Use of nitric oxide in preterm infants

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator used to treat neonates with respiratory failure, recently approved in Europe for use in hypoxaemic respiratory failure associated with pulmonary hypertension in neonates >34 weeks' gestation. Moreover, iNO is often used outside the licensed indication (off-label) in preterm neonates, because its administration may potentially attenuate preterm lung injury and therefore reduce the risk or severity of bronchopulmonary dysplasia (BPD) if iNO is used at an early stage of disease.

In total, 11 trials have been published investigating the use of iNO in 2536 preterm infants. Individual trials vary in terms of timing, dose and duration of iNO treatment as well as degree of exposure to antenatal steroids and concomitant respiratory treatments.

Trials on early prophylactic treatment with iNO show that its administration reduces mortality and death/BPD. Subgroup analyses indicate that iNO may be more effective in larger preterm infants (>1000 g) and those with milder respiratory disease (oxygenation index <7). In this patients, iNO treatment also reduces the risk of severe cerebral injury. A single study on long-term outcome has shown that prophylactic iNO treatment is associated with improved neurodevelopmental status at 2 years of age. Abnormal developmental outcome was observed less frequently in infants treated with iNO compared with controls.

For what concerns early rescue treatment, iNO may have a beneficial effect. The pooled estimate indicates a modest reduction in death/BPD, but post-hoc analysis again suggested that treatment with iNO is more effective in preterm babies with a birth weight >1000 g. Conversely, there was higher mortality among babies <1000 g treated with iNO compared with controls and a higher rate of severe intraventricular hemorragia. There is currently little information regarding long-term outcomes in babies receiving early rescue treatment with iNO.

Late treatment with iNO in babies requiring ongoing respiratory support may be effective in reducing death/BPD and the duration of respiratory support and hospitalisation, but this effect is quite limited. There is some evidence that late treatment may be more effective when started at 7-14 days than at 15-21 days. The only study to report long-term outcomes in this setting did not show any effect with iNO treatment.

Potential complications of treatment include toxicity related to iNO or its metabolites, leading to airway inflammation, lung injury and surfactant dysfunction. Other possible complications include methaemoglobinaemia and a prolongation of bleeding time. Despite this array of potential side effects, none of the randomised controlled trials in preterm infants has shown an excess of clinically important adverse effects with iNO treatment.

In conclusion, outcomes from randomised clinical trials suggest that there is currently insufficient evidence about long-term safety and efficacy to recommend the routine use of iNO. There is also a paucity of data regarding the optimal timing, dose and duration of treatment. The most promising indication for iNO in preterm infants is early prophylactic treatment to prevent death/BPD. A large ongoing European randomised controlled trial may provide further useful information about the safety and efficacy of iNO in this setting.

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