Nitric oxide: Two-edged sword in treating preemies

Doctors have been trying for many years to improve the survival rate of very premature infants, whose lungs are often not up to the task of living outside the womb. Inhaled nitric oxide has shown some success in treating full-term infants with life-threatening lung disease, and physicians have been eager to learn if this treatment would help premature infants as well.

Now a new study led by researchers at the School of Medicine involving more than 400 tiny preemies has shown that, although nitric oxide did not improve the odds of survival or decrease the likelihood of long-term lung disease in the group overall, it may benefit a sub-group of newborns weighing more than 1,000 grams, or 2.2 pounds, at birth.

"This study suggests that the key to the effective use of inhaled nitric oxide may lie in choosing the right patients," said Krisa Van Meurs, MD, a neonatologist at Lucile Packard Children's Hospital and professor of pediatrics. "Because of its effect on bleeding, it may not be useful in certain critically ill babies." Van Meurs is the lead author of the study, published in the July 7 issue of the New England Journal of Medicine.

Inhaled nitric oxide works by dilating blood vessels in the lungs to allow the more efficient delivery of oxygen and the elimination of carbon dioxide. It also helps to send blood to the most oxygenated areas of the lung and to decrease inflammatory responses that make the lungs less efficient. However, because research suggested it can also increase the already significant risk of brain hemorrhage in premature infants, physicians have been very cautious about its use, fearing the potential benefit may not be worth the risk in this group.

The study is the first large multicenter trial testing the effects of inhaled nitric oxide in the sickest, smallest preemies. All 420 infants in the study were born before 34 weeks gestation, weighing between 401 and 1,500 grams, or about 14 ounces to 3.3 pounds. They were all suffering severe respiratory failure despite all other usual medical treatments. The infants were randomly assigned to receive either nitric oxide or a placebo. "These children are very severely ill," said Van Meurs, noting that even with the latest medical treatment the control group's mortality rate was 44 percent.

The researchers found that nitric oxide was no better than the placebo treatment at improving survival rates or preventing long-term lung damage in the infants when considered as a group. But when they separated them by weight, they saw a clear difference: Those weighing 1,000 grams or less who received nitric oxide had a significantly higher rate of brain hemorrhage and were more likely to die than those who received the placebo--43 percent vs. 33 percent and 62 percent vs. 48 percent, respectively.

Still, the study had an upside: those infants who weighed more than 1,000 grams reaped significant benefit from the nitric oxide, which decreased the likelihood of death or long-term lung damage to 50 percent vs. 69 percent for the placebo group.

Although Van Meurs cautions that more research is needed to confirm these preliminary findings, a companion article in the same NEJM issue suggests that nitric oxide may benefit less severely ill infants. In the meantime, researchers urge physicians to confine the use of inhaled nitric oxide in infants born before 34 weeks to clinical trials.

In addition to studying the short-term effects of inhaled nitric oxide, the researchers are conducting a long-term follow-up evaluating how the treatment affects the neurological development of the infants.

The study was conducted as part of the National Institute of Child Health and Human Development's Neonatal Research Network and supported by the Stanford General Clinical Research Center. In addition to Van Meurs, Stanford researchers David Stevenson, MD, and M. Bethany Ball contributed to the study.