Performance Comparison of Nebulizer Designs:
`Constant-Output, Breath-Enhanced, and Dosimetric
`
`Joseph L Rau PhD RRT FAARC, Arzu Ari MSc CRT CPFT, and Ruben D Restrepo MD RRT
`
`INTRODUCTION: Design differences among pneumatically powered, small-volume nebulizers affect drug
`disposition (percentage of the dose delivered to the patient, lost to deposition in the equipment, and lost via
`exhalation to ambient air) and thus affect drug availability and efficacy. OBJECTIVE: Evaluate in vitro the
`dose disposition with 5 nebulizer models, of 3 types (constant-output, breath-enhanced, and dosimetric), using
`simulated normal, adult breathing. METHODS: We compared 5 nebulizer models: 2 constant-output (Misty-
`Neb and SideStream), 1 breath-enhanced (Pari LCD), and 2 dosimetric (Circulaire and AeroEclipse). Each
`nebulizer was filled with a 3-mL unit-dose of albuterol sulfate and powered by oxygen at 8 L/min. The
`nebulizers were connected to an induction throat, connected to a breathing simulator. We measured (1)
`inhaled drug (subdivided into mass deposited in the induction throat and mass deposited in the filter at the
`distal end of the induction throat), (2) exhaled drug (lost to the ambient air), (3) drug lost to deposition in the
`apparatus, and (4) drug left in the unit-dose bottle. The duration of nebulization (until sputter) was measured
`with a stopwatch. All drug amounts were analyzed via spectrophotometry and expressed as a percentage of
`the total dose. RESULTS: The mean ⴞ SD inhaled drug percentages were: Misty-Neb 17.2 ⴞ 0.4%, Side-
`Stream 15.8 ⴞ 2.8%, Pari LCD 15.2 ⴞ 4.2%, Circulaire 8.7 ⴞ 1.0%, and AeroEclipse 38.7 ⴞ 1.3%. The
`mean ⴞ SD percentages of drug lost to the ambient air were: Misty-Neb 26.8 ⴞ 0.7%, SideStream 17.3 ⴞ
`0.4%, Pari LCD 18.3 ⴞ 0.8%, Circulaire 12.3 ⴞ 0.8%, and AeroEclipse 6.6 ⴞ 3.3%. The mean ⴞ SD
`percentages of drug lost to deposition in the apparatus were: Misty-Neb 52.3 ⴞ 0.6%, SideStream 63.4 ⴞ
`3.0%, Pari LCD 62.5 ⴞ 4.0%, Circulaire 75.8 ⴞ 0.5%, and AeroEclipse 51.0 ⴞ 2.1%. Duration of nebuli-
`zation was shortest with the Circulaire and longest with the AeroEclipse (p < 0.05 via 1-way analysis of
`variance). CONCLUSIONS: The nebulizers we tested differ significantly in overall drug disposition. The
`dosimetric AeroEclipse provided the largest inhaled drug mass and the lowest loss to ambient air, with the
`test conditions we used. Key words: nebulizers; aerosols, drug therapy; drug administration, inhalation; respi-
`ratory drug administration. [Respir Care 2004;49(2):174–179. © 2004 Daedalus Enterprises]
`
`Introduction
`
`Gas-powered jet nebulizers are commonly used for de-
`livering medications in the clinical and home-care settings.
`
`Joseph L Rau PhD RRT FAARC, Arzu Ari MSc CRT CPFT, and Ruben
`D Restrepo MD RRT are affiliated with Cardiopulmonary Care Sciences,
`Georgia State University, Atlanta, Georgia.
`
`Arzu Ari MSc CRT CPFT presented a version of this report at the
`American Association for Respiratory Care OPEN FORUM at the 47th
`International Respiratory Congress, held December 1–4, 2001, in San
`Antonio, Texas.
`
`Correspondence: Joseph L Rau PhD RRT FAARC, Cardiopulmonary
`Care Sciences, MSC 8R0319, Georgia State University, 33 Gilmer Street
`SE, Unit 8, Atlanta GA 30303. E-mail: jrau@gsu.edu.
`
`Over the past few years nebulizer design changes have
`created nebulizer categories, termed constant-output,
`breath-enhanced, and dosimetric.1 Constant-output nebu-
`lizers are the traditional T-piece nebulizers that generate
`aerosol constantly, during the inhalation, exhalation, and
`breath-hold. With constant-output nebulizers some of the
`aerosol is lost during exhalation, which causes release of
`aerosol to the ambient air through the expiratory limb of
`the T-piece.2– 4 Constant-output nebulizers have been crit-
`icized as unreliable and inefficient, because a low percent-
`age of the dose reaches the patient.5–7 A length of large-
`bore tubing is usually attached to the expiratory side of the
`constant-output nebulizer T-piece, to reduce drug loss and
`increase the inhaled amount.8 –9
`Breath-enhanced nebulizers are designed to allow re-
`lease of more aerosol during inhalation, when ambient air
`
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`PERFORMANCE COMPARISON OF NEBULIZER DESIGNS
`
`is drawn through the nebulizer.9 During exhalation, gas
`flow through the nebulizer falls back to the power-gas
`flow only, exhaled gas is routed out the expiratory valve in
`the mouthpiece, and aerosol is contained in the nebulizer
`chamber. Examples of breath-enhanced nebulizers include
`Pari LC Plus and Pari LCD. Coates et al10 and Dennis11
`found better drug output with breath-enhanced nebulizers.
`Dosimetric nebulizers release aerosol only during inha-
`lation.1 The Circulaire represented an early attempt to con-
`vert a constant-output nebulizer to a dosimetric device, by
`attachment of a storage bag with a 1-way valve in the
`mouthpiece connector.12,13 A recently introduced nebu-
`lizer, the AeroEclipse, has a breath-actuated valve that
`triggers aerosol generation only during inhalation, elimi-
`nating the need for a storage bag or reservoir.
`Theoretically, both breath-enhanced and dosimetric
`nebulizers would have reduced or no aerosol loss during
`exhalation. However, although there may be reduced ex-
`halation loss of aerosol, does the emitted drug amount in
`fact increase, or is there a shift in the location of lost
`aerosol, from exhaled/ambient to device? With the Circu-
`laire does the storage of aerosol increase or decrease the
`inhaled drug? We found no studies of all 3 categories of
`nebulizer, including the Circulaire, using the same set of
`realistic breathing conditions14 and that characterized the
`total drug disposition, including emitted drug, device loss,
`and exhaled/ambient drug loss. The purpose of the present
`study was to evaluate in vitro the total drug disposition of
`constant-output, breath-enhanced, and dosimetric nebuliz-
`ers, using simulated normal adult breathing.
`
`Methods
`
`Study Design
`
`The nebulizer brands tested were AirLife Misty-Neb
`(Allegiance Healthcare, McGaw Park, Illinois), AirLife
`SideStream (Allegiance Healthcare, McGaw Park, Illinois),
`Circulaire (Westmed, Tucson, Arizona), Pari LCD (PARI
`Respiratory Equipment, Monterey, California), and Aero-
`Eclipse (Monaghan Medical, Plattsburgh, New York). The
`Misty-Neb and SideStream are traditional constant-output
`nebulizers. The Pari LCD is a breath-enhanced nebulizer.
`The Circulaire and AeroEclipse were considered dosimet-
`ric devices, based on Dennis’s definition.1 The Circulaire
`was tested with the supplied nebulizer. Figure 1 shows the
`principle of operation of each nebulizer brand tested.
`Three of each of the 5 nebulizer brands were tested,
`using a simulated normal adult breathing pattern. Each
`device nebulized a unit-dose of albuterol sulfate solution,
`2.5-mg base equivalent (Proventil, Schering, Kenilworth,
`New Jersey), with a 3 mL total fill volume. No additional
`diluent was added to any nebulizer. All the nebulizers
`were powered by 50-psi oxygen at 8 L/min.
`
`Lung Model
`
`The nebulizers were connected to a breathing simulator
`(Series 1101, Hans Rudolph, Kansas City, Missouri), which
`provides a complete breathing cycle with both inhalation and
`exhalation phases. Tidal volume was set at 600 mL, inhala-
`tion flow at 30 L/min, and respiratory rate at 12 breaths/min,
`giving a 1:3 inspiratory-expiratory ratio. Figure 2 shows the
`equipment configuration. An induction port (throat) (Thermo
`Andersen, Franklin, Massachusetts), as described in the United
`States Pharmacopeia (USP) for use with cascade impactor
`testing,15 was placed between the nebulizer outlet and the
`breathing simulator. The throat, which has a diameter of ap-
`proximately 19 mm and a right angle, was used as a simple
`geometric analogue of the upper airway, to allow inertial
`impaction of larger aerosol particles. This allowed a stan-
`dardized basis for comparison of inhaled aerosol from each
`nebulizer tested. A filter (2-way nonconductive anesthesia
`filter, Baxter Healthcare, Deerfield, Illinois) was attached to
`the distal end of the throat, between the throat and the breath-
`ing simulator. We defined the total inhaled drug mass as the
`amount in the throat plus the filter.
`In cascade impactor testing the throat is placed verti-
`cally, but in our experiments the throat was placed hori-
`zontally to prevent the inhalation filter from collecting
`drug that might condense on the throat wall and then drip
`onto the inhalation filter. The mouthpieces were removed
`from the 2 constant-output nebulizers (Misty-Neb and Side-
`Stream) and the T-piece was connected directly to the
`throat and the breathing simulator. A 15-cm length of
`large-bore corrugated tubing, as supplied by the nebulizer
`manufacturer, was attached to the exhalation outlet of the
`T-piece, and exhaled drug was collected by a filter at the
`end of the tubing (see Fig. 2).
`The breath-enhanced Pari LCD, which is a disposable unit,
`has a nonvalved opening at the top of the chamber and open
`exhalation ports in the mouthpiece (see Fig. 1). With the Pari
`LCD we placed exhalation filters at the chamber top and at the
`outlet of a T-piece, which replaced the mouthpiece (see Fig. 2).
`The Circulaire contains a 1-way valve in the nebulizer T-piece,
`which directs aerosol toward the mouth. There is also an exha-
`lation port with a size-adjustable opening between the 1-way
`inspiratory valve and the mouthpiece (see Fig. 1). An exhalation
`filter was attached to the exhalation port, with maximum open-
`ing; the T-piece assembly, without the mouthpiece, was attached
`to the throat and breathing simulator (see Fig. 2). The Aero-
`Eclipse has a 1-way exhalation flapper valve integrated into the
`mouthpiece assembly. An inhalation flow of approximately 6
`L/min causes the spring-loaded valve to engage and generate
`aerosol (see Fig. 1). The mouthpiece was replaced with a T-
`piece, and an outwardly directed 1-way valve was added to the
`exhalation outlet of the T-piece so that inhalation flow came
`from the nebulizer and allowed breath-actuated triggering of the
`nebulizer (see Fig. 2).
`
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`

`PERFORMANCE COMPARISON OF NEBULIZER DESIGNS
`
`Fig. 1. Functional diagrams of the 5 nebulizer brands tested, illustrating principle of operation and patterns of gas flow during inhalation and
`exhalation.
`
`Measurement of Drug
`
`In each nebulizer trial the total aerosol drug mass was
`measured and consisted of the total inhaled drug mass,
`exhaled/ambient drug loss, and drug lost in the device.
`We also measured drug remaining in the unit-dose bot-
`tle. The total inhaled drug mass was divided into drug
`collected in the throat and drug from the collecting filter
`attached to the throat outlet. Exhaled drug was collected
`on a filter attached to the exhalation outlet of the neb-
`ulizer. The drug remaining in the nebulizer apparatus
`(including adapters, T-piece, and mouthpiece) was col-
`lected by washing, and analyzed. Each nebulizer was
`weighed empty, after filling, and at the end of nebuli-
`zation, to calculate the volume left, as described by
`Coates et al.10 Solvent was added to the calculated vol-
`ume, drug concentration was then determined by spec-
`trophotometry, and the drug mass was calculated. Each
`nebulizer was operated until the onset of sputter, with
`no tapping of the nebulizer (as is usually done when
`
`administering aerosol to a patient), and the time to sput-
`ter was recorded with a stopwatch. All drug amounts
`were analyzed via spectrophotometry (Beckman Instru-
`ments, Fullerton, California), at a wavelength of 276
`nm. The solvent was 0.1 molar normal hydrochloric
`acid (JT Baker Company, Phillipsburg, New Jersey).
`Collecting filters were washed for 1 min with gentle
`agitation. Longer washing did not yield additional drug.
`Measurements with 2 filters in series verified that no
`drug was lost through the first filter. The spectropho-
`tometer was calibrated prior to trials, using a holmium
`oxide filter (Beckman Instruments, Fullerton, Califor-
`nia) to determine wavelength accuracy, and set to zero
`using the solvent alone before each analysis. A regres-
`sion curve and prediction equation were developed from
`serial dilutions of known albuterol sulfate solution
`(Sigma, St Louis, Missouri). Concentrations of sample
`solutions, and thereby drug amounts of albuterol, were
`calculated from this known concentration/absorbance
`relationship.
`
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`PERFORMANCE COMPARISON OF NEBULIZER DESIGNS
`
`Fig. 2. Setup for nebulizer performance testing. Right Panel: Configuration for the constant-output nebulizers (Misty-Neb and SideStream).
`Left Panels: Configurations for the Pari LCD, Circulaire, and AeroEclipse. NEB ⫽ nebulizer. Tee ⫽ T-piece.
`
`Data Analysis
`
`Means and standard deviations were calculated for each
`component of the total drug mass and for time of nebuli-
`zation. Differences between the total inhaled mass and the
`inhalation-filter mass (ie, total inhaled drug minus drug
`deposited in the throat) were compared with 1-way anal-
`ysis of variance. Differences were considered statistically
`significant when p ⬍ 0.05. Multiple follow-up compari-
`sons to identify differences among nebulizers were per-
`formed using Scheffe´’s S method.16 All statistical calcu-
`lations were performed using commercially available
`software (SYSTAT 7.0, SPSS, Chicago, Illinois).
`
`Results
`
`Table 1 shows the dose disposition results, expressed as
`percentages of total drug recovered from the throat, inha-
`lation filter, exhalation filter, nebulizer apparatus, and drug
`remaining in the unit-dose bottle. The mean ⫾ SD total
`drug mass of albuterol sulfate recovered from all sources
`and expressed as the base was 2.56 ⫾ 0.09 mg, which
`corresponds well to the 2.5-mg nominal dose of the unit-
`dose albuterol nebulizer solution we used.
`
`The percentage of total inhaled drug mass differed sig-
`nificantly (by 1-way analysis of variance) among the 5
`nebulizer brands tested (p ⫽ 0.0001). Table 1 shows which
`groups of individual brands did not significantly differ
`from each other (homogeneous subsets), based on fol-
`low-up comparisons. The total inhaled drug obtained from
`the constant-output nebulizers, Misty-Neb and SideStream,
`was similar to that from the breath-enhanced Pari LCD,
`ranging from 15% to 17%. The 2 nebulizers considered
`dosimetric (Circulaire and AeroEclipse) differed from each
`other, and the Circulaire differed from the Misty-Neb. The
`inhaled drug mass from the Circulaire was approximately
`half that of the constant-output and breath-enhanced nebu-
`lizers, whereas the inhaled mass of the AeroEclipse was
`about 2.5 times greater than the constant-output and breath-
`enhanced nebulizers.
`The inhalation filter mass differed significantly (by
`1-way analysis of variance) among the 5 nebulizer brands
`(p ⫽ 0.0001). Table 1 shows groups of brands that did not
`significantly differ from each other, based on follow-up
`comparisons. The dosimetric nebulizers (Circulaire and
`AeroEclipse) had the least exhaled drug loss: approxi-
`mately 7–12%. The duration of nebulization also differed
`significantly among the nebulizers (p ⫽ 0.0001).
`
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`

`PERFORMANCE COMPARISON OF NEBULIZER DESIGNS
`
`Table 1. Aerosol Deposition and Loss, and Nebulization Time With 5 Nebulizer Brands*
`
`Total inhaled (%)
`Inhalation filter (%)
`Exhaled to ambient (%)
`Deposited in nebulizer apparatus (%)
`Remained in unit-dose bottle (%)
`Nebulization time (min)
`
`Misty-Neb
`
`17.2 ⫾ 0.4†
`14.4 ⫾ 0.5†§
`26.8 ⫾ 0.7
`52.3 ⫾ 0.6
`3.7 ⫾ 1.1
`11.9 ⫾ 0.3
`
`SideStream
`
`15.8 ⫾ 2.8†‡
`14.7 ⫾ 2.7†
`17.3 ⫾ 0.4
`63.4 ⫾ 3.0
`3.6 ⫾ 0.5
`9.5 ⫾ 0.1
`
`Pari LCD
`
`15.2 ⫾ 4.2†‡
`13.3 ⫾ 4.2†§
`18.3 ⫾ 0.8
`62.5 ⫾ 4.0
`4.1 ⫾ 0.6
`8.4 ⫾ 1.2
`
`Circulaire
`
`8.7 ⫾ 1.0‡
`7.4 ⫾ 1.0§
`12.3 ⫾ 0.8
`75.8 ⫾ 0.5
`3.0 ⫾ 0.4
`7.0 ⫾ 0.5
`
`AeroEclipse
`
`38.7 ⫾ 1.3
`34.2 ⫾ 1.3
`6.6 ⫾ 3.1
`51.0 ⫾ 2.1
`3.7 ⫾ 0.6
`14.4 ⫾ 1.1
`
`*The percent values represent percent of total dose. The inhalation filter percentage is a subset of the total inhaled percentage: specifically, the inhalation filter percentage equals the total inhaled
`minus the amount deposited in the throat. Subsets of nebulizer brands with no significant differences (p ⬍ 0.05) based on follow-up comparisons are indicated for total inhaled percentage and
`inhalation filter percentage. Nebulization time was until sputter.
`†No significant difference between Misty-Neb, SideStream, and Pari LCD
`‡No significant difference between SideStream, Pari LCD, and Circulaire
`§No significant difference between Misty-Neb, Pari LCD, and Circulaire
`
`Discussion
`
`The focus of the present study was to measure drug
`disposition with different nebulizer design categories tested
`under the same conditions. We found differences among
`the nebulizers in total inhaled mass of aerosolized bron-
`chodilator and in the location and amounts of aerosol drug
`lost to ambient air and to the nebulizer apparatus. Though
`the total inhaled drug mass was similar for the constant-
`output (Misty-Neb and SideStream) and the breath-
`enhanced (Pari LCD) nebulizers, the 2 dosimetric nebu-
`lizers differed in opposite directions. The Circulaire had
`the lowest and the AeroEclipse the highest inhaled mass of
`all the devices tested. We hypothesize that greater appa-
`ratus drug loss in the Circulaire’s bag storage system ac-
`counts for the smaller inhaled mass. With the AeroEclipse
`the apparatus drug loss was similar to the Misty-Neb, but
`inhalation-only aerosol generation shifted aerosol from ex-
`haled to inhaled. Both the Circulaire and the AeroEclipse
`lost less to the ambient air, as expected, based on their
`design and function. The Circulaire contains aerosol dur-
`ing the exhalation phase, and the AeroEclipse’s breath-
`actuation limits aerosol generation to the inhalation phase.
`With breath-actuation, exhaled/ambient loss from the Aero-
`Eclipse was half that of the Circulaire.
`We could find only 1 study, in the form of an abstract,
`by Hess et al, that tested the same nebulizers under a
`uniform set of breathing variables to allow direct compar-
`ison of nebulizer performance.17 Their study measured to-
`tal nebulizer output of albuterol and calculated fine parti-
`cle mass from particle size measurements. They did not
`measure exhaled or nebulizer apparatus drug loss. The fine
`particle mass output was greatest with the AeroEclipse and
`least with the Circulaire. The Pari LCD, SideStream, and
`Misty-Neb were intermediate between the AeroEclipse and
`Circulaire. That is the same order of output found in our
`study for total inhaled mass and for inhalation filter mass
`(total inhaled mass minus throat loss).
`
`Other studies have measured drug output from one or
`several of the nebulizers tested in our study, using various
`breathing conditions. Our measurements of inhaled drug
`mass from the constant-output SideStream agree well with
`Dennis’s in vitro research on the SideStream.11 Devadason
`et al measured inhaled drug mass from a Pari LC, using
`volunteers and filter collection at the mouth.9 They found
`19% for the total inhaled drug, which is higher than the
`15% in our study of the Pari LCD with simulated breath-
`ing. That difference may be due to design differences among
`Pari models, notably between the Pari LC Plus, a nondis-
`posable, reusable unit, and the Pari LCD, a disposable
`unit. The Pari LC Plus has a 1-way valve in the top of the
`nebulizer chamber, which allows ambient air to be en-
`trained during inhalation, with no loss of aerosol on ex-
`halation. The LCD has a simple opening with no valve in
`the top of the nebulizer chamber, and we observed visible
`loss of a small amount of aerosol through that opening
`during exhalation. The Pari LC Plus also has a 1-way
`flapper valve in the mouthpiece, whereas the Pari LCD has
`simple nonvalved openings on either side of the mouth-
`piece. Design differences may also account for the differ-
`ence in exhaled loss between our study (18%) and the
`study by Dennis, who found approximately 11% exhaled
`loss with the Pari LC Plus.11
`Inhaled drug from a breath-enhanced nebulizer also in-
`creases or decreases as a function of inhalation flow.18
`Measuring inhaled mass at a single flow with the Pari
`LCD, as we did, could be seen as limiting, but our peak
`inhalation flow corresponded to the highest uniform flow
`in a study by Knoch et al of the Pari IS-2; this was also the
`flow that gave the highest emitted drug mass in their study.18
`The effect of variable flow or different inhalation wave-
`forms (eg, uniform flow versus a sine waveform) with
`breath-enhanced nebulizers requires further investigation.
`The Circulaire represents an adaptation of a constant-
`output nebulizer to create a dosimetric device, if we accept
`Dennis’s definition of dosimetric as a nebulizer that re-
`
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`PERFORMANCE COMPARISON OF NEBULIZER DESIGNS
`
`leases “aerosol only during the inhalation cycle” and that
`makes “all released aerosol available for patient inhala-
`tion.”1 In an vitro study of the Circulaire, using albuterol,
`Piper found an emitted drug mass of 0.32 ⫾ 0.01 mg,13
`which is approximately 13% of the nominal dose of 2.5
`mg albuterol, compared to 8.7 ⫾ 0.99% found in our
`study. That difference may be due to the fact that in Pip-
`er’s study emitted drug on inhalation was not directly mea-
`sured but rather calculated based on intermittent sampling.
`Measures of drug mass lost in the constant-output and
`breath-enhanced nebulizers have ranged between 55% and
`66% in a number of studies.5,9,11,19,20 That range agrees
`well with the 52– 63% apparatus loss we found for those
`types of nebulizers. Our measurement of drug remaining
`in the AeroEclipse (51%) was identical to that reported by
`Fink et al.21
`A limitation in the present study was the use of the USP
`throat as a simple model of the upper respiratory tract,
`rather than measuring particle size distribution and the fine
`particle fraction. The USP throat was designed to capture
`the large and high-velocity aerosol particles emitted from
`a metered-dose inhaler, when testing at a constant flow of
`approximately 30 L/min. The throat has also been adopted
`by the USP as a model throat for testing dry powder in-
`halers,15 in the testing of which the flow varies through the
`throat, with the testing conditions prescribed in the USP,
`Chapter 601, on aerosols. With a dry powder inhaler there
`is no high-velocity, large-particle fraction, as there is with
`a metered-dose inhaler.15 The measurements of throat loss
`in our study do not represent a certain particle size nor
`provide an estimate of the fine particle mass that could
`reach the lower respiratory tract. Our use of the throat
`provides a standard model for the comparative evaluation
`of nebulizer designs. Based on the mechanism of inertial
`impaction, which is a function of particle mass and veloc-
`ity, we would expect the model throat loss (the difference
`between the total inhaled mass and the inhalation filter
`mass) to be a very approximate measure of larger aerosol
`particles. Measurements of fine particle fractions have been
`reported elsewhere for the Misty-Neb,17 SideStream,11,17
`Pari LC Plus,11 Pari LCD,17 Circulaire,13,17 and Aero-
`Eclipse.17
`
`Conclusions
`
`Our results indicate that design differences among nebu-
`lizers affect drug disposition in inhaled mass, apparatus
`loss, and exhaled/ambient loss. Use of reservoir systems to
`store aerosol during the exhalation phase can cause large
`apparatus losses and thus decrease inhaled mass, whereas
`generating aerosol only during inhalation (ie, breath-actu-
`ated nebulization) increases inhaled mass and decreases
`ambient drug loss. Clinical comparisons are necessary to
`
`determine if these differences substantially affect clinical
`outcomes.
`
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