Study Casts Doubt on Lung Treatment for Preterm Infants

Contrary to an earlier finding, inhaled nitric oxide therapy (a treatment for lung problems in premature infants) does not reduce the infant's chances for death or further lung problems, according to a study by the National Institute of Child Health and Human Development of the National Institutes of Health.

The study appears in the July 7 New England Journal of Medicine.

"Premature infants weighing less than 1500 grams should not receive inhaled nitric oxide therapy unless they are part of a research study," said NICHD Director Duane Alexander, M.D.

Inhaled nitric oxide therapy is effective for treating full term infants with lung complications. In term infants, whose lungs are fully formed, these complications typically result from lung infection. For the treatment, nitric oxide gas is mixed with oxygen and given to an infant through a breathing apparatus. The treatment makes the blood vessels in the lung tissue relax, allowing the lungs to absorb oxygen more easily.

Because the treatment works well for term infants, researchers had been interested in its possible use to treat lung complications in preterm infants. Earlier research in preterm infants treated with inhaled nitric oxide therapy showed varied results.

A team of researchers with NICHD's Neonatal Research Network enrolled 420 infants born at less than 34 weeks' gestation, weighing between 401 to 1500 grams (14 ounces to 3 pounds, 2 ounces). All infants required assisted ventilation and had a diagnosis of respiratory distress syndrome, sepsis or pneumonia, or other severe breathing problems. The infants were randomly assigned to receive either inhaled nitric oxide or a placebo.

The researchers found that there was no difference between the infants who received the inhaled nitric oxide and those who did not: 60 percent of the infants who received it and 68 percent of those who did not, developed bronchopulmonary dysplasia, a serious lung condition involving lung inflammation and scarring. Both groups also had high death rates (52 percent in the inhaled nitric oxide group and 44 percent in the placebo group).

While earlier research on the use of inhaled nitric oxide on premature infants with breathing problems showed potential benefits of the therapy, the infants in that research study were larger and less critically ill than those in the current study.

"Contrary to our hopes as neonatologists, inhaled nitric oxide treatment did not reduce the incidence of death or further lung problems," said one of the study's authors, Rosemary Higgins, M.D., of the NICHD's Pregnancy and Perinatology Branch. "The smallest and sickest infants were not helped by this treatment."

Dr. Higgins added that the smaller infants presumably were unable to benefit from inhaled nitric oxide therapy because their lungs were not developed sufficiently.

After the study was completed, the researchers took a closer look at the data. Such after-the-fact analyses typically need to be confirmed by further research. This second look at the data revealed information about various subgroups of the study. The researchers found that infant weight affected the outcome among infants receiving inhaled nitric oxide. Infants in this group weighing between 1000 and 1500 grams had a significantly lower death rate than infants in the placebo group. Infants weighing less than 1000 grams in this group had a higher death rate than those in the placebo group.

In addition, infants receiving inhaled nitric oxide through conventional mechanical ventilation had a higher mortality rate than those receiving the therapy through high-frequency ventilation. Conventional mechanical ventilation resembles the inhaling and exhaling motion of normal breathing. In contrast, high frequency ventilation consists of numerous soft pulses delivered to the lungs.

One of the main concerns in the past of using inhaled nitric oxide to treat premature infants who have lung problems is that this treatment may trigger intracranial bleeding—bleeding inside the brain. Data analysis after the study showed that the smaller premature infants in the treatment group—a subset of those weighing less than 1000 grams—had a higher rate of intracranial bleeding than infants in the placebo group.

"We have more work to do to better understand how to best help premature infants with severe lung problems," Dr. Higgins said.


The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.

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