In vitro delivery of aerosolized treprostinil via modern mechanical ventilation

The Tyvaso Inhalation System is a hand-held nebulizer system used to administer treprostinil, an approved therapy for pulmonary arterial hypertension. Our goal was to establish an in vitro method for delivering a standard dose of treprostinil through a ventilator circuit and artificial airway.

An AeroTech II jet nebulizer (continuous air flow at 10 L/min; Biodex Medical Systems) was placed in the ventilator circuit with a test lung. Two ventilators were tested, the Dräger Evita 2 Dura (Dräger Medical GmbH) and Avea (CareFusion), without humidity. Delivered dose was defined by capturing radiolabeled particles exiting the endotracheal tube with a filter (Pari) and measuring radioactivity. Particle distributions were measured distal to the endotracheal tube by cascade impaction. We hypothesized that drug delivery would be determined by the number of breaths needed, such that the complete time of inspiration totaled 29 sec (e.g., number of breaths needed=29 sec/TI, where TI is the inspiratory time of an average breath read from the ventilator display).

Nebulizer output was linear for 6 min, and the standard prescribed target dose of 54 μg (3.1% of full ampule) was delivered in 29 sec. Using our TI algorithm to control delivery, the mean inhaled dose±SD was 72.2±16.5 μg (range 47.2-98.6; n=23). Dräger delivered higher doses than Avea. Effects of mode, breathing pattern, and positive-end expiratory pressures were not significant. The mass median aerodynamic diameter and fine particle fraction were 0.71±0.015 and 0.997±0.0006, respectively.

Using the algorithm, it was possible to deliver aerosolized treprostinil, at controlled doses, via mechanical ventilation over a wide range of controlled breathing patterns. The conditions of nebulization must be precisely followed (one full ampule per treatment, use of the AeroTech II nebulizer, continuous nebulization using an external flow of 10 L/min, bypass of the humidifier or removal of in-line heat and moisture exchanger, and treatment completed in 6 min or less).