ArticlesInhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial
Introduction
More than 12% of all babies are born preterm (<37 weeks of gestation), and account for more than 85% of all perinatal complications and deaths.1 Survival of extremely premature newborn babies (<28 weeks of gestation) has increased because of improvements in perinatal care.2 These infants, however, are at high risk of developing long-term medical and neurocognitive impairment, including bronchopulmonary dysplasia. This disease was originally described as lung injury associated with radiological findings of streaky densities alternating with hyperlucent areas.3 In the revised definition, bronchopulmonary dysplasia is characterised as arrested lung growth, with reduced alveolarisation, and a dysmorphic vasculature.4 Surfactant deficiency, ventilator-induced lung injury, oxygen toxicity, and inflammation have been reported as important pathogenic factors.5 Evidence suggests that blood vessels in the lung actively promote normal alveolar development.6 Conversely, disrupted pulmonary vasculature, and reduction in mRNA and protein vascular endothelial growth factor and its receptors was noted in infants dying as a result of bronchopulmonary dysplasia.7 These findings led to the development of a vascular hypothesis as the basis for the revised definition of bronchopulmonary dysplasia.8 Modulation of angiogenic growth factors and vascular precursor cells might have therapeutic potential for lung diseases that are characterised by alveolar damage, such as bronchopulmonary dysplasia.9 Inhaled nitric oxide reversed the effects of inhibition of vascular endothelial growth factor, and stimulated angiogenesis and alveolarisation in animal models of bronchopulmonary dysplasia.10, 11 It improved angiogenesis and alveolarisation in the lung through enhanced signalling mediated by the vascular endothelial growth factor in preclinical studies,9, 12, 13, 14 but these findings have been difficult to confirm in clinical studies. The inhaled nitric oxide might also have beneficial effects on lung inflammation and oxidant injury.15 This gas was approved for treatment of persistent pulmonary hypertension in term babies, but it might also provide benefit to sick premature newborn babies, and reduce the incidence and severity of bronchopulmonary dysplasia. Inhaled nitric oxide is a potent and selective pulmonary vasodilator and, in many situations, will improve oxygenation by improving ventilation perfusion mismatching in the failing lung.16, 17, 18, 19, 20, 21
Results from controlled clinical trials of inhaled nitric oxide for the treatment or prevention of bronchopulmonary dysplasia in preterm infants with different degrees of respiratory distress have been inconclusive.22, 23, 24, 25, 26 Some data have suggested a reduction in the incidence of acute brain injury (intraventricular haemorrhage or periventricular leukomalacia),23, 26, 27 whereas others have not.24, 28 Inhaled nitric oxide was not associated with any positive outcomes in severely affected infants,22, 24 whereas it was in mildly affected babies.23, 25, 26 We investigated the potential benefits of inhaled nitric oxide in relation to lung vascularisation and development, and postulated that a low concentration of this gas would enhance survival of infants without them developing bronchopulmonary dysplasia.
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Patients and study design
This study was done in 36 centres in nine countries in the European Union between May, 2005, and February, 2008; the last patient achieved the primary endpoint in May, 2008. The study was approved by the national health authority in each country and locally at the institution by the ethics committees. Written informed consent for participation was obtained from parents in accordance with local requirements. A steering committee made up of experts from participating countries designed and
Results
The intention-to-treat population was all 800 babies who were entered into the study and randomly assigned to treatment (figure 1). Of these, 792 (99%) were given the assigned treatment. The groups were well matched for baseline characteristics (table 1). In both groups, most infants were white, according to the mother. Most mothers were given antenatal corticosteroids (table 1). Most babies were intubated for mechanical ventilation at study entry and received postnatal surfactant; similar
Discussion
Treatment with inhaled nitric oxide did not significantly increase survival of premature infants without development of bronchopulmonary dysplasia at postmenstrual age 36 weeks. Unlike Van Meurs and colleagues,24 we targeted a population of babies with mild to moderate respiratory distress with fraction of inspired oxygen of less than 0·50, which corresponds to an oxygenation index between 5 and 10 on routinely used levels of mean airway pressure with intermittent mandatory ventilation or
Acknowledgments
INO Therapeutics (Clinton, New Jersey, USA) sponsored the study. J-CM has received research grants from Ikaria and INO Therapeutics, and the French Ministry of Health to study the effects of inhaled nitric oxide on the developing brain of the rat pup. DF has received research grants from the British Heart Foundation. AG has received research grants from the ventilator manufacturers, Abbott Laboratories and MedImmune. The report was edited by Peloton Advantage.
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