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

Background: Inhaled furosemide (FUR) shows potential for relieving refractory dyspnoea by sensitising slowly adapting receptors (SARs) in the tracheobronchial tree. However, clinical trials have yielded inconsistent results. We hypothesise this is due to a "Dyspnoea Paradox", where high inspiratory flows cause excessive inertial impaction in the throat. Methods: We evaluated FUR solution delivery using the Aerogen Solo vibrating mesh nebuliser under simulated dyspnoeic conditions. The study integrated three modelling approaches: (1) Standard Pharmacopoeial characterisation; (2) In vitro deposition measurements in a realistic human airway replica; and (3) Computational modelling using Large Eddy Simulation (LES) and Multiple-Path Particle Dosimetry (MPPD). Results: Standard ACI measurements indicated optimal aerodynamic properties (MMAD 3.03 µm). However, realistic modelling revealed a critical aerodynamic barrier with high deposition in the upper regions of airways (53.8%–66.2%). MPPD underestimated localised hotspots in the upper lobes compared to advanced 3D models. Conclusion: Standard Pharmacopoeial methods yield “false positive” predictions for dyspnoeic patients. To overcome the "Dyspnoea Paradox", strategies should shift to flow-governed delivery or shape-optimised carriers.