NIH Consensus Development Conference Statement: Inhaled Nitric-Oxide Therapy for Premature Infants

Abstract

Premature birth is a major public health problem in the United States and internationally. Infants born at or before 32 weeks' gestation (2% of all births in the United States in 2007) are at extremely high risk for death in the neonatal period or for pulmonary, visual, and neurodevelopmental morbidities with lifelong consequences including bronchopulmonary dysplasia, retinopathy of prematurity, and brain injury. Risks for adverse outcomes increase with decreasing gestational age. The economic costs to care for these infants are also substantial (estimated at $26 billion in 2005 in the United States). It is clear that the need for strategies to improve outcomes for this high-risk population is great, and this need has prompted testing of new therapies with the potential to decrease pulmonary and other complications of prematurity. Inhaled nitric oxide (iNO) emerged as one such therapy. To provide health care professionals, families, and the general public with a responsible assessment of currently available data regarding the benefits and risks of iNO in premature infants, 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 National Institutes of Health convened a consensus-development conference. Findings from a substantial body of experimental work in developing animals and other model systems suggest that nitric oxide may enhance lung growth and reduce lung inflammation independently of its effects on blood vessel resistance. Although this work demonstrates biological plausibility and the results of randomized controlled trials in term and near-term infants were positive, combined evidence from the 14 randomized controlled trials of iNO treatment in premature infants of ≤ 34 weeks' gestation shows equivocal effects on pulmonary outcomes, survival, and neurodevelopmental outcomes.

Use of Inhaled Nitric Oxide in Preterm Infants

“…After reviewing the published evidence, the panel concluded that the available evidence does not support the use of iNO in early routine, early rescue, or later rescue regimens in the care of infants born at less than 34 weeks' gestation and that hospitals, clinicians, and the pharmaceutical industry should avoid marketing iNO for this group of infants. 8 An individual-patient data meta-analysis of 14 randomized controlled trials reached similar conclusions. 9 The purpose of this clinical report is to summarize the existing evidence for the use of iNO in preterm infants and provide guidance regarding its use in this population.…”

“…8 A retrospective economic evaluation using patient-level data from the NOCLD trial (the only trial showing clinical benefit) reported that the overall mean cost per infant for the initial hospitalization was similar in the treated and placebo groups; however, when iNO therapy was initiated between 7 and 14 days of age, there was a 71% probability that the treatment decreased costs and improved outcomes. 45 Cost-benefit analysis from 2 other studies failed to show any costbenefit.…”

Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience

“…The National Institutes of Health (NIH) consensus panel (2011) and the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn (2014) reported that the available evidence was insufficient to recommend the routine use of iNO in premature neonates of <34 weeks' gestation who need respiratory support to prevent or ameliorate bronchopulmonary dysplasia (BPD) [8,9]. However, the NIH statement did suggest that some neonates of <34 weeks' gestation, such as those with PH, may benefit from iNO.…”

“…Given the lack of definitive evidence from randomized clinical studies regarding the benefits associated with the use of iNO in preterm neonates with HRF and PH, and the variability across published consensus guidelines regarding the use of iNO in this setting [8][9][10], assessment of a large observational data set could provide support for the clinical community in their need to define whether iNO should be utilized in their preterm neonatal patients. The observational Japanese registry evaluated in this report represents the largest data set currently available regarding the use of iNO in premature neonates with HRF and PH.…”

El rol de la hipertensión pulmonar en la displasia broncopulmonar

“…Sin embargo, los estudios controlados aleatorizados reunidos en un metaanálisis Cochrane reciente, con más de 3000 prematuros enrolados en más de 12 estudios, no lograron demostrar disminución del riesgo de displasia broncopulmonar. Actualmente, las indicaciones para iNO son más bien terapéuticas y reservadas para crisis de hipertensión pulmonar en dosis de 5-20 ppm en pacientes seleccionados, siguiendo así lo propuesto en el consenso del NIH 2011 16,17,18 . En la búsqueda de otras opciones para intervenir la vía alterada de NO y poder aumentar su disponibilidad, han aparecido estudios respecto a la suplementación con L-arginina y L-citrulina, siendo esta segunda la más prometedora ya que se han reportado efectos adversos en los ensayos clínicos con L-arginina.…”