Early Inhaled Nitric Oxide for Respiratory Failure in Newborns

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE3

Total Enrollment

302 participants

Study Classification

INTERVENTIONAL

Study Start Date

1998-08-31

Study Completion Date

2003-08-31

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.

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Early iNO Management

Initiation of iNO in use for term and near-term infants in respiratory failure with an oxygenation index between 15-25.

Group Type EXPERIMENTAL

Inhaled Nitric Oxide

Intervention Type DRUG

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).

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).

Group Type ACTIVE_COMPARATOR

Standard iNO therapy

Intervention Type DRUG

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).

Interventions

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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).

Intervention Type 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).

Intervention Type DRUG

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

Maximum Eligible Age

14 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Medical College of Wisconsin, Children's Hospital of Wisconsin

Principal Investigators

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G. Ganesh Konduri, MD

Role: STUDY_DIRECTOR

University of Wisconsin, Madison

Waldemar A. Carlo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Carlos Fajardo, MD

Role: PRINCIPAL_INVESTIGATOR

St. Joseph's Hospital

Krisa P. Van Meurs, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Gail Knight, MD

Role: PRINCIPAL_INVESTIGATOR

San Diego Children's Hospital

Richard A. Ehrenkranz, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Charles R. Bauer, MD

Role: PRINCIPAL_INVESTIGATOR

University of Miami

Barbara J. Stoll, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Greg M. Sokol, MD

Role: PRINCIPAL_INVESTIGATOR

Indiana University

Seetha Shankaran, MD

Role: PRINCIPAL_INVESTIGATOR

Wayne State University

Lu-Ann Papile, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico

Edward F. Donovan, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Avroy A. Fanaroff, MD

Role: STUDY_DIRECTOR

Case Western Reserve University, Rainbow Babies and Children's Hospital

William Oh, MD

Role: PRINCIPAL_INVESTIGATOR

Brown University, Women & Infants Hospital of Rhode Island

Sheldon B. Korones, MD

Role: PRINCIPAL_INVESTIGATOR

University of Tennessee

Abbot R. Laptook, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas, Southwestern Medical Center at Dallas

Mary Wearden, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Kathleen A. Kennedy, MD MPH

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center, Houston

Dennis E. Mayock, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

St. Joseph's Hospital

Phoenix, Arizona, United States

Site Status

Stanford University

Palo Alto, California, United States

Site Status

San Diego Children's Hospital

San Diego, California, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

University of Miami

Miami, Florida, United States

Site Status

Emory University

Atlanta, Georgia, United States

Site Status

Indiana University

Indianapolis, Indiana, United States

Site Status

Wayne State University

Detroit, Michigan, United States

Site Status

University of New Mexico

Albuquerque, New Mexico, United States

Site Status

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States

Site Status

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

Site Status

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States

Site Status

University of Tennessee

Memphis, Tennessee, United States

Site Status

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Site Status

Texas Children's Hospital

Houston, Texas, United States

Site Status

University of Texas Health Science Center at Houston

Houston, Texas, United States

Site Status

University of Washington School of Medicine

Seattle, Washington, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND

PMID: 10053039 (View on PubMed)

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.

Reference Type BACKGROUND

PMID: 14510322 (View on PubMed)

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.

Reference Type RESULT

PMID: 14993550 (View on PubMed)

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.

Reference Type RESULT

PMID: 17307536 (View on PubMed)