In Vitro Performance of an Investigational Vibrating-Membrane Nebulizer with Surfactant under Simulated, Non-Invasive Neonatal Ventilation Conditions: Influence of Continuous Positive Airway Pressure Interface and Nebulizer Positioning on the Lung Dose

Abstract

Non-invasive delivery of nebulized surfactant has been a long-pursued goal in neonatology. Our aim was to evaluate the performance of an investigational vibrating-membrane nebulizer in a realistic non-invasive neonatal ventilation circuit with different configurations. Surfactant (aerosols were generated with a nebulizer in a set-up composed of a continuous positive airway pressure (CPAP) generator with a humidifier, a cast of the upper airway of a preterm infant (PrINT), and a breath simulator with a neonatal breathing pattern. The lung dose (LD), defined as the amount of surfactant collected in a filter placed at the distal end of the PrINT cast, was determined after placing the nebulizer at different locations of the circuit and using either infant nasal mask or nasal prongs as CPAP interfaces. The LD after delivering a range of nominal surfactant doses (100–600 mg/kg) was also investigated. Surfactant aerosol particle size distribution was determined by laser diffraction. Irrespective of the CPAP interface used, about 14% of the nominal dose (200 mg/kg) reached the LD filter. However, placing the nebulizer between the Y-piece and the CPAP interface significantly increased the LD compared with placing it 7 cm before the Y-piece, in the inspiratory limb. (14% ± 2.8 vs. 2.3% ± 0.8, nominal dose of 200 mg/kg). The customized eFlow Neos showed a constant aerosol generation rate and a mass median diameter of 2.7 μm after delivering high surfactant doses (600 mg/kg). The customized eFlow Neos nebulizer showed a constant performance even after nebulizing high doses of undiluted surfactant. Placing the nebulizer between the Y-piece and the CPAP interface achieves the highest LD under non-invasive ventilation conditions.

Extended Pharmacopeial Characterization of Surfactant Aerosols Generated by a Customized eFlow Neos Nebulizer Delivered through Neonatal Nasal Prongs

“…It has previously been discussed that complex suspensions, such as surfactant formulations, could clog the pores of the vibrating mesh of the nebulizer [34]. However, we have recently demonstrated the consistent performance of the eFlow Neos in nebulizing Poractant alfa, achieving constant nebulization times after continuously delivering the same surfactant dose as reported in this study [35]. Nevertheless, in our previous study, surfactant aerosols were generated towards the open air, in the framework of laser diffraction experiments, whereas, in this study, surfactant aerosols were generated in a tightly sealed neonatal ventilation circuit.…”

A Compartment-Based Mathematical Model for Studying Convective Aerosol Transport in Newborns Receiving Nebulized Drugs during Noninvasive Respiratory Support

“…Our simulation data are in line with the experimental findings of previous in vitro and in vivo studies. For instance, Bianco et al [ 12 ] found that the overall nebulized surfactant reaching the patient (i.e., adding extrapulmonary surfactant deposition to the amount reaching the lung) in a realistic in vitro neonatal noninvasive ventilation setting was approximately 50% when they used the settings and parameters of our baseline case reported in this study ( Figure 2 A).…”

“…In neonatal settings, pressure support is commonly delivered to the baby by means of devices in which the pressure generator is embedded into the interface (e.g., variable flow CPAP generator). In this configuration, the nebulizer can only be placed along the inspiratory limb resulting in an overdiluted aerosol [ 27 ], which leads to very low lung deposition [ 11 , 12 ]. We are not considering that case but the most favorable, in terms of lung deposition: pressure support is generated by a two-limb mechanical ventilator and the nebulizer is connected between the Y-piece and the interface.…”

“…To circumvent this limitation, the most common approach for evaluating the delivery of aerosolized drugs relies on the estimation of the lung deposition from in vitro tests [ 11 , 12 , 13 , 14 ], in vivo preclinical studies [ 15 , 16 , 17 , 18 ], or mathematical modeling [ 19 ]. Most of these studies evaluated the overall drug deposition by quantifying the overall amount of aerosol that impacts against the walls of the different extra pulmonary components of the system (i.e., connecting tubes, patient interface, nebulizer chamber, and patients upper airways), the particles exhaled into the expiratory limb of the ventilation circuit, and the particles delivered into the lung [ 12 , 20 , 21 ]. These studies have been useful to investigate the impact of breathing flows, particle size, gravity, geometric characteristics of nebulizers, ventilation–patient interfaces and breathing circuits, and other fluid dynamic factors on the aerosol deposition.…”

Nebulization of High-Dose Poractant Alfa in Newborn Piglets on Nasal Continuous Positive Airway Pressure Yields Therapeutic Lung Doses of Phospholipids

“…In the nebulization group, 600 mg/kg of undiluted poractant alfa mixed with 200 MBq 99m Tc-nanocolloid (Nanocoll, GE Healthcare AB, Stockholm, Sweden) was continuously nebulized via the nasal prongs. The mass median diameter of the poractant particles determined by laser diffraction for this nebulizer system is 3.0 AE 0.1 µm in diameter with a geometric standard deviation (SD) of 1.5 µm, 6 which is within the range described to facilitate deposition in the airways of neonates. 19 After completed nebulization, we removed the nebulizer from the circuit and maintained the piglets in nCPAP for 10 minutes.…”