Abstract

The use of inhaled nitric oxide (iNO), a gas molecule that acts by the formation of cAMP and finally induces vascular dilation, has been demonstrated to reduce the need for the use of extracorporeal membrane oxygenation in term and near-term infants with hypoxic respiratory failure and pulmonary hypertension. The selective effect on pulmonary vascular resistance is related to the inhaled administration, so iNO acts only on those preconstricted vessels associated with ventilated air spaces.

This effect has also been demonstrated in preterm newborns, so pulmonary vessels can also respond to low-dose iNO with vasodilatation when pulmonary hypertension is associated with hypoxaemic respiratory failure. So there is a possible benefit of using low-dose iNO in preterm infants with severe hypoxaemic respiratory failure decreasing the need for high FiO₂ and respiratory support by improving ventilation/perfusion (V/Q) inequality and decreasing the need for mechanical ventilation, a well-known factor that contributes to the development of bronchopulmonary dysplasia (BPD).

It is probable that “new BPD” is in some way related to an insult in the immature lung that prevents its growth after delivery and some experimental studies in immature laboratory animals proved this theory. The administration of iNO to animal models of BPD also demonstrated an anti-inflammatory, pro-angiogenesis and stimulation of airway growth. Other effects, such as improving surfactant function, still need to be demonstrated in clinical trials but can also improve its effectiveness.

These confirmed actions seen in the premature animal lung of iNO makes it a potential drug for use in treating and preventing BPD in preterm infants.

Clinical trials have been developed to try and demonstrate some effect in preventing or treating human BPD, but until now randomised controlled trials have only demonstrated the safety of this drug when used in a selected group of preterm infants, soon after delivery and not severely sick.

Also in this group of patients there is some effect in decreasing BPD, but still there are some questions to resolve, such as why not all preterm infants respond in the same way to iNO therapy?, why less sick preterm infants respond better than the sickest when they respond less if at all?, is there any relationship with postnatal age at the beginning of using iNO?, and more exciting, is there any relationship with the length of therapy and response to the drug?.

So target population, dose, duration and long-term safety have to be established.

New trials soon to be published, such as the European Randomised Controlled Trial, Inot 27, will help in responding to these questions.