Inhaled nitric oxide safe for tiny preemie lungs, UCSF study finds

A nationwide study led by researchers at UCSF provides evidence that inhaled nitric oxide is safe and effective for the prevention of the most common type of long-term lung disease of very premature infants.

“Chronic lung disease is a major source of morbidity in these infants. Neonatologists have been trying to figure out how to prevent it for years,” said Philip Ballard, MD, PhD, lead study author and professor of pediatrics at UCSF.
The benefit of inhaled nitric oxide for infants born close to term who suffer from the lung disease known as pulmonary hypertension has been known for some time, but the effect in preemies had not been clearly determined, according to Ballard.

Nitric oxide is a gaseous compound normally produced by the body, however, premature infants produce insufficient amounts. Recent clinical studies done elsewhere have found positive effects of inhaled nitric oxide in very premature infants, while some animal research has suggested that inhaled nitric oxide in preemies might interfere with the production of pulmonary surfactant, a substance critical to normal lung development and functioning.

The new study findings, reported in the August 2007 issue of “Pediatrics,” found no adverse affects of inhaled nitric oxide on surfactant production or function, said Ballard, a neonatologist at UCSF Children’s Hospital.

“Inhaled nitric oxide is a promising therapy, but we’ve been concerned about safety. We found no adverse effects of inhaled nitric oxide and perhaps a beneficial effect in terms of surfactant function,” Ballard said.

The lungs of very premature infants are underdeveloped, fragile and too weak to breathe independently. Mechanical ventilation with oxygen keeps these infants alive but often results in chronic lung disease, or bronchopulmonary dysplasia (BPD), with severe inflammation and retarded development of the lungs.

BPD is the most common long-term lung disease in premature infants in the United States, affecting about 15,000 babies each year. About half of the infants born between 24 and 30 weeks and weighing less than 2 pounds develop BPD. The condition is life-threatening, and those who survive can suffer long-term disabilities including asthma, mental retardation and cerebral palsy.

The controlled, randomized clinical trial of nitric oxide was headed by Roberta Ballard, MD, UCSF professor emeritus of neonatology who coordinated the trial while serving as chief of the division of neonatology at Children’s Hospital of Philadelphia. The trial included 582 very premature infants who were enrolled between 2000 and 2005 in the study at 7 to 21 days old at 21 hospitals around the country.

Laboratory studies were performed in 83 of these infants to examine whether inhaled nitric oxide had a negative effect on pulmonary surfactant, a lipid-protein mixture that coats the lungs and greatly reduces surface tension.

Surfactant essentially allows the lungs to inflate easily after exhalation, eliminating the work of breathing. Very premature infants produce insufficient amounts of surfactant, so any therapy that inhibited the work of surfactant would be harmful.

In the study, half the infants were treated with nitric oxide and half received a placebo. Fluid from their lungs was then collected and examined for surfactant levels and properties. Findings showed that “there were no significant differences” between the two groups in surfactant amount and that inhaled nitric oxide may have a positive effect on surfactant function.

“This is very good news in terms of the safety profile for this promising new therapy,” Ballard said.  Prevention of BPD in very premature infants has included the use of vitamin A therapy, which has a small but positive effect, and dexamethasone, a corticosteroid, Ballard said.

“Inhaled nitric oxide is going to be safer than the corticosteroid and more effective than both therapies,” he said.

Other study authors include Roberta Ballard, MD, of UCSF; Jeffrey D. Merrill, MD; Rodolfo Godinez, MD, PhD; Marye Godinez, MD; Theresa McDevitt, MS; Yue Ning, MS; Xianaqun Luan, MS; and Avital Cnaan, PhD, all of the Children’s Hospital of Philadelphia and University of Pennsylvania; William Truog, MD, of Children’s Mercy Hospitals and Clinics/University of Missouri-Kansas City School of Medicine; and Sergio Golombek, MD, MPH, and Lance Parton, MD, of New York Medical College/Marie Fareri Children’s Hospital.

The study was supported by a grant from the National Institutes of Health and from the General Clinical Research Centers Program. INO Therapeutics, Inc., provided the study equipment and the nitric oxide.

One of the nation’s top children’s hospitals, UCSF Children’s Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 1,600 babies born there.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.