Preventing Lung Disease Using Surfactant + Steroid (The PLUSS Trial)

Bronchopulmonary dysplasia (BPD) is a chronic inflammatory lung disease characterised by disordered alveolar and vascular development, most commonly affecting extremely preterm infants exposed to mechanical ventilation and oxygen therapy for respiratory distress syndrome (RDS). BPD is associated with mortality, and adverse long-term pulmonary and neurodevelopmental outcomes. Despite advances in neonatal care including antenatal corticosteroids, exogenous surfactant, and the increasing use of ‘non-invasive’ ventilation, the incidence of BPD is not decreasing. BPD remains the most important pulmonary complication in extremely preterm infants occurring in about 50% of survivors to 36 weeks post menstrual age, with no new therapies shown to prevent it. Laboratory and clinical studies suggest a crucial role for lung inflammation (pre- and post-natal) and host immune response in the pathogenesis of BPD. A subcommittee of perinatal experts of the National Health, Lung, Blood Institute summarised the current state of knowledge regarding BPD and identified potential points in its pathogenesis susceptible to therapeutic interventions. One recommendation was to study the use of selective anti-inflammatory therapies, to attenuate the inflammatory response in the developing lung to potentially prevent BPD. As inflammation is a primary mediator of injury in the pathogenesis of BPD, anti-inflammatory agents such as postnatal corticosteroids have long been the focus of preventive interventions. Whilst systemic (intravenous or oral) corticosteroids reduce inflammation and improve respiratory function, their early use may be associated with many side effects. Given the serious adverse effects of systemic corticosteroid administration, safer alternatives are sought.Inhaled or nebulised corticosteroids are technically challenging to deliver with conflicting results from trials as the dose, optimal timing of initiating treatment and the duration are unknown. Local administration of corticosteroids to the lung via the intra-tracheal route has the potential to maximise anti-inflammatory effects on the distal airway, minimise systemic absorption and decrease the risk of adverse effects. Exogenous surfactant is a proven effective therapy for RDS in preterm infants. Combining budesonide with surfactant is a simple intervention that may prevent BPD in the high-risk population of extremely preterm infants. The aim of the PLUSS trial is to evaluate the safety and efficacy of early intratracheal corticosteroid (budesonide) combined with exogenous surfactant as the vehicle for distribution compared with exogenous surfactant alone to increase survival without BPD at 36 weeks’ PMA in extremely preterm infants born <28 weeks’ gestation. This is a multicentre, double-blind, two-arm, parallel 1:1 placebo-controlled randomised trial. Families, healthcare providers, outcome assessors and data analysts will be blinded to the randomisation group. Infants enrolled in the study will be randomised to receive intratracheal surfactant and budesonide or surfactant alone.