(M0930-09-61) Effective Aerosol Delivery of Dry Powder Inhalers during Mechanical Ventilation: Role of Humidity and Circuit Parameters

Purpose: Mechanically ventilated patients frequently require inhaled medications for managing pulmonary diseases. Compared to oral or parenteral administration, inhalation provides targeted lung delivery, rapid therapeutic onset, and fewer systemic side effects1. Nebulizers and pressurized metered-dose inhalers are routinely integrated into ventilator circuits because they actively produce aerosol medication independent of patient effort2. Conversely, dry powder inhalers (DPIs) are passive devices that rely on the patient's inspiratory airflow for powder dispersion, making their use challenging in mechanically ventilated settings. This limitation can be overcome by utilizing airflow from the ventilator to actuate the DPI through enclosure within a dedicated delivery chamber integrated into the ventilator circuit, thus enabling controlled powder dispersion even without spontaneous breathing3. Another critical barrier to incorporating DPIs into ventilator circuits is impaired powder dispersion caused by humidified air4. However, switching off conventional pass-over humidifiers, currently the most widely used system, is not recommended, as this requires time for the system to return to ambient conditions and carries the risk of failing to reactivate humidification, which may result in prolonged delivery of dry air and lead to airway dryness and mucosal injury. To resolve this issue, a novel humidifier was developed that sprays water through a nozzle into fine mono-disperse droplets, which are then heated and evaporated. This design enables precise control over the moisture output and humidity levels (absolute humidity: 0-44 mg/L) in the ventilator circuit, offering improved flexibility compared to conventional humidifiers. This study aimed to evaluate the aerosol delivery efficiency of DPI under various humidity conditions during mechanical ventilation, identifying optimal delivery conditions.

Methods: Onbrez Breezhaler® (Novartis Pharmaceuticals Ltd., UK) was selected as the model DPI, delivering a labeled dose of 150 µg of indacaterol per actuation. Ventilator airflow was heated and humidified by either the Absolute Humidifier Prototype (Medspray Humidification, Netherlands; absolute humidity: 0–44 mg/L, equivalent to 0–100% RH at 37˚C) or a conventional humidifier (MR850, Fisher & Paykel, New Zealand). The impact of two endotracheal tube (ETT) sizes (IDs: 7.5 and 9.5 mm) on aerosol delivery was also assessed. Ventilator settings included a respiratory frequency of 15 breaths/min, square waveform at 50 L/min flow rate, and tidal volumes of 400, 600, and 800 mL. Before testing, the humidifier was stabilized for 30 minutes, and the ETT was wrapped with an external heating pad and maintained at 37 °C. The DPI chamber, housing the Breezhaler, was connected to the ventilator circuit during the expiratory phase, followed by powder dispersion for 15 breaths. Components were subsequently eluted, and drug deposition was then quantified using HPLC. Experiments was performed in triplicate.

Results: Figure 2 shows the drug deposition across ventilator circuit components at a tidal volume of 600 mL under varying humidity levels (Prototype: 0-44 mg/L; MR850 humidifier) and ETT sizes (7.5 and 9.5 mm). Increasing humidity levels from 22 to 44 mg/L resulted in a gradual increase in inhaler drug retention, accompanied by a corresponding decrease in deposition on the inspiratory filter. Specifically, under 9.5 mm ETT condition, inhaler retention significantly increased across humidity levels from 22, 33, and 44 mg/L (25.9 ± 1.4%, 34.1± 2.8%, and 47.8 ± 1.2%, respectively, p  < 0.05), while inspiratory filter deposition markedly reduced (40.9 ± 2.1%, 35.2 ± 0.9%, 12.0 ± 1.5%, p < 0.05). This trend was consistent across different tidal volumes and ETT sizes. These observations suggest that higher humidity enhances interparticle cohesion, impeding powder dispersion. Additionally, increasing the ETT size from 7.5 to 9.5 mm led to decreased ETT deposition and increased inspiratory filter deposition, indicating improved aerosol delivery efficiency with larger ETT tube diameters. Figure 3 compares inspiratory filter deposition at various tidal volumes using a 9.5 mm ETT. Below a humidity level of 22 mg/L, tidal volume had minimal impact on deposition. However, at higher humidities (33 and 44 mg/L), inspiratory filter deposition decreased at lower tidal volumes. This may be attributed to moisture-induced powder agglomeration, hindering capsule emptying. In contrast, extended inspiratory times associated with higher tidal volumes at the square flow waveform likely facilitate improved powder emission under humid conditions. Across all tested conditions, drug deposition on the expiratory filter remained below 5%, suggesting a low risk of expiratory filter obstruction.

Conclusion: This study demonstrated a clinically feasible method for effective DPI drug delivery in the ventilator circuit. Lower humidity (0-22mg/L), larger ETT sizes, and higher tidal volumes consistently improved aerosol delivery efficiency. In addition, minimal expiratory filter deposition ( < 5%) suggests efficient drug delivery to the patient; however, the deposition pattern and exhaled fraction require further investigation. Further studies are ongoing to explore the impact of these parameters on the aerodynamic particle size distributions.

References: 1 McCarthy, S. D., González, H. E., & Higgins, B. D., Future Trends in Nebulized Therapies for Pulmonary Disease. Journal of personalized medicine, 10(2), 37 (2020).
2 Dugernier, J., Ehrmann, S., Sottiaux, T. et al., Aerosol delivery during invasive mechanical ventilation: a systematic review. Crit Care 21, 264 (2017).
3 Okuda, T., Tang, P., Yu, J., Finlay, W. H., & Chan, H. K., Powder aerosol delivery through nasal high-flow system: In vitro feasibility and influence of process conditions. International journal of pharmaceutics, 533(1), 187–197 (2017).
4 Radivojev S, Pinto JT, Fröhlich E, Paudel A. Insights into DPI sensitivity to humidity: An integrated in-vitro-in-silico risk-assessment. J Drug Deliv Sci Technol. 52:803–17 (2019).

Figure 1. Experimental setup for DPI drug delivery in the mechanical ventilator circuit.

Figure 2. The deposition of indacaterol across ventilator circuit components at various humidity levels and ETT sizes. The ventilator set a tidal volume of 600 mL, a respiratory frequency of 15 breaths/min, a flow rate of 50 L/min, and a square waveform.

Figure 3. The deposition of indacaterol in the inspiratory filter at various tidal volumes and humidity levels. ETT size of 9.5mm was used. The ventilator set a respiratory frequency of 15 breaths/min, a flow rate of 50 L/min, and a square waveform.