Article, Respiratory Medicine

Mechanical factors affecting nebulized albuterol aerosol particle sizes for asthma drug delivery

a b s t r a c t

Background: Nebulized particles must have diameters between 1 to 5 um (optimal particle size range [OPSR]) to be deposited in the lower respiratory tract. The purpose of this study is to determine factors that affect the particle size distributions of nebulized albuterol.

Methods: We used a sophisticated laser diffraction machine to measure aerosol particle size distributions. We compared the percentage of particles in the OPSR at different flow rates through single-use disposable (SUD) and semipermanent nebulizers at different flow rates under different conditions.

Results: The SUD nebulizer produced OPSR percentages of 16%, 28%, 40%, 50%, 56%, and 62% at 3, 4, 5, 6, 7, and 8 Liters per minute (Lpm), respectively. The semipermanent nebulizer, however, produced OPSR percentages of 57%, 57%, 60%, and 64% at 3, 4, 5, and 6 Lpm, respectively. The home pump produced a gas flow rate of 5.2 Lpm through the SUD nebulizer and 4.2 Lpm through the semipermanent nebulizer. Single-use disposable nebulizer performance did not degrade with use up to 150 nebulizations. Optimal particle size range percentages did not change significantly with large or small nebulization volumes.

Conclusion: Single-use disposable nebulizers do not degrade with use, but their performance is highly dependent on gas flow rates. At the flow rate achieved by the home pump, the semipermanent nebulizer performs better than the SUD nebulizer.

(C) 2014

Introduction

Albuterol and other asthma medications are commonly delivered to the lungs via nebulization. To deposit within the bronchial tree, particle sizes in the aerosol from the nebulization process should ideally be in the range of 1 to 5 um (10-6 m) [1-3]. Particles less than 1 um will remain suspended in air and will not deposit within the bronchial tree. Particles greater than 5 um tend to deposit in the upper respiratory tract.

Many factors are known to affect the efficacy of drug delivery in nebulizer systems. Environmental factors include temperature and relative humidity of the ambient air as well as surface tension of the nebulizing solutions. Device factors include flow rates, compressor airflow vs ultrasonic nebulization, design of the nebulizer device, and the characteristics of the drug solution. Patient factors include inspiratory flow, anatomy, patient education, cleaning, maintenance,

? This study was funded by a grant from the Hawaii Pedriatric Association Reasearch & Education Foundation.

* Corresponding author. Department of Pediatrics, University of Hawai’i John A. Burns School of Medicine, Honolulu, HI 96826, USA. Tel.: +1 808 369 1220; fax: +1 808 369

12120.

E-mail addresses: [email protected], [email protected] (L.G. Yamamoto).

and disinfection procedures [4]. Albuterol is most frequently nebulized in emergency departments using single-use disposable (SUD) nebulizer units (Fig. 1) driven by Compressed air or oxygen outlets. It is a common practice for patients to take these home for home nebulizer use, yet there is a concern that the useful lifespan of SUD nebulizers is too short to be used at home.

The purpose of this study is to assess the differences in albuterol aerosol particle size distributions using home SUD nebulizers, semipermanent nebulizers (Fig. 2), and air pumps that are used for home nebulizers, along with changes in airflow rates, nebulization chamber volumes, and age of the devices.

Materials and methods

We used a sophisticated laser diffraction particle size analyzer (Spraytec; Malvern Instruments, Worcestershire, UK) to measure the size distribution of nebulized particles passing through the laser detection fields serially at 1-second interval for the duration of the nebulization. With the receiver lens attached, droplets with diameters between 0.1 and 900 um can be measured. The schematic of this setup is shown in Fig. 3. Albuterol vials were nebulized under different conditions to see if any of these conditions would affect the particle size distribution.

http://dx.doi.org/10.1016/j.ajem.2014.02.015

0735-6757/(C) 2014

570 N.K. Itoga et al. / American Journal of Emergency Medicine 32 (2014) 569572

Fig. 3. Schematic representation of aerosol particle size analysis setup.

Fig. 1. SUD nebulizer.

To sufficiently study the effect of various nebulization factors, we varied several factors to determine if there was a significant change in nebulized aerosol particle size distributions, based on the associated hypotheses below.

  • Gas flow rates were set at 3, 4, 5, 6, 7, and 8 Liters per minute (Lpm) via an adjustable flow regulated gas cylinder. A commercial home nebulizer pump with a single fixed gas flow rate was also tested. Hypothesis: Gas flow rates affect nebulized aerosol particle size distributions because rapid flow rates are likely to result in faster air streams through the nebulizer device resulting in a different particle distribution compared with slower air streams through the same nebulizer device.
  • Medication volume within the nebulizer chamber: 3 mL of albuterol vs 6 mL of albuterol. Hypothesis: Air streaming through

Fig. 2. Semipermanent nebulizer.

a deep column of fluid (6 mL) is likely to result in a different nebulized aerosol particle size distribution compared with air streaming through a shallow column of fluid (3 mL).

  • Type of medication used: 6 vs 3 mL of albuterol plus 2.5 mL of ipratropium. Hypothesis: Albuterol and ipratropium might have different molecular properties affecting particle interaction and surface tension, which may result in different nebulized aerosol particle size distributions.
  • Age of the SUD nebulizer. We took initial particle size distribution measurements of an SUD nebulizer and then took subsequent measurements after 50, 100, and 150, 3-mL saline nebulizations. Hypothesis: SUD nebulizers are not designed for long-term home use, and as a result, they might wear out (the nebulization air port might enlarge), which might result in suboptimal nebulized aerosol particle distributions.
  • Nebulizer type: Semipermanent nebulizer vs SUD nebulizer. Hypothesis: Semipermanent nebulizers will perform better over a longer period compared with SUD nebulizers.

Specification of special materials used:

Albuterol 3 mL unit dose vials (0.083% albuterol sulfate) (Nephron Pharmaceuticals Corporation, Orlando, FL) chilled to 4?C. Ipratropium 2.5 mL unit dose vials (0.5 mg ipratropium bromide) (The Ritedose Corporation, Columbia, SC) chilled to 4?C.

Home nebulizer pump: Vios Adult Aerosol Delivery System (PARI Respiratory Equipment Inc, Midlothian, VA).

SUD nebulizers: Misty Max 10 (Care Fusion Corporation, San Diego, CA).

Fig. 4. A representative plot of the particle size distribution per unit time (second) along with the top and bottom decile particle sizes. The upper line of gray triangles is the 90th percentile particle size (10% of the particles are larger than this, and 90% are smaller than this). The middle line of dark squares is the 50th percentile particle size (median). A mean of all these medians yields the MMPD. The lower line of light gray diamonds is the 10th percentile particle size (90% of the particle are larger than this, and 10% are smaller than this).

N.K. Itoga et al. / American Journal of Emergency Medicine 32 (2014) 569572 571

Fig. 5. Sample distribution of aerosol particle sizes at a single point in time. Particles within the light gray region represent absorbable droplets (approximately 1-5 um). Particles to the left of this are too small, and particles to the right of this are too large.

Semipermanent nebulizers: PARI LC Plus Nebulizer (PARI Respi- ratory Equipment Inc).

For studies involving the commercial home nebulizer pump, the nebulizer was connected to the pump via a mass flow meter, which recorded the pump flow rate. For studies involving the adjustable flow gas cylinder, the nebulizer was connected to a grade 4.0 (99.99% purity) compressed air cylinder via a mass flow controller, which regulated and recorded the gas flow rate. The nebulizer was positioned vertically with the opening placed 2 cm away from the laser detecting area such that, and the nebulizer outflow directed the aerosol into the detection zone. Because the focus of this study was the performance of the nebulizer (ie, its output), no tubes or face masks were connected to the nebulizer to minimize variation in setup. Aerosol particle size distribution data was automatically recorded every second into a Microsoft Excel (Microsoft Corporation, Redmond,

WA) spreadsheet. Gas flow rates were also recorded into a separate spreadsheet. Results were triplicated to ensure repeatability.

Results

A representative plot of the particle size distribution per unit time (second) along with the top and bottom decile particle sizes is shown in Fig. 4. The upper line of gray triangles is the 90th percentile particle size (10% of the particles are larger than this, and 90% are smaller than this). The middle line of dark squares is the 50th percentile particle size (median). A mean of all these medians yields the mean median particle diameter (MMPD). The lower line of light gray diamonds is the 10th percentile particle size (90% of the particle are larger than this, and 10% are smaller than this). Fig. 5 shows a sample distribution of aerosol particle sizes at a single point in time. The particle size

Table 1

Mean median particle diameter (MMPD) and the percentage of particles within the optimal particle size range (%OPSR) with the single-use disposable (SUD) nebulizer versus the semi-permanent nebulizer at varying gas flow rates and a home pump system

analyzer records this data every second. Particles within the light gray region represent absorbable droplets (approximately 1-5 um). Particles to the left of this are too small, and particles to the right of this are too large.

Although aerosol particle size measurements were recorded every second from start to finish, to standardize the measurements used for comparison and to ensure that the nebulization system had reached steady state, the data that we used for analysis started 30 seconds after nebulization initiation and then continued for 120 consecutive measurements (120 seconds).

The particle size analyzer categorized data in constant size increments that we could not override. Although we were most interested in particles in the 1 to 5 um range, the particle size analyzer category bins ran from 1.000 um on the low end to 5.412 um on the high end. Thus, all data in this report referring to the 1 to 5 um optimal particle size range (OPSR), actually refers to particles in the 1.000 to

5.412 um size.

The performance results of the SUD nebulizer compared with the semipermanent nebulizer are summarized in Table 1. The semiper- manent nebulizer has a higher resistance to airflow as manifested by a lower flow rate achieved via the fixed pressure pump and the inability to achieve flow rates of 7 and 8 Lpm. These runs show that the SUD nebulizer performed poorly at low gas flow rates but improves substantially at higher gas flow rates. The semipermanent nebulizer performed well at all flow rates. The home pump generated 5.2 Lpm gas flow through the SUD nebulizer with a percentage of optimal particle size significantly lower than that achieved by the semiper- manent nebulizer, which experienced a gas flow rate of 4.2 Lpm using the home pump.

Table 2 summarizes the results of nebulizing 6 mL of albuterol vs 3 mL of albuterol plus 2.5 mL of ipratropium via the SUD nebulizer and the semipermanent nebulizer. The table shows the results at the onset

Table 2

Comparison of MMPD and percentage of OPSR with an SUD nebulizer and a semipermanent nebulizer at the beginning or end of 6.0 and 5.5 mL nebulization runs

Flow rates (Lpm)

SUD nebulizer Semipermanent nebulizer MMPD (um) %OPSR MMPD (um) %OPSR

mL Albuterol 3 mL Albuterol + 2.5 mL ipratropium

3 8.12 +- 0.26 16.1% +- 1.1 4.47 +- 0.07 56.9% +- 1.2

4 6.59 +- 0.23 28.0% +- 2.6 4.32 +- 0.02 57.3% +- 1.2

SUD nebulizer at 8 Lpm

MMPD (um) %OPSR MMPD (um) %OPSR

5 5.48 +- 0.10 40.1% +- 1.8 3.99 +- 0.02 60.1% +- 0.6

6 4.80 +- 0.16 49.5% +- 3.4 3.51 +- 0.04 64.2% +- 0.5

4.33 +- 0.19 56.4% +- 2.6 Flow rate not achievable
  • 4.03 +- 0.16 61.6% +- 2.7 Flow rate not achievable
  • Pump 5.53 +- 0.02 39.0% +- 0.4 4.41 +- 0.02 56.1% +- 0.5

    @5.2 Lpm @4.2 Lpm

    First 2 minutes 3.67 +- 0.03 66.5% +- 0.4 3.67 +- 0.08 67.0% +- 1.7

    Last 2 minutes 3.63 +- 0.14 64.0% +- 2.6 3.74 +- 0.17 62.2% +- 0.5

    Semipermanent nebulizer at 5 Lpm

    First 2 minutes 3.59 +- 0.04 67.0% +- 1.2 3.65 +- 0.07 66.9% +- 0.6

    Last 2 minutes 3.57 +- 0.02 66.5% +- 0.4 3.58 +- 0.08 66.0% +- 1.2

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    only an MMPA of particle distribution of nebulized particles without the distribution or dye techniques that needed to be combined with the nebulized solution and then separately analyzed with a microscope [5].

    This study demonstrates that OPSR percentages are improved with higher gas flow rates when using the SUD nebulizer but are not significantly changed with the semipermanent nebulizer. Single-use disposable nebulizers perform well and have similar OPSR percent- ages compared with semipermanent nebulizers when the SUD nebulizer flow rate is high (8 Lpm). Although hospital compressed air and oxygen outlets can easily achieve 8 Lpm flow rates, the home pump was only able to achieve a flow rate of 5.2 Lpm with the SUD nebulizer attached. This means that home nebulization treatments using an SUD nebulizer are less effective than hospital nebulization treatments using an SUD nebulizer, and it could explain the poor performance of SUD nebulizers with home pumps. This disadvantage

    Fig. 6. Percentage of particles in the OPSR for an SUD nebulizer after 0 (new), 50, 100,

    and 150 nebulizations at 7 and 5 Lpm and via the fixed pump (roughly 5.2 Lpm).

    of nebulization (when the fluid column is deep) and at the end of the nebulization (when the fluid column is shallow). These results show no significant changes between albuterol vs albuterol + impratro- pium or between a deep fluid column vs a shallow fluid column.

    To determine the effects of aging the SUD nebulizer, we nebulized 3-mL saline units through an SUD nebulizer using the home pump. Fig. 6 summarizes the results after 0 (new), 50, 100, and 150 nebulizations. This shows that the performance of the SUD nebulizer does not change significantly with use up to 150 nebulizations. Thus, although it is called an SUD nebulizer, its performance is roughly the same after many nebulizations.

    Discussion

    Previous studies have shown that the gas flow rates affect the MMPD, with higher flow rates leading to smaller nebulized particle sizes [1-3]. This study is novel as the MMPA of nebulized particles are simultaneously measured with the percentage of particles in the 1 to 5 um range (the OPSR), thereby quantifying the amount of particles that will be deposited in the lower respiratory tract. Previous measuring techniques included a laser diffraction machine that gave

    can be overcome by using a semipermanent nebulizer, as that nebulizer performed well even with the home pump, as shown in Table 1.

    This study demonstrates that fluid volumes within the nebulizer (3 vs 6 mL) and the presence of ipratropium did not result in substantial changes in the OPSR percentages. Furthermore, although the performance of an SUD nebulizer with a home pump is poor from the onset, continued use of an SUD nebulizer does not result in further degradation.

    In conclusion, SUD nebulizers do not degrade with use, but their performance is highly dependent on gas flow rates. At the flow rate achieved by the home pump, the semipermanent nebulizer performs better than the SUD nebulizer.

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