Stefan Minocchieri

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. 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. 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). 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).

Summary Background Nebulized surfactant therapy has been proposed as an alternative method of surfactant administration. The use of a perforated vibrating membrane nebulizer provides a variety of advantages over conventional nebulizers. We investigated the molecular structure and integrity of poractant alfa pre‐ and post‐nebulization. Method Curosurf® was nebulized using an Investigational eFlow® Nebulizer System. Non‐nebulized surfactant (“NN”), recollected surfactant droplets from nebulization through an endotracheal tube (“NT”) and nebulization of surfactant directly onto a surface (“ND”) were investigated by transmission electron microscopy. Biophysical characteristics were assessed by the Langmuir–Wilhelmy balance and the Captive Bubble Surfactometer. Results Volume densities of lamellar body‐like forms (LBL) and multi‐lamellar forms (ML) were high for “NN” and “NT” samples (38.8% vs. 47.7% for LBL and 58.2% vs. 47.8% for ML). In the “ND” sample, we found virtually no LBL's, ML's (72.6%) as well as uni‐lamellar forms (16.4%) and a new structure, the “garland‐like” forms (9.4%). Surface tension for “NN” and “NT” was 23.33 ± 0.29 and 25.77 ± 1.12 mN/m, respectively. Dynamic compression–expansion cycling minimum surface tensions were between 0.91 and 1.77 mN/m. Conclusion The similarity of surfactant characteristics of nebulized surfactant via a tube and the non‐nebulized surfactant suggests that vibrating membrane nebulizers are suitable for surfactant nebulization. Alterations in surfactant morphology and characteristics after nebulization were transient. A new structural subtype of surfactant was identified. Pediatr Pulmonol.