Early Inhaled Nitric Oxide for Respiratory Failure in Newborns

Study Overview
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Brief Summary
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This prospective, randomized controlled trial tested whether initiating iNO therapy earlier would reduce death and reduce the use of extracorporeal membrane oxygenation (ECMO) -- temporary lung bypass -- therapy compared with the standard recommendation threshold. Infants who were born at >34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) >15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to receive either early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy. The neurodevelopment of the subjects were evaluated at 18-22 months corrected age.

Detailed Description
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Respiratory failure occurs in near term and term infants as a complication of perinatal aspiration syndromes, pneumonia, sepsis, respiratory distress syndrome and primary pulmonary hypertension. Recently a collaborative trial of the NICHD Neonatal Research Network and the Canadian Inhaled Nitric Oxide Study Group (the NINOS trial) demonstrated that inhaled nitric oxide (iNO) reduced the number of deaths and the need for extracorporeal membrane oxygenation (ECMO) therapy -- a lung bypass mechanism -- from 64 percent to 46 percent. The standard recommended threshold for initiation of iNO therapy, based on this trial, was an oxygenation index (OI) >=25. The purpose of this study is to determine if administration of inhaled nitric oxide earlier in the course of respiratory failure and to infants with less severe respiratory failure, decreases the incidence of ECMO or death, as suggested by the sub-group analysis of the original NINOS trial. This prospective, randomized controlled trial tested whether initiating iNO therapy earlier would reduce death and reduce the use of ECMO therapy compared with the standard recommendation threshold. Infants who were born at >34 weeks' gestation (near- or full-term) were enrolled when they required assisted ventilation and had an oxygenation index (OI) >15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to receive either early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy. The neurodevelopment of the subjects were evaluated at 18-22 months corrected age. The study compared the outcome of infants received iNO at OI >15 and <25, with a control group that received a simulated early procedure with iNO actually given based on the standard recommendation. iNO was delivered at 20 ppm during the initial dose-response evaluation. Infants in either group who showed subsequent deterioration with OI >25 on two consecutive measurements at least one hour apart, or a rapid deterioration with OI >30 on two consecutive measurements 15 minutes apart, received iNO therapy as part of standard medical management. Specific guidelines were followed for the use of high frequency ventilation and surfactant during study gas administration to prevent them from confounding the results of the study. Study recruitment was discontinued after 3 years due to a persistent decline in enrollment. Infants were given neurodevelopmental exams at 18-22 months corrected age.

Official Title
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Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants With Respiratory Failure

Conditions
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Infant, Newborn, Hypertension, Pulmonary, Persistent Fetal Circulation Syndrome, Pneumonia, Aspiration, Respiratory Distress Syndrome, Newborn, Respiratory Insufficiency

Intervention / Treatment
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* Drug: Inhaled Nitric Oxide
* Drug: Standard iNO therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants born at >34 weeks gestational age Require assisted ventilation for hypoxic respiratory failure Have a diagnosis of primary persistent pulmonary hypertension (PPHN), respiratory distress syndrome, perinatal aspiration syndrome, pneumonia/sepsis, or suspected pulmonary hypoplasia Have an oxygenation index >15 and <25 based on 2 arterial blood gases taken at least 15 minutes apart or an Fi02 >80% In-dwelling arterial line Parental consent Exclusion Criteria: Known structural congenital heart disease, except patent ductus arteriosus and atrial level shunts Congenital diaphragmatic hernia Use of high frequency jet ventilation at the time of randomization Prior exposure to inhaled nitric oxide therapy

Ages Eligible for Study
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Maximum Age: 14 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early iNO Management<br>Initiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25. | Drug: Inhaled Nitric Oxide<br>* Study gas was initiated at a concentration of 5 ppm, and the dose was increased to 20 ppm when the infant had <=20 mm Hg increase in PaO2 (less than full response).<br>|
| Active Comparator: Standard iNO management<br>Begin a sham initiation of iNO in term and near-term infants in respiratory failure with an oxygenation index (OI) between 15-25; initiated actual iNO therapy based on standard threshold (OI >=25). | Drug: Standard iNO therapy<br>* Begin a sham initiation of iNO in term and near-term infants in respiratory failure with an oxygenation index (OI) between 15-25; initiated actual iNO therapy based on standard threshold (OI >=25).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or use of extracorporeal membrane oxygenation (ECMO) |  | Hospital discharge or 120 days of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Use of iNO therapy based on the standard recommended threshold |  | Hospital Discharge or 120 days of life | 
| Progression to severe respiratory failure (OI>40) | Severe respiratory failure, defined as OI >40 | Hospital discharge or 120 days of life | 
| Neurodevelopmental impairment |  | 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, Hypertension, pulmonary, Hypoxic respiratory failure, Meconium aspiration, Methemoglobinemia, Nitric oxide, Oxygen inhalation therapy, Persistent Fetal Circulation Syndrome, Pneumonia, aspiration, Respiratory distress syndrome, Respiratory insufficiency, Severe respiratory failure