The study was performed as a collaboration between the investigators in the Neonatal Research Network of the NICHD and the Canadian Inhaled Nitric Oxide Study (CINOS) group. The study was stopped on May 2, 1996, 2 months before its scheduled completion date, after review of the results by the study's Data and Safety Monitoring Committee revealed that inhaled nitric oxide significantly reduced the need for surgical intervention.
Hypoxic respiratory failure is a potentially fatal condition in which newborn infants, for a variety of reasons, cannot breathe in enough oxygen to survive. Among the causes of hypoxic respiratory failure are respiratory distress syndrome, in which the lungs are immature and poorly formed; meconium aspiration, in which an infant, shortly before birth, inhales amniotic fluid which has been contaminated by a bowel movement; pulmonary hypertension, or high blood pressure in the lungs; and congenital diaphragmatic hernia, a malformation of the diaphragm associated with inadequate lung formation.
Until now, the only effective treatment for hypoxic respiratory failure has been a surgical treatment called ECMO (extracorporeal membrane oxygenation), a highly invasive procedure in which blood is removed from a large vein that empties into the infant's heart, pumped into a system that oxygenates the blood, and then returned to the large vessels in the infant's neck. As a result of this procedure, one of the carotid arteries, which carries blood to the right side of the brain, is often permanently lost. ECMO is expensive, requires constant monitoring, and is associated with a nearly 20 percent rate of neurologic abnormalities. Of the 1,000 newborns in the U.S. who are treated with ECMO each year, approximately 82 percent survive.
"Because of the risks and costs associated with ECMO, a non-invasive alternative treatment such as nitric oxide therapy represents a major advance," Dr. Wright said.
In all, 235 term infants who were less than 14 days old and who had received the maximum conventional therapy were enrolled in the study with the informed consent of their parents. The infants were randomized to one of two groups, 121 to the control group, which received the maximum conventional therapy of 100 percent oxygen, and 113 to the intervention group, which received a mixture of oxygen and nitric oxide.
At the study's conclusion, 64 percent of those who received conventional therapy either were referred to treatment with ECMO or had died. In contrast, 46 percent of the nitric oxide group were referred for ECMO treatment or had died. In all, death occurred in 14 percent of the nitric oxide group and 17 percent of the control infants (no significant difference).
Dr. Wright added that the nitric oxide therapy could not only benefit the approximately 1,000 infants who undergo ECMO each year, but could also benefit an estimated 2 to 3 times as many children.
Nitric oxide relaxes the blood vessels that line the lung, allowing it to absorb more oxygen. Unlike other treatments that expand the blood vessels in the lung, nitric oxide does not decrease blood pressure elsewhere in the body.
Because hypoxic respiratory failure is an uncommon disease in newborns, previous studies that have attempted to prove that nitric oxide reduces the incidence of death or the need for ECMO have failed because they have been unable to enroll enough infants to assess the impact of nitric oxide on these important outcomes. Because this study was conducted within the NICHD's Neonatal Research Network in collaboration with the CINOS group (funded by the Medical Research Council of Canada), investigators were able to enroll enough infants in fewer than 18 months to be able to evaluate the therapy. Eight Neonatal Research Centers and 11 CINOS centers participated in the trial.
Established in 1986, the Neonatal Research Network is a national network of 14 tertiary neonatal centers which conduct multi-center trials in neonatology, focusing specifically on the optimal management and care of infants in neonatal intensive care units.