Early Inhaled Nitric Oxide for Respiratory Failure in Newborns (Early iNO)

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

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.

Study Overview

• Status: Terminated
• Conditions: Respiratory Insufficiency; Hypertension, Pulmonary; Pneumonia, Aspiration; Persistent Fetal Circulation Syndrome; Respiratory Distress Syndrome, Newborn; Infant, Newborn
• Intervention / Treatment: Drug: Inhaled Nitric Oxide; Drug: Standard iNO therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 302
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
    • San Diego, California, United States, 92130
      • San Diego Children's Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee
  • Texas
    • Dallas, Texas, United States, 75235
      • University Of Texas Southwestern Medical Center At Dallas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 weeks (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Early iNO Management; 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; 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).
ACTIVE_COMPARATOR: Standard iNO management; 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; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Canadian Institutes of Health Research (CIHR); National Center for Research Resources (NCRR); Mallinckrodt
• Investigators: Study Director: G. Ganesh Konduri, MD, University of Wisconsin, Madison; Principal Investigator: Carlos Fajardo, MD, St. Joseph's Hospital; Principal Investigator: Gail Knight, MD, San Diego Children's Hospital; Study Director: Avroy A. Fanaroff, MD, Case Western Reserve University, Rainbow Babies and Children's Hospital; Principal Investigator: Abbot R. Laptook, MD, University of Texas, Southwestern Medical Center at Dallas; Principal Investigator: Dennis E. Mayock, MD, University of Washington

Publications and helpful links

General Publications

• Sokol GM, Van Meurs KP, Wright LL, Rivera O, Thorn WJ 3rd, Chu PM, Sams RL. Nitrogen dioxide formation during inhaled nitric oxide therapy. Clin Chem. 1999 Mar;45(3):382-7.
• Sokol GM, Ehrenkranz RA. Inhaled nitric oxide therapy in neonatal hypoxic respiratory failure: insights beyond primary outcomes. Semin Perinatol. 2003 Aug;27(4):311-9. doi: 10.1016/s0146-0005(03)00043-0.
• Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A; Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004 Mar;113(3 Pt 1):559-64. doi: 10.1542/peds.113.3.559.
• Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A, Johnson Y; Neonatal Inhaled Nitric Oxide Study Group. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr. 2007 Mar;150(3):235-40, 240.e1. doi: 10.1016/j.jpeds.2006.11.065.

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: August 1, 1998
• Primary Completion (ACTUAL): May 1, 2001
• Study Completion (ACTUAL): August 1, 2003

Study Registration Dates

• First Submitted: June 1, 2000
• First Submitted That Met QC Criteria: June 1, 2000
• First Posted (ESTIMATE): June 2, 2000

Study Record Updates

• Last Update Posted (ACTUAL): September 26, 2017
• Last Update Submitted That Met QC Criteria: September 22, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Nitric oxide; Hypertension, pulmonary; Oxygen inhalation therapy; Severe respiratory failure; Respiratory insufficiency; NICHD Neonatal Research Network; Respiratory distress syndrome; Methemoglobinemia; Persistent Fetal Circulation Syndrome; Hypoxic respiratory failure; Meconium aspiration; Pneumonia, aspiration
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Infant, Premature, Diseases; Hypertension; Syndrome; Respiratory Insufficiency; Pneumonia; Hypertension, Pulmonary; Pneumonia, Aspiration; Persistent Fetal Circulation Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: NICHD-NRN-0019; M01RR000633 (U.S. NIH Grant/Contract); U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); U01HD019897 (U.S. NIH Grant/Contract); U10HD021415 (U.S. NIH Grant/Contract); U10HD027881 (U.S. NIH Grant/Contract); M01RR008084 (U.S. NIH Grant/Contract); M01RR006022 (U.S. NIH Grant/Contract); M01RR000750 (U.S. NIH Grant/Contract); M01RR000070 (U.S. NIH Grant/Contract); M01RR000997 (U.S. NIH Grant/Contract); U10HD021397 (U.S. NIH Grant/Contract); U10HD034167 (U.S. NIH Grant/Contract); M01RR001032 (U.S. NIH Grant/Contract); M01RR016587 (U.S. NIH Grant/Contract)