Aerodynamic barriers to inhaled furosemide delivery during dyspnoea revealed by experimental and computational modelling

Inhaled furosemide shows potential for relieving refractory dyspnoea, yet clinical trials have yielded inconsistent results. We hypothesise this failure stems from a "Dyspnoea Paradox", where high inspiratory flows create an aerodynamic barrier. We evaluated furosemide delivery using a vibrating mesh nebuliser under simulated dyspnoeic conditions (tidal volume 1.39 L, frequency 28.6 min⁻¹). The study integrated standard Pharmacopoeial characterisation, in vitro deposition in a realistic human airway replica, and computational modelling (Large Eddy Simulation and Multiple-Path Particle Dosimetry). While standard tests indicated optimal aerodynamic properties (MMAD 3.03 μm), realistic modelling revealed a critical barrier. Both experimental and computational results showed excessive deposition in the upper parts of the airways, caused by a "Laryngeal Jet" that increases inertial impaction and turbulent dispersion. Standard Pharmacopoeial methods thus yield false-positive predictions of delivery efficiency for dyspnoeic patients. We propose a mechanistic hypothesis that rapid inhalation associated with air hunger filters out a significant portion of the therapeutic dose before it reaches the target tracheobronchial receptors, which may partially explain the inconsistent clinical outcomes. Clinical strategies must therefore shift from dose escalation to flow-governed delivery or shape-optimised carriers to overcome this aerodynamic filtration.