Evaluation of a Novel Dry Powder Surfactant Aerosol Delivery System for Use in Premature Infants Supported with Bubble CPAP

Abstract

Aerosolized lung surfactant therapy during nasal continuous positive airway pressure (CPAP) support avoids intubation but is highly complex, with reported poor nebulizer efficiency and low pulmonary deposition. The study objective was to evaluate particle size, operational compatibility, and drug delivery efficiency with various nasal CPAP interfaces and gas humidity levels of a synthetic dry powder (DP) surfactant aerosol delivered by a low-flow aerosol chamber (LFAC) inhaler combined with bubble nasal CPAP (bCPAP). A particle impactor characterized DP surfactant aerosol particle size. Lung pressures and volumes were measured in a preterm infant nasal airway and lung model using LFAC flow injection into the bCPAP system with different nasal prongs. The LFAC was combined with bCPAP and a non-heated passover humidifier. DP surfactant mass deposition within the nasal airway and lung was quantified for different interfaces. Finally, surfactant aerosol therapy was investigated using select interfaces and bCPAP gas humidification by active heating. Surfactant aerosol particle size was 3.68 µm. Lung pressures and volumes were within an acceptable range for lung protection with LFAC actuation and bCPAP. Aerosol delivery of DP surfactant resulted in variable nasal airway (0-20%) and lung (0-40%) deposition. DP lung surfactant aerosols agglomerated in the prongs and nasal airways with significant reductions in lung delivery during active humidification of bCPAP gas. Our findings show high-efficiency delivery of small, synthetic DP surfactant particles without increasing the potential risk for lung injury during concurrent aerosol delivery and bCPAP with passive humidification. Specialized prongs adapted to minimize extrapulmonary aerosol losses and nasal deposition showed the greatest lung deposition. The use of heated, humidified bCPAP gases compromised drug delivery and safety. Safety and efficacy of DP aerosol delivery in preterm infants supported with bCPAP requires more research.

Keywords: aerosol delivery; bubble CPAP; dry powder lung surfactant; humidification; nasal prongs; nebulizer; particle size; preterm infant airway model; synthetic lung surfactant.

Figure 1

Experimental Set-up and Low-Flow Aerosol Chamber (LFAC) System. The B-YL: Trehalose surfactant was aerosolized with a LFAC, a cylindrical chamber/inhaler with several holes at one end that accommodates a perforated DP capsule and dispenses aerosol into the inhalation pathway via the nasal prong interface. The LFAC does not require auxiliary electricity or compressed medical gases to operate. It uses a 60 mL bellows on the posterior end of the LFAC to generate the airflow flow (~8 L/min) necessary to spin the drug capsule and release aerosol. A series of one-way valves and a three-way stopcock allow the bellows to reinflate without entraining aerosol back into the LFAC capsule or inhaler chamber. The black arrows show the direction of aerosol flow through the LFAC during bellows deflation (inhalation) and entrainment of ambient flow which allows the bellows to reinflate (exhalation) with the use of one-way valves.

Figure 2

Bi-nasal short prongs configured to provide CPAP and intermittent aerosol delivery. The RAM Cannula (Neotech Valencia, CA, USA) and Hudson Nasal Prongs (Hudson-RCI, Temecula, CA, USA), two commonly used interfaces, were adapted to provide specialized flow channels for medication delivery to disperse the aerosol plume directly into the bCPAP source gas flow. The RAM cannula (A) 15 mm adaptor was attached to an elbow adaptor with a perpendicular CPAP port and small port which allowed Injector Outlet Tubing to be inserted within 2 cm of the cannula tubing openings. The Hudson cannula (B) integrates a port for measuring pressure which was used in this testing to disperse aerosol into the CPAP flow by attaching the LFAC injector between the CPAP inlet and nasal prongs using a Luer fitting. The Ginevri prongs (Ginevri srl, Rome, Italy) were adapted to the AFECTAIR^® connector (C) that has an internal channel designed to separate the fluidic paths of the aerosol and CPAP flow. The LFAC aerosol inlet was inserted into the internal channel of the AFECTAIR connector via a 15 mm adaptor (see blue arrow) and the patient interface port was attached to the Ginevri prongs inlet adaptor (see red arrow).

Figure 3

Neotech Aerosol Delivery Prongs. The Neotech prototype cannulae are designed with a perpendicular access channel to improve aerosol delivery efficiency and safety. The aerosol/CPAP patient manifold decouples LFAC and CPAP flow pathways so that the mixing of aerosol with CPAP flow occurs within a short timeframe to minimize aerosol dilution and losses to the expiratory limb by bCPAP flow. The major physical differences between Neotech prototypes 1 (A) and 2 (B) is the addition of an angled expiratory manifold outlet with prototype 2. We speculated that the small increase in downstream resistance with an angled outlet could enhance aerosol streaming into the nasal prongs and provide a higher inhaled surfactant dose. Computational fluid dynamics (CFD) helped to illustrate the potential behavior of incoming LFAC aerosol flow through the drug delivery channels and the boundary condition that prevents the bCPAP flow from mixing with aerosol in the manifold during inhalation (C). The small internal diameter of the parallel drug delivery channels attenuates pressure generated by LFAC (~25 cm H₂O) resulting in high gas velocity at the patient manifold. Upon inhalation, airway pressure at the prong outlet (and lung) decreases in relation to the bCPAP level (6 cm H₂O), and when the LFAC is timed with inhalation, aerosol enters the nasal airway and the flow and pressure exceeding the set point CPAP level (~6 cm H₂O) is diverted to the the bCPAP circuit and released within the water column, preventing over pressurization in the lungs. If the is LFAC is mistimed with the patient effort, any increase in PIP > CPAP would be minimal because LFAC flow is released through the water-seal, preventing excessive pressure and volume delivery to the lungs during medication delivery. At end-inhalation, LFAC flow ceases and back-pressure within the drug delivery channels increases, and the patient can exhale through the prongs, patient manifold, and bCPAP column. The black arrows show the direction of aerosol flow through the LFAC during bellows deflation (inhalation) and entrainment of ambient flow which allows the bellows to reinflate (exhalation) with the use of one-way valves.

Figure 4

LFAC compatibility during aerosol surfactant delivery with bCPAP and different airway nasal interfaces. All interfaces had an acceptable level of safety on delivered tidal volume, peak inspiratory pressure, and PEEP within the test lung. LFAC: low-flow aerosolization chamber; PEEP: Positive end expiratory pressure. n = 20 breaths/group. Values are means ± SD. The dotted lines represents the maximum acceptable pressure and volume limits commonly associated with increased risk for pulmonary injury and inflammation in preterm infants.

Figure 5

Surfactant aerosol deposition in the nasal airway and lung model with LFAC and bCPAP with passive humidification. Main-stream interfaces (RAM and Hudson) showed low aerosol delivery deposition to nasal airway and lung, while side-stream interfaces (Ginevri and 2 types of Neotech) showed greater aerosol delivery deposition to nasal airway and lung, especially for lung delivery with both Neotech prongs. n = 6/group. Values are means ± SD. **, p < 0.01; ***, p < 0.001. Values were compared using one-way ANOVA with post-hoc Tukey multiple comparison. Capsule: residual powder in capsule after procedure. Nasal Airway: aerosol deposition in the nasal passages, pharynx, larynx, and tracheal adaptor. Lung: aerosol deposition captured within the filter at the distal trachea region.

Figure 6

Surfactant aerosol deposition in the nasal airway and lung model with LFAC and bCPAP with active heating and humidification. (A) Humidity-resulted in low deposition to nasal airway and lung. n = 5–6/group. Values are means ± SD. ***, p < 0.001. Values were compared using the two-tailed unpaired t-test between without (w/o) and with humidity in each interface. There was high deposition and agglomeration of DP surfactant within the LFAC delivery tubing (B), nasal prongs (C) and nasal airway opening (D). Red arrow: powder deposition.

Figure 7

Mass balanced showing proportion of drug mass at each location referenced to the capsule dose for passive and active humidification of bCPAP gases. Lung: aerosol deposition captured with filter at trachea region. Nasal Airway: aerosol deposition in the nasal passages, pharynx, larynx, and tracheal adaptor. Capsule: residual powder in capsule after procedure. Depositional loss: aerosol depositing within the LFAC, nasal prong interfaces, bCPAP system.