Children's Mercy Researchers Help Identify Nitric Oxide Benefits for Lung Disease Patients.

KANSAS CITY, Mo. -- Premature, very-low-birth-weight infants receiving inhaled nitric oxide during their second week of life have an improved chance of surviving without chronic lung disease, according to a national study of nearly 600 babies.

For thousands of infants born prematurely each year in the United States, the treatment may help them to breathe easier and shorten their hospital stay.

"Chronic lung disease is the most significant, and critical, long-term pulmonary complication for premature infants," says William Truog, MD, neonatologist at Children's Mercy Hospitals and Clinics and one of the lead researchers in the study that was based at The Children's Hospital of Philadelphia. "This is good news."

Researchers are continuing to follow the infants' health outcomes up to two years of age; some have already completed the study. Dr. Truog said by two years of age scientists will also know if the treatment also results in fewer subsequent hospitalizations and developmental issues for these vulnerable babies.

The multicenter Nitric Oxide Chronic Lung Disease Study Group (NOCLD) published the study in the July 27 New England Journal of Medicine.

In addition to the clinical benefits, the researchers found no apparent adverse effects from the nitric oxide up to 44 weeks of age.

An estimated 10,000 to 15,000 infants in the U.S. have chronic lung disease of prematurity. Ongoing medical care for these infants, such as multiple hospitalizations, prolonged respiratory treatments and follow-up for neurodevelopmental problems, accounts for a significant portion of the overall public health burden of prematurity. In a report released this month, the Institute of Medicine estimated that overall costs for the more than 500,000 babies born prematurely in the U.S. totaled $26 billion, or $51,000 per infant.

Dr. Truog has been involved in research with nitric oxide for several years. Children's Mercy was one of a few hospitals involved in the testing of nitric oxide in other acute lung disorders in full-term infants. That study also showed very positive results.

The NOCLD clinical trial included 21 neonatal intensive care units throughout the country, enrolling infants with birth weights between 500 and 1250 grams, or about one to three pounds. Their median gestational age was 26 weeks (full-term babies are born at about 40 weeks gestational age). All the infants were receiving oxygen through ventilators and were at high risk of developing chronic lung disease, also known as bronchopulmonary dysplasia, because their lungs were immature and underdeveloped. In this condition, scarring and inflammation in lung tissue make breathing difficult, and the infant often requires prolonged mechanical ventilation and hospitalization.

Although treatment with nitric oxide, a substance naturally produced in the body, is already known to benefit full-term infants with pulmonary hypertension, its value for pre-term infants was uncertain. "The mechanism by which nitric oxide affects the lungs is not fully understood," said Roberta A. Ballard, M.D., a neonatologist at The Children's Hospital of Philadelphia, "but animal studies and pilot studies in infants previously suggested that nitric oxide restores normal growth and development in very immature lungs."

The trial was randomized and double-blinded, with 294 infants receiving inhaled nitric oxide and 288 receiving a placebo. The rate of survival without chronic lung disease at 36 weeks after the mother's last menstrual period was 43.9 percent in treated infants compared to 36.8 percent in the control group.

The effect was more pronounced for the infants entered earlier (between seven and 14 days): 49.1 percent in treated infants vs. 27.8 percent in controls. Lung disease was also less severe in treated infants at 40 and 44 weeks, with treated infants having shorter hospitalizations and less need for mechanical ventilation or oxygen therapy than the control infants.

The NOCLD team expects to provide definitive recommendations for clinical use of nitric oxide after it analyzes follow-up studies of the children's neurodevelopmental status at two years of age. The follow-up studies will be accomplished by the end of 2007, said Dr. Ballard.