NEW YORK (Reuters Health) – Premature infants of < 34 weeks’ gestation on respiratory support should not be treated with inhaled nitric oxide, according to a new consensus statement from the National Institutes of Health (NIH). There simply isn’t enough evidence that inhaled nitric oxide (iNO) affects outcomes either positively or negatively in the premature set. That’s despite the fact that the U.S. Food and Drug Administration approved iNO for term and near-term infants with persistent pulmonary hypertension. However, three trials clearly showed worse neurologic and pulmonary outcomes and increased mortality when iNO was given to preemies weighing less than 1000 g. The panel therefore urges special caution in using iNO in this patient population. Other than that, the effect of iNO did not vary according to subgroups based on gender, gestational age, ethnic group/race, or socioeconomic status, or those subject to growth restriction, multiple gestation, chorioamnionitis or antenatal steroid use. Likewise, timing of initiation, mode of delivery, dose and duration, or concurrent therapies did not confound the effects of iNO therapy. The statement is a product of a consensus-development conference convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, and the Office of Medical Applications of Research of the NIH. It is published in the February issue of Pediatrics, released online on January 10th. Lead author Dr. F. Sessions Cole, from Washington University School of Medicine in St. Louis, and coauthors note that off-label use of iNO for preterm infants has increased a lot in recent years, despite the lack of evidence and its high costs (up to $3000/day). Part of this is due to its “biological plausibility,” they say, as shown in animal models where nitric oxide reduced blood vessel resistance and lung inflammation and enhanced lung growth. Their evidence was drawn from a systematic review by a group from the Johns Hopkins University Evidence-Based Practice Center (published separately in the same journal issue), an as-yet-unpublished Cochrane review, and an unpublished individual-patient-data meta-analysis. The Johns Hopkins review, authored by Dr. Pamela K. Donahue and associates, included 14 randomized controlled trials with seven follow-up studies and 1 observational study, with a total of 3461 premature infants. Studies ran from birth to 27 days, and the iNO dose varied from a maximum of 5 ppm to a range of 5 to 40 ppm. Data showed no significant difference in mortality between iNO and control groups, either within the first year or up to 5 years of age. iNO dosage had no influence on survival. They also detected no effect of iNO on bronchopulmonary disease at 36 weeks’ postmenstrual age or on neurodevelopment at up to 5 years of age. Rates of other complications of prematurity (e.g., patent ductus arteriosus, sepsis, necrotizing enterocolitis, severe retinopathy of prematurity, pulmonary hemorrhage, or air leaks) did not respond to iNO therapy. However, Dr. Donahue’s team does not conclude that “we should abandon the possibility that iNO may someday become a component of a treatment strategy for some preterm infants who receive respiratory support.” Both the Johns Hopkins team and the NIH panel call for more research into the short- and long-term pulmonary and neurodevelopmental outcomes of iNO treatment in preemies. They hope to see further investigation into potential effect-modifying factors, including patient factors and different treatment-related variables. Until then, Dr. Cole and associates advise, “Hospitals, clinicians, and the pharmaceutical industry should avoid marketing iNO for premature infants of < 34 weeks’ gestation.” Reference:
NIH Consensus Development Conference Statement: Inhaled Nitric-Oxide Therapy for Premature Infants

Pediatrics 2011.