ObjectiveTo evaluate if nebulised surfactant reduces intubation requirement in preterm infants with respiratory distress treated with nasal continuous positive airway pressure (nCPAP).DesignDouble blind, parallel, stratified, randomised control trial.SettingSole tertiary neonatal unit in West Australia.PatientsPreterm infants (290–336 weeks’ gestational age, GA) less than 4 hours of age requiring 22%–30% supplemental oxygen, with informed parental written consent.InterventionsInfants were randomised within strata (290–316 and 320–336 weeks’ GA) to bubble nCPAP or bubble nCPAP and nebulised surfactant (200 mg/kg: poractant alfa) using a customised vibrating membrane nebuliser (eFlow neonatal). Surfactant nebulisation (100 mg/kg) was repeated after 12 hours for persistent supplemental oxygen requirement.Main outcome measuresThe primary outcomes were requirement for intubation and duration of mechanical ventilation at 72 hours. Data analysis followed the intention-to-treat principle.Results360 of 606 assessed infants were eligible; 64 of 360 infants were enrolled and randomised (n=32/group). Surfactant nebulisation reduced the requirement for intubation within 72 hours: 11 of 32 infants were intubated after continuous positive airway pressure (CPAP) and nebulised surfactant compared with 22 of 32 infants receiving CPAP alone (relative risk (95% CI)=0.526 (0.292 to 0.950)). The reduced requirement for intubation was limited to the 320–336 weeks’ GA stratum. The median (range) duration of ventilation in the first 72 hours was not different between the intervention (0 (0–62) hours) and control (9 (0–64) hours; p=0.220) groups. There were no major adverse events.ConclusionsEarly postnatal nebulised surfactant may reduce the need for intubation in the first 3 days of life compared with nCPAP alone in infants born at 290–336 weeks’ GA with mild respiratory distress syndrome. Confirmation requires further adequately powered studies.Trial registration numberACTRN12610000857000.

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). Electronic supplementary material The online version of this article (10.1186/s12931-019-1096-9) contains supplementary material, which is available to authorized users.

Instilled bolus surfactant is the only approved surfactant treatment for neonatal respiratory distress syndrome. However, recent trends towards increased utilization of noninvasive respiratory support for preterm infants with surfactant deficiency have created a demand for a similarly noninvasive means of administering exogenous surfactant. Past approaches to surfactant nebulization met with varying success due to inefficient aerosol devices resulting in low intrapulmonary delivery doses of surfactant with variable clinical effectiveness. The recent development of vibrating membrane nebulizers, coupled with appropriate positioning of the interface device, indicates that efficient delivery of aerosolized surfactant is now a realistic goal in infants. Evidence of clinical effect despite low total administered dose in pilot studies, together with suggestions of enhanced homogeneity of pulmonary distribution indicate that this therapy may be applied in a cost-effective manner, with minimal patient handling and disruption. These studies need to be subjected to appropriately designed randomized controlled trials. Further work is also required to determine the optimum delivery route (mask, intranasal prong, nasopharyngeal or laryngeal), dosing amount and redosing interval.