum Age: 2 Minutes

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo 20ppm<br>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 | Other: Nitrogen<br>* 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.<br>|
| Experimental: Inhaled Nitric Oxide (iNO) 20 ppm<br>Inhaled 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 | Drug: iNO<br>* 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.<br>* Other names: Inhaled Nitric Oxide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 20 minutes | 
| Rate of Hyperoxia | FiO2 >60% at any 5 second increment during the study period of 20 minutes for each infant in each arm. | 20 minutes | 
| 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. | at 20 minutes (end of study) | 
| Heart Rate During Resuscitation | Measured and recorded heart rates every 5 seconds on study as described as beats per minute (BPM) | 5, 10 and 20 minutes on study | 
| Need for Intubation | Infants requiring placement of endotracheal tube as part of the Neonatal Resuscitation Program algorithm for airway management. | by end of study, 20 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Hospital Discharge | 
| Infants With Patent Ductus Arteriosus (PDA) Requiring Treatment | Count of patients requiring either pharmacologic or surgical treatment for persistent PDA | Prior to infant discharge from the hospital | 
| 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) | Prior to infant discharge from the hospital | 
| 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. | Prior to infant discharge from the hospital | 
| 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. | at 36 weeks adjusted gestational age of participant | 
| 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. | at any time during study period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prematurity, Oxygen exposure, Nitric Oxide