Factors Determining In Vitro Lung Deposition of Albuterol Aerosol Delivered by Ventolin Metered-Dose Inhaler

Abstract

Background: The effectiveness of metered-dose inhalers (MDIs) in delivering medication to the lungs highly depends on its correct usage technique. Current guidelines state optimal technique for high lung deposition should include a slow inhalation (>5 seconds) at an inspiratory flow rate of 30 L/min and inhaler actuation at the start of inhalation. However, these recommendations were based on clinical studies using CFC (chlorofluorocarbon)-MDIs and in vitro studies of HFA (hydrofluoroalkane)-MDIs using idealized MDI techniques of uniform inhalation and actuation, disregarding the nonuniform techniques of actual patients.

Methods: To better understand the effects of time-varying MDI usage parameters on lung deposition of aerosol delivered by an HFA-MDI, we conducted an in vitro study modeled on real-life variable inspiratory flow and actuation techniques recorded from 15 subjects with asthma/chronic obstructive pulmonary disease (COPD). We developed a model representing the time-varying inspiratory flow waveforms and actuation timings based on 43 MDI techniques recorded from patients. Furthermore, we constructed an in vitro experimental setup using a mouth-throat cast, programmable MDI actuator, and breath simulator to evaluate lung deposition for the MDI techniques derived from our model.

Results: High inspiratory flow rates, 60-90 L/min, consistently resulted in high in vitro lung deposition (>40%) of aerosol (albuterol delivered from Ventolin HFA-MDI) compared to 30 L/min when MDI actuation occurred in the first half of inhalation. Also, positive coordination resulted in higher in vitro lung deposition compared with negative or zero coordination (actuating before or at the start of inspiration). Furthermore, variation in coordination affected lung deposition more significantly (23%) than flow rate or duration of inspiration (≤5%).

Conclusions: In an in vitro experimental model based on inhalation data from patients with asthma and COPD, we demonstrated that aerosol lung deposition emitted from Ventolin HFA-MDI is most optimal for MDI actuation in the first half of inspiration at high flow rates (60-90 L/min).

Keywords: COPD; aerosol; asthma; inhaler technique; lung deposition; metered-dose inhaler.

FIG. 1.

Schematic illustrates the MDI technique recording setup utilized in recording MDI techniques. The MDI is fitted with a plastic cap that connects to a calibrated flow meter. During inhalation through the MDI, the air flows in from the vent at the top of the flow meter and passes through the MDI as shown. The flow meter is also attached to a force sensor that synchronously detects and records the time of MDI actuation. The inhalation and actuation data are stored on the flow meter and are retrieved later on a PC. MDI, metered-dose inhaler; PC, personal computer.

FIG. 2.

Histogram of 43 MDI techniques collected from 15 subjects with asthma and COPD. Data collected consist of the inspiratory flow waveform and the time of MDI actuation. The distribution of three MDI technique steps of interest, (a) peak inspiratory flow rate, (b) duration of inhalation, and (c) time of actuation, is shown in (a–c), respectively. The black bars correspond to the correct technique as recommended by GINA guidelines, (a) peak flow rate between 30 and 60 L/min, (b) minimum inhalation of at least 5 seconds, and (c) time of actuation immediately after the start of inhalation (a positive value, 0–0.5 seconds). The gray bars correspond to the errors in MDI use, (a) peak inspiratory flow rate less than 30 L/min or greater than 60 L/min, (b) inhalation of less than 5 seconds, and (c) MDI actuation before the start of inhalation (a negative value) or late in the inhalation (a large positive value, greater than 0.5 seconds). COPD, chronic obstructive pulmonary disease.

FIG. 3.

The inspiratory flow waveforms recorded during MDI use by subjects with asthma and COPD, and the trapezoidal approximation to the waveforms are presented. (a) Shows a subset of the 43 waveforms collected from 15 subjects, representing the different inspiratory flow rates, duration of inhalation, and waveform shapes. (b) Shows the trapezoidal model for a particular 3 L flow waveform. Here, f_p = 60 L/min (or 1 L/s), t_d = 4.5 seconds and t_h = 1.5 seconds. Thus the total inhalation volume is area of trapezoid = (1/2) f_p (t_d + t_h) = 1/2 × 1 × (4.5 + 1.5) = 3 L. (c) Shows the different combinations of 3 L waveforms generated for f_p = 30, 60, and 90 L/min and the ratio τ = 1.33, 3, and 8, corresponding to long, , and short duration of inhalation, respectively. As an example, a 90 L/min medium duration (τ = 3) and a 60 L/min short duration (τ = 1.33) are highlighted in bold. (d) Shows the trapezoidal approximation (dashed lines) for two of the waveforms recorded.

FIG. 4.

(a) Schematic to illustrate the in vitro experimental setup used in our work. A PC (personal computer) controls the motorized robotic MDI actuator, two flow meters, and the PWG. All the parts of the system are sealed using silicone connectors to minimize air leaks. The MDI is connected to the AIT, which represents the mouth–throat part of the body. The AIT is then connected to the collection filter, which acts as the lungs of the body. The different combinations of MDI techniques, inspiratory flow rates, duration of inhalations, and time of actuation are produced using the combination of the programmable PWG and motorized actuator. (b) Is a photograph of the actual setup used in the in vitro lung deposition experiments. AIT, Alberta Idealized Throat; PWG, pulmonary waveform generator.

FIG. 5.

The percentage deposition in the in vitro lung (black bar), AIT (gray bar), and MDI mouthpiece (white bar) for the in vitro experiments are presented. The graph shows the results from experiments performed for inhalation (flow, duration)-dependent MDI techniques with MDI actuation fixed at the first half of inspiration. Each group of bars represents one MDI technique; the error bars show the range due to three repetitions of each experiment. The baseline result is shown in the beginning marked 0 L/min. The error margins for in vitro lung deposition ranged from ±0.2% to ±2.3%, average ±1.3%. Three flow rates, 30, 60, and 90 L/min, were used for each of the experiments. (a–c) Show the variation in lung deposition with shape ratio, τ (corresponding to the duration of inhalation), for the three different flow rates 30, 60, and 90 L/min, respectively. The short, medium, and long labels on the x-axis refer to τ equal to 1.33, 3, and 8, respectively. The inhalers were actuated at the beginning of the inhalation, t_a = 0.6t_r. We found that the mean in vitro lung deposition (black bar) is higher for 60–90 L/min than 30 L/min (p < 0.001), always greater than 40%. The maximum mean in vitro lung deposition was found to be 44.2% for the case of inspiration with PIFR 60 L/min and duration of 4.5 seconds. PIFR, peak inspiratory flow rate.

FIG. 6.

The percentage deposition in the in vitro lung (black bar), AIT (gray bar), and MDI mouthpiece (white bar) as a function of coordination or time of MDI actuation relative to the start of inspiration are presented. Each group of bars represents one MDI technique, the error bars show the range due to three repetitions of each experiment. The baseline result is shown in the beginning marked 0 L/min. The other bars correspond to the MDI technique of PIFR 60 L/min and duration 5.33 seconds, actuated at −0.5, 0 seconds, 0.6t_r, 0.5t_d, and (t_d − 0.6t_r). The error margins for in vitro lung deposition ranged from ±0.2% to ±2.3%, average ±1.3%. We found that the mean in vitro lung deposition is highest for actuation in the first half of inspiration, 43.8%, and lowest for negative coordination.