From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.

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).

Valoración del daño cerebral tras la administración de surfactante / Brain damage assesment after surfactant administration

Objetivo: La terapia de reemplazo de surfactante se asocia frecuentemente a fluctuaciones del flujo sanguíneo cerebral (FSC). Presentamos la administración de surfactante nebulizado para evitar las fluctuaciones del FSC. Métodos: El estudio se llevó a cabo en muestras cerebrales (congeladas y fijadas) de corderos prematuros que recibieron surfactante instilado (SFinstil, administración clásica) o surfactante nebulizado (SFneb). Se analizaron el FSC regional, la actividad de las enzimas antioxidantes, el Factor de Necrosis Tumoral (TNFα) y el número de células apoptóticas (TUNEL). También se realizó una valoración semi-cuantitativa del daño cerebral por un anátomo- patólogo. Se analizaron zonas corticales (corteza frontal y occipital), zonas internas (tálamo, estriado e hipocampo), el cerebelo y el bulbo cefalorraquídeo. Resultados: La administración de surfactante nebulizado produjo una respuesta hemodinámica cerebral diferente a la instilación intratraqueal, especialmente en las zonas internas donde a los cinco minutos el FSC registrado resultó ser significativamente superior en el grupo SFinstil. No se registraron diferencias significativas en la actividad de las enzimas antioxidantes. El porcentaje de células positivas para TNFα y el número de células TUNEL positivas en las zonas internas fue significativamente superior en el grupo SFinstil (p<0.05). La valoración histológica determinó un mayor grado de necrosis neuronal (p<0.05) en el tálamo en el grupo SFinstil. Conclusión: La administración de surfactante en forma de aerosol debería tenerse en cuenta como una alternativa menos agresiva a la instilación intratraqueal (AU)

Objective: Surfactant replacement therapy has been associated with cerebral blood flow (CBF) fluctuations. We propose the administration of aerosolized surfactant to prevent those fluctuations. Methods: Brain samples (frozen and paraffin-fixed) of preterm lambs received instilled surfactant (SFinstil, common administration) or aerosolized surfactant (SFneb). Regional CBF, the activity of antioxidant enzymes, the number of TNFα positive cells and the number of apoptotic cells (TUNEL) were determined. In addition, a semi-quantitative histological evaluation was performed by an expert pathologist. Cortical zones (frontal and occipital), inner zones (thalamus, striatum and hippocampus), cerebellum and the brain stem were analyzed. Results: Surfactant delivered as an aerosol produced a different cerebral hemodynamic response than surfactant instillation, especially towards the inner zones, where already five minutes after the start of the therapy the regional CBF was significantly higher in the SFinstil group. There were no differences between groups in the activity of antioxidant enzymes. The percentage of TNFα positive cells and the number of TUNEL positive cells in the inner zones was significantly higher in the SFinstil group. The histological score also showed a significantly higher necrosis in the SFinstil group compared to the SFneb group. Conclusion: Surfactant delivered as an aerosol should be considered as a less harmful method of surfactant administration (AU)

Bronchoalveolar lavage versus bolus administration of lucinactant, a synthetic surfactant in meconium aspiration in newborn lambs.

This study was designed to study effects of lung lavage versus the classical bolus instillation with a peptide-based synthetic surfactant (lucinactant) in a model of Meconium Aspiration Syndrome (MAS). Eighteen newborn lambs received meconium and were randomized to: the experimental meconium installation (eMAS) group-lambs with eMAS kept on conventional mechanical ventilation (control); the SF-Bolus group-eMAS receiving a lucinactant bolus (30 mg/ml); or the D-SF-Lavage group-eMAS treated with dilute lucinactant bronchoalveolar lavage (10 mg/ml). Systemic and pulmonary arterial pressures, blood gases, and pulmonary mechanics were recorded for 180 min. In addition, the intrapulmonary distribution of the lucinactant was determined using dye-labeled microspheres. Following meconium instillation, severe hypoxia, hypercapnia, acidosis, and pulmonary hypertension developed, and dynamic compliance decreased (50% from baseline). After lung lavage with dilute lucinactant, gas exchange significantly improved versus bolus instillation (P < 0.05). Further, only in the lavage group did pulmonary arterial pressure return to basal values and dynamic compliance significantly increased. Both lung lavage and bolus techniques for the administration of lucinactant resulted in a non-uniform lung distribution. In conclusion, in newborn lambs with respiratory failure and pulmonary hypertension induced by meconium, lung lavage with dilute lucinactant seems to be an effective and safe alternative for treatment for MAS.