Defense Date

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Engineering

First Advisor

Dr. P. Worth Longest

Abstract

The administration of pharmaceutical aerosols to infants on mechanical ventilation needs to be improved by increasing the efficiency of delivery devices and creating better ways of evaluating potential therapies. Aerosolized medicines such as surfactants have been administered to ventilated infants with mixed results, but studies have shown improvement in respiratory function with a much lower dose than with liquid instillation through an endotracheal tube (ETT). An aerosolized medicine must be transported through the ventilation tubing and deposit in the lungs to have the desired therapeutic response.

This work has taken a systematic approach to (i) develop new devices for the efficient production of small sized charged pharmaceutical aerosols, (ii) adapt a lead device to an infant ventilation system, (iii) develop a novel breathing infant lung (BIL) in vitro model capable of capturing lung delivery efficiency in an infant without the need for human subjects testing, and (iv) evaluate the hypothesis that small sized charged pharmaceutical aerosols can improve drug delivery efficiency to the lungs of a ventilated infant. Three new devices were developed and screened for the efficient generation of small sized charged pharmaceutical aerosols, which were: wick electrospray, condensational vapor, and a modified vibrating mesh nebulizer in a streamlined low flow induction charger (LF-IC). Of these devices, only the LF-IC produced a small [mean(SD) = 1.6(0.1) micrometers] and charged (1/100 Rayleigh limit) aerosol at a pharmaceutically relevant production rate [mean(SD) = 183(9) micrograms per minute]. The LF-IC was selected as a lead device and adapted for use in an infant ventilation system, which produced an increase in in vitro lung filter deposition efficiency from 1.3% with the commercial system to 34% under cyclic ventilation conditions. The BIL model was first shown to produce a realistic pressure-volume response curve when exposed to mechanical ventilation. The optimized LF-IC was then implemented in the BIL model to demonstrate superior reduction in inspiratory resistance when surfactant was delivered as an aerosol compared to liquid instillation. For the delivery of an aerosolized medication, the lung deposition efficiency increased from a mean(SD) 0.4(0.1)% when using the conventional delivery system to 21.3(2.4)% using the LF-IC in the BIL model, a 59-fold increase. The charged aerosol produced by the LF-IC was shown to have more depositional loss in the LF-IC than an uncharged aerosol, but the charge decreased the exhaled fraction of aerosol by 17%, which needs additional study to achieve statistical significance.

Completion of this work has produced a device that can achieve lung delivery efficiency that is 59-fold greater than aerosols from conventional vibrating mesh nebulizers in invasively ventilated infants using a combination of small particle size, synchronization with inspiration and appropriate charge. The BIL model produced in this work can be used to test clinically relevant methods of administering medications to infants and can be used to provide more accurate delivery estimates for development of new nebulizers and inhalers. The LF-IC developed in this work could be used for controlled and efficient delivery of aerosolized antibiotics, steroids, non-steroidal anti-inflammatories, surfactants, and vasodilators.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-29-2015