Early Inhaled Nitric Oxide for Respiratory Failure in Newborns (Early iNO)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Infant, Newborn Hypertension, Pulmonary Persistent Fetal Circulation Syndrome Pneumonia, Aspiration Respiratory Distress Syndrome, Newborn Respiratory Insufficiency |
Drug: Inhaled Nitric Oxide Drug: Standard iNO therapy |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants With Respiratory Failure |
- Death or use of extracorporeal membrane oxygenation (ECMO) [ Time Frame: Hospital discharge or 120 days of life ] [ Designated as safety issue: Yes ]
- Use of iNO therapy based on the standard recommended threshold [ Time Frame: Hospital Discharge or 120 days of life ] [ Designated as safety issue: Yes ]
- Progression to severe respiratory failure (OI>40) [ Time Frame: Hospital discharge or 120 days of life ] [ Designated as safety issue: Yes ]Severe respiratory failure, defined as OI >40
- Neurodevelopmental impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
| Enrollment: | 302 |
| Study Start Date: | August 1998 |
| Study Completion Date: | August 2003 |
| Primary Completion Date: | May 2001 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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).
|
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.
Eligibility| Ages Eligible for Study: | up to 14 Days |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United States, Alabama | |
| University of Alabama at Birmingham | |
| Birmingham, Alabama, United States, 35233 | |
| United States, Arizona | |
| St. Joseph's Hospital | |
| Phoenix, Arizona, United States, 85013 | |
| United States, California | |
| Stanford University | |
| Palo Alto, California, United States, 94304 | |
| San Diego Children's Hospital | |
| San Diego, California, United States, 92130 | |
| United States, Connecticut | |
| Yale University | |
| New Haven, Connecticut, United States, 06504 | |
| United States, Florida | |
| University of Miami | |
| Miami, Florida, United States, 33136 | |
| United States, Georgia | |
| Emory University | |
| Atlanta, Georgia, United States, 30303 | |
| United States, Indiana | |
| Indiana University | |
| Indianapolis, Indiana, United States, 46202 | |
| United States, Michigan | |
| Wayne State University | |
| Detroit, Michigan, United States, 48201 | |
| United States, New Mexico | |
| University of New Mexico | |
| Albuquerque, New Mexico, United States, 87131 | |
| United States, Ohio | |
| Cincinnati Children's Medical Center | |
| Cincinnati, Ohio, United States, 45267 | |
| Case Western Reserve University, Rainbow Babies and Children's Hospital | |
| Cleveland, Ohio, United States, 44106 | |
| United States, Rhode Island | |
| Brown University, Women & Infants Hospital of Rhode Island | |
| Providence, Rhode Island, United States, 02905 | |
| United States, Tennessee | |
| University of Tennessee | |
| Memphis, Tennessee, United States, 38163 | |
| United States, Texas | |
| University of Texas Southwestern Medical Center at Dallas | |
| Dallas, Texas, United States, 75235 | |
| Texas Children's Hospital | |
| Houston, Texas, United States, 77030 | |
| University of Texas Health Science Center at Houston | |
| Houston, Texas, United States, 77030 | |
| United States, Washington | |
| University of Washington School of Medicine | |
| Seattle, Washington, United States, 98195 | |
| Study Director: | G. Ganesh Konduri, MD | University of Wisconsin, Madison |
| Principal Investigator: | Waldemar A. Carlo, MD | University of Alabama at Birmingham |
| Principal Investigator: | Carlos Fajardo, MD | St. Joseph's Hospital |
| Principal Investigator: | Krisa P. Van Meurs, MD | Stanford University |
| Principal Investigator: | Gail Knight, MD | San Diego Children's Hospital |
| Principal Investigator: | Richard A. Ehrenkranz, MD | Yale University |
| Principal Investigator: | Charles R. Bauer, MD | University of Miami |
| Principal Investigator: | Barbara J. Stoll, MD | Emory University |
| Principal Investigator: | Greg M. Sokol, MD | Indiana University |
| Principal Investigator: | Seetha Shankaran, MD | Wayne State University |
| Principal Investigator: | Lu-Ann Papile, MD | University of New Mexico |
| Principal Investigator: | Edward F. Donovan, MD | Cincinnati Children's Medical Center |
| Study Director: | Avroy A. Fanaroff, MD | Case Western Reserve University, Rainbow Babies and Children's Hospital |
| Principal Investigator: | William Oh, MD | Brown University, Women & Infants Hospital of Rhode Island |
| Principal Investigator: | Sheldon B. Korones, MD | University of Tennessee |
| Principal Investigator: | Abbot R. Laptook, MD | University of Texas Southwestern Medical Center at Dallas |
| Principal Investigator: | Mary Wearden, MD | Texas Children's Hospital |
| Principal Investigator: | Kathleen A. Kennedy, MD MPH | The University of Texas Health Science Center, Houston |
| Principal Investigator: | Dennis E. Mayock, MD | University of Washington |
More Information
Additional Information:
Publications:
| Responsible Party: | G. Ganesh Konduri, Lead Principal Investigator, Medical College of Wisconsin, Children's Hospital of Wisconsin |
| ClinicalTrials.gov Identifier: | NCT00005773 History of Changes |
| Other Study ID Numbers: | NICHD-NRN-0019, U01HD019897, U10HD021364, U10HD021373, U10HD021385, U10HD021397, U10HD021415, U10HD027853, U10HD027856, U10HD027871, U10HD027880, U10HD027881, U10HD027904, U10HD034167, U10HD034216, U10HD040689, M01RR000070, M01RR000633, M01RR000750, M01RR000997, M01RR001032, M01RR006022, M01RR008084, M01RR016587 |
| Study First Received: | June 1, 2000 |
| Last Updated: | May 12, 2011 |
| Health Authority: | United States: Federal Government United States: Institutional Review Board United States: Food and Drug Administration |
Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
|
Pneumonia, aspiration NICHD Neonatal Research Network Hypertension, pulmonary Hypoxic respiratory failure Meconium aspiration Methemoglobinemia |
Nitric oxide Oxygen inhalation therapy Persistent Fetal Circulation Syndrome Respiratory distress syndrome Respiratory insufficiency Severe respiratory failure |
Additional relevant MeSH terms:
|
Pneumonia, Aspiration Hypertension Hypertension, Pulmonary Persistent Fetal Circulation Syndrome Pneumonia Respiratory Distress Syndrome, Newborn Respiratory Distress Syndrome, Adult Respiratory Insufficiency Vascular Diseases Cardiovascular Diseases Lung Diseases Respiratory Tract Diseases Infant, Newborn, Diseases Respiratory Tract Infections Respiration Disorders |
Infant, Premature, Diseases Nitric Oxide Bronchodilator Agents Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Pharmacologic Actions Anti-Asthmatic Agents Respiratory System Agents Therapeutic Uses Free Radical Scavengers Antioxidants Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Endothelium-Dependent Relaxing Factors |
ClinicalTrials.gov processed this record on June 18, 2013