Inhaled Nitric Oxide Study for Respiratory Failure in Newborns (NINOS)

The Randomized Inhaled Nitric Oxide Study (NINOS) in Full-Term and Nearly Full-Term Infants With Hypoxic Respiratory Failure

Respiratory failure in term newborns is associated with increased rates of death and long-term neurodevelopmental problems. This large international multicenter trial randomized newborns who had failed to respond to intensive care, including high levels of ventilator support, to receive either inhaled nitric oxide (iNO) or 100 percent oxygen to test whether iNO would decrease their risk of dying or requiring temporary lung bypass. Infants were followed during their initial hospitalization; their outcome was assessed at 18 to 24 mos of 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: Placebo

Detailed Description

Respiratory failure in term newborns is associated with significant morbidity and mortality, despite maximal conventional therapy. Neonates with pulmonary hypertension have been treated with iNO, a selective pulmonary vasodilator. This multicenter, double-masked placebo-controlled randomized trial tested whether iNO would reduce the risk of death and/or the initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. The sample size was based on a reduction of the primary event (death or ECMO) from 50 percent to 30 percent; 90 percent power; and a two-tailed Type I error of 0.05.

Infants were evaluated at baseline for pulmonary, cardiac, bleeding status, and therapies received. Those who were greater than 34 wks gestation and 14 days old or less and required assisted ventilation with an OI (mean airway pressure x FiO2 divided by the PaO2 x 100) greater than 25 were eligible. They were randomly assigned to receive iNO at 20 ppm or 100 percent oxygen as a control. Infants whose PaO2 increased by less than 20 mm Hg after 30 minutes were studied at 80ppm iNO or control gas.; MetHg and NO2 concentrations were monitored regularly. Management, including surfactant administration, included prospectively defined criteria for study gas response, escalation, reinitiation, and weaning. The maximum total time on study gas was 336 hrs (after 240 hrs, the INO concentration was required to be no more than 5 ppm). Patients were followed to death, discharge, or 120 days and evaluated at 18-24 mos by a masked certified examiner.

• Study Type: Interventional
• Enrollment (Actual): 235
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Hospital
    • Edmonton, Alberta, Canada
      • Royal Alexandra Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • Health Sciences Center
  • Ontario
    • Hamilton, Ontario, Canada
      • McMaster University
    • Ottawa, Ontario, Canada
      • Children's Hospital of Eastern Ontario
  • Quebec
    • Montreal, Quebec, Canada
      • Montreal Children's Hospital
    • Sherbrooke,, Quebec, Canada
      • Université de Sherbrooke,
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Royal University Hospital
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20052
      • George Washington 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
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

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:

• Greater than 34 wks gestational age
• One or more of the following diagnoses: primary pulmonary hypertension of the newborn, respiratory distress syndrome, perinatal aspiration syndrome, pneumonia/sepsis, suspected pulmonary hypoplasia
• Oxygenation Index (OI) greater than 15 and less than 25 on 2 arterial blood gases at least 15 min apart
• Indwelling arterial line
• Echocardiography before randomization
• Parental consent

Exclusion Criteria:

• Congenital diaphragmatic hernia
• Known congenital heart disease
• Decision not to provide full therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inhaled Nitric Oxide; Inhaled Nitric Oxide (iNO)	Drug: Inhaled nitric oxide; Inhaled Nitric oxide at a concentration of 20 ppm
Placebo Comparator: Oxygen; 100% oxygen	Drug: Placebo; 100% Oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Death or initiation of ECMO	Before hospital discharge or 120 days of life

Secondary Outcome Measures

Outcome Measure	Time Frame
PaO2 levels, oxygenation index, and alveolar-arterial oxygen gradient	30 minutes after drug administration
Neurodevelopmental outcome	18-22 Months Corrected Age
Duration of hospital stay	At hospital discharge
Duration of assisted ventilation, air leaks, or chronic lung disease	At hospital discharge
Transfers for ECMO	At hospital discharge
Meeting ECMO criteria	At hospital discharge

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Center for Research Resources (NCRR); Medical Research Council of Canada
• Investigators: Principal Investigator: Avroy A. Fanaroff, MD, Case Western Reserve University, Rainbow Babies and Children's Hospital; Principal Investigator: William William Oh, MD, Brown University, Women & Infants Hospital of Rhode Island; Principal Investigator: N. Singhal, MD, Foothills Hospital, Calgary, Canada; Principal Investigator: Neil N. Finer, MD, Royal Alexandra Hospital; Principal Investigator: A. Solimano, MD, British Columbia Children's Hospital; Principal Investigator: C. Fajardo, MD, Health Sciences Center, Winnipeg, Manitoba; Principal Investigator: H. Kirpalani, MD, McMaster University; Principal Investigator: R. Walker, MD, Children's Hospital of Eastern Ontario; Principal Investigator: A. Johnston, MD, Montreal Children's Hospital of the MUHC; Principal Investigator: P. Blanchard, MD, Université de Sherbrooke, Sherbrooke, Quebec; Principal Investigator: K. Sankarhan, MD, Royal University Hospital, Saskatoon, Saskatchewan

Publications and helpful links

General Publications

• Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997 Feb 27;336(9):597-604. doi: 10.1056/NEJM199702273360901. Erratum In: N Engl J Med 1997 Aug 7;337(6):434.
• Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics. 1997 Jun;99(6):838-45. doi: 10.1542/peds.99.6.838.
• Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). J Pediatr. 2000 May;136(5):611-7. doi: 10.1067/mpd.2000.104826.
• Sokol GM, Fineberg NS, Wright LL, Ehrenkranz RA. Changes in arterial oxygen tension when weaning neonates from inhaled nitric oxide. Pediatr Pulmonol. 2001 Jul;32(1):14-9. doi: 10.1002/ppul.1083.
• 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.

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: October 1, 1995
• Primary Completion (Actual): May 1, 1996
• Study Completion (Actual): May 1, 1998

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-0014; U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (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); 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)