Nebulized Aerosol Characteristics During Nasal High-Flow: Effect of Flow, Formulation and Impactor Temperature

Background: Aerosol delivery during nasal high-flow (NHF) therapy occurs within a heated and humidified environment where formulation composition, NHF rate, and Next Generation Impactor (NGI)/system temperature may jointly influence aerosol behavior. However, their combined effects following NHF-conditioned transport remain incompletely characterized. Methods: A balanced 4 × 2 × 2 full-factorial design evaluated NGI/system temperature (5, 21, 37, and 40 °C), formulation (isotonic and 3% hypertonic salbutamol formulations), and NHF rate (30 and 50 L·min^-1). Aerosols generated using a vibrating mesh nebulizer integrated within an NHF system were transported through an adult nasal replica coupled to an NGI. Particle-size, fine-particle, delivery-efficiency, and regional-deposition metrics were analyzed using factorial ANOVA. Results: NHF rate exerted the greatest influence on downstream aerosol delivery, with increasing NHF rate reducing delivery efficiency, Fine Particle Dose (FPD), and NGI deposition while increasing NHF circuit retention. Significant Temperature × Formulation × Flow interactions were observed for MMAD (p = 0.0055), D16 (p < 0.0001), GSD (p = 0.0009), Fine Particle Fraction (FPF) (p = 0.0042), and dose-normalized FPD (p = 0.0149). The hypertonic formulation exhibited greater thermal sensitivity across several particle metrics. Although increasing NGI/system temperature generally reduced MMAD, D16, and D84, similar reductions in MMAD frequently produced markedly different responses in FPF, FPD, delivery efficiency, and regional deposition. All aerosols remained within ranges commonly associated with pulmonary deposition. Conclusions: Aerosol characteristics during NHF are governed by interacting effects of flow, formulation, and NGI/system temperature. Measurements conducted at NGI/system temperatures approaching body temperature provide additional mechanistic insight, particularly for hypertonic aerosols, and support integrated assessment of particle-size, delivery, and deposition outcomes rather than APSD metrics alone.