Background: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal.
Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical
challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate
the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-
tailored aerosol delivery strategy.
Methods: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos
nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated
in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of
the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an
infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the
100–600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing
rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung
mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured
as a proxy of surfactant deposition efficacy.
Results: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median
diameter, MMD = 3 μm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg
nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly
improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated
with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of
oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg).
Conclusions: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable
aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a
pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg.
This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial
(EUDRACT No.:2016–004547-36).
