STANFORD, Calif. - Doctors have been trying for many years to improve the survival rate of very premature infants, whose immature 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 Stanford University 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 specific 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 at Stanford and professor of pediatrics at the School of Medicine. "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 current study is the first large multicenter trial testing the effects of inhaled nitric oxide in the very sickest and smallest premature infants. All 420 infants in the study were born before 34 weeks gestation and weighed 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; the study was blinded so that neither the family members nor the physicians knew which option the infant was receiving.
"These children are very severely ill," said Van Meurs, pointing out that even with the very latest in medical treatment the mortality rate in the control group 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. When they separated them according to weight, however, they saw a clear difference: Infants weighing 1,000 grams, or about 2.2 pounds, or less who received nitric oxide had a significantly higher rate of brain hemorrhage and were more likely to die than those who had received the placebo - 43 percent vs. 33 percent and 62 percent vs. 48 percent, respectively.
However, those infants who weighed more than 1,000 grams reaped significant benefit from the nitric oxide treatment, 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 necessary to confirm these preliminary findings, a companion article in the same issue of the NEJM also suggests that nitric oxide may benefit less severely ill infants. In the meantime, however, the researchers urge that physicians confine the use of inhaled nitric oxide in infants born before 34 weeks of gestation to clinical trials.
In addition to studying the short-term effects of inhaled nitric oxide, the researchers are also conducting a long-term follow-up evaluating how the treatment affects the neurological development of the infants.
The Preemie Inhaled Nitric Oxide Study was conducted as part of the National Institute of Child Health and Human Development's Neonatal Research Network and further supported by the Stanford General Clinical Research Center. In addition to Van Meurs, Stanford/Packard researchers David Stevenson, MD, and M. Bethany Ball contributed to the study.
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