Aerosol delivery during invasive mechanical ventilation: development of a preclinical ex vivo respiratory model for aerosol regional deposition

Abstract

In intensive care units, nebulization is a usual route for drug administration to patients under mechanical ventilation (MV). The effectiveness of inhalation devices as well as depositions sites of aerosols for ventilated patients remain poorly documented. In vivo human inhalation studies are scarce due to ethical restrictions because imaging techniques require radioaerosols to assess regional aerosol deposition. Thus, we developed an ex vivo respiratory model under invasive MV for preclinical aerosol deposition studies. The model was composed of ex vivo porcine respiratory tracts. MV was achieved thanks to a tracheal intubation and a medical ventilator under controlled conditions. Respiratory features were studied using analogical sensors. Then regional homogeneity of gas-ventilation was assessed with 81mKrypton scintigraphies. Finally, a proof of concept study for aerosol deposition was performed. Obtained respiratory features as well as gamma-imaging techniques, which demonstrated a homogenous regional ventilation and about 18% ± 4% of the nebulized dose deposited the respiratory tract, were in good agreement with human data available in the literature. This original ex vivo respiratory model provides a feasible, reproducible and cost-effective preclinical tool to achieve aerosol deposition studies under MV.

Nano-delivery to the lung - by inhalation or other routes and why nano when micro is largely sufficient?

“…To reach this objective, innovative ex vivo respiratory models appear to be an interesting preclinical tool to assess aerosol regional deposition of nano-delivery systems in healthy and pathological-like respiratory tracts [165,201]. Composed of a 3D-printed Ear-Nose-Throat replica connected to ex vivo animal respiratory tract in a hypobaric chamber simulating passive ventilation, these models appear as an innovative and promising way to quantitatively assess aerosol deposition into the lungs and to transpose it more easily to human [202,203].…”

Impact of gas humidification and nebulizer position under invasive ventilation: preclinical comparative study of regional aerosol deposition.

“…Nevertheless, a difference arose in our results for RT distribution when the position upstream HH and dry condition interacts. Indeed, these parameters (condition D-1) allowed a more peripheral deposition compared to each other condition, as previously described (25). However, this nding must be rst balanced with an absolute RT deposited fraction lower than other conditions and then with the risks for patients when interrupting the humidi cation for nebulization.…”

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

“…Mechanical ventilation (MV) largely impacts the aerosolization efficiency and deposition within the respiratory tracts of the pulmonary delivered siRNA/siRNA carriers 83 , 84 . Harmfully, the presence of heat and humidity in the ventilator circuit can reduce the efficiency of drug delivery 83 .…”

“…In patients receiving mechanical ventilation, it is difficult to ensure that the aerosolized particles are efficiently delivered to distal airways 85 . It has been reported that the aerosol generated by nebulizers in mechanically ventilated patients was mostly deposited in proximal airways with a lung deposition lower than 20% of the nominal dose 84 , 86 . Thus, inhalation devices and administration procedures have to be improved for patients under MV 84 .…”

“…It has been reported that the aerosol generated by nebulizers in mechanically ventilated patients was mostly deposited in proximal airways with a lung deposition lower than 20% of the nominal dose 84 , 86 . Thus, inhalation devices and administration procedures have to be improved for patients under MV 84 . Positively, the time required to deliver a specified amount of drug to its target and the proportion of drugs delivered could be better managed by controlling the ventilator settings (tidal volume, airflow, inspiratory time/total duration of the breath) 83 , 85 .…”