Inhaled nitric oxide protects the brains of high-risk premature infants
NO news is good news
July 6, 2005
Despite tremendous advances in neonatal intensive care, premature babies with underdeveloped lungs remain at risk for brain injury and delayed development. In the July 7, 2005, issue of the New England Journal of Medicine, researchers from the University of Chicago report that adding tiny amounts of nitric oxide to the oxygen given to these premature infants on a mechanical ventilator in the first week of hospitalization reduced by nearly half the number of children with abnormal mental development at age 2.
This study follows a 2003 report by the same group showing that inhaled nitric oxide decreased the risk of chronic lung disease, severe bleeding into the brain and death in premature infants with respiratory distress syndrome.
The latest study, which focused on the mental development of the same children when assessed by neurologists near their second birthday, found that only 24 percent of the children who received nitric oxide at birth had delayed mental development or a disability, such as blindness, cerebral palsy or hearing loss, compared to 46 percent of those who received standard treatment of oxygen with no nitric oxide.
"This is the first therapy for premature infants that has demonstrated a significant impact on brain development," said study director Michael Schreiber, MD, professor of pediatrics at the University of Chicago. "Not only does nitric oxide extend life in a large group of premature infants, it also improves the quality of life for the children and their parents."
Premature birth is one of the leading causes of infant death and disability in the United States. An estimated 60,000 children a year are born early with lungs so underdeveloped that they need help to breathe. These children have a much greater risk for death and lifelong health problems, including brain injury and delayed development.
The researchers followed 138 children from the original study--70 patients from the control group and 68 patients from the nitric oxide group. Between January 2000 and February 2004, these children received physical and neurological examinations and were screened for development problems, visual impairment, cerebral palsy and hearing loss at the University of Chicago's Neonatal High-Risk Follow-up Clinic.
Thirty-four percent of the children who did not receive nitric oxide showed delayed brain development compared to only 16 percent of those who did receive nitric oxide.
Twelve percent of the oxygen-only patients had cerebral palsy compared to 9 percent of those who received nitric oxide. In the oxygen-only group, one child also suffered hearing loss and two children were blind.
"These findings are enormously rewarding," Schreiber said. "Despite everything we have tried in neonatology, no therapy has ever improved cognitive function. Babies born at 2 pounds have only a 50 percent chance at 2 years of age of being considered totally normal - meaning no cerebral palsy and normal IQs. Our results showed that nitric oxide therapy significantly increases the percentage of developmentally normal babies."
If multi-center studies currently under way can confirm these findings, treatment with nitric oxide could become standard for about 30,000 children a year, or about one-half of all premature infants.
"Inhaled nitric oxide may significantly improve the quality of life of both the child and his or her family," the authors conclude, "and may decrease the societal burden of caring for these high-risk children."
The children who received nitric oxide showed improved brain development despite other factors that increase risk, such as low birth weight, male sex and low socioeconomic status.
"We really don't know yet exactly how nitric oxide helps the brain," said co-author Jeremy Marks, MD, PhD, associate professor of pediatrics at the University of Chicago. "Although we have shown in our laboratory that immature brains produce nitric oxide to protect themselves from injury, we don't know whether the nitric oxide we administer to sick preemies affects their brains directly or through improved lung function and better growth, both of which are key determinants of brain development."
Much more testing needs to be done. Even the optimal dose and duration of nitric oxide treatment are unknown. "Those will be our next steps," Schreiber said.
Meanwhile, the researchers will continue to follow children from the original study until they reach age 5 to assess their progress in kindergarten and to learn how teachers rate the children's abilities in the classroom.
INO Therapeutics Inc., which supplies nitric oxide for medical use, and the Sheba Foundation supported this study. The two were not involved with the study design, collection, analysis, or interpretation of the data, or manuscript preparation.
Other contributing authors of the paper are Kurt Hecox, MD, PhD, in the department of pediatrics, and Dezheng Huo, PhD, in the department of health studies, at the University of Chicago, and Karen K.L. Mestan, MD, now at Northwestern University, who was a neonatology fellow at the University of Chicago while the study was being conducted.
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