UL
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`DECEMBER 2002
`
`VOLUME 47
`
`‘NUMBER 12
`ISSN 0020-1324-HECACP
`
`
`
`
`_ REIPIRATORU
`CARE :
`
`
`A MONTHLY SCIENCE JOURNAL
`47TH YEAR—ESTABLISHED 1956
`
`SPECIAL ISSUE
`
`LIGUID NEBULIZATIGN:
`EMERGING TECHNOLOGIES
`PART II
`
`CONFERENCE PROCEEDINGS
`
`- Nebulizers That Force Pressurized
`
`Liquids Through Nozzles
`
`- Nebulizers That Use a Vibrating Mesh or
`Plate with Multiple Apertures
`
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`were:E3431MOLSEM
`
`- The Electrospray and Its Application to
`Targeted Drug Inhalation
`
`- Smart Nebulizers
`
`- Standardization Issues in Assessing
`Nebulizer Performance
`
`* The Future of Nebulization
`
`- Conference Summary
`
`IPR2021-00406
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`

`

`Standardization Issues: In Vitro Assessment of Nebulizer Performance
`
`John H Dennis PhD MSC
`
`Introduction
`Standardization Issues
`European Nebulizer Standard
`Nebulizer Versus Nebulizer System
`Measuring Aerosol Output and Aerosol Droplet Size Using the Methods in
`the European Standard
`Aerosol Output
`Aerosol Particle Size
`Clinical Relevance of the European Standard in Vitro Methods
`European Respiratory Society Guidelines on the Use of Nebulizers
`Type Testing Using the European Standard
`Characteristics of “Good” and “Bad” Nebulizer Systems
`How to Select the Optimal System for a Given Patient Group or Specific Use
`Implementation and Use of Standard Operating Practice As a Means to
`Improve the Efficacy of Nebulizer Therapy
`Standardize the Way Current Nebulizer Systems Are Used
`Assess Drug Output from the Current Nebulizer System
`Evaluate Alternative Nebulizer Systems
`Future Developments in Nebulized Drug Delivery
`Summary
`
`The delivery of nebulized drugs is poorly controlled and the choice of the most appropriate delivery
`device is poorly understood, particularly because of off-license prescriptions and a lack of evidence-
`based medicine. Standardized in vitro methods for measuring nebulizer performance have been
`adopted in Europe, by the 2001 publication of a European Standard, prEN13544—1. These stan-
`dardized methods were subsequently incorporated within the European Respiratory Society neb-
`ulizer guidelines, which will provide clinicians with useful information to improve nebulizer ther-
`apies. Standards for measuring nebulizer performance should be considered in North America and
`elsewhere. Careful consideration should be given to either adopting the methods embodied in the
`European Standard or developing the basis for developing that standard further through the
`International Standards Organization. Either way, confusion among clinicians would be reduced
`and nebulizer safety and aerosol delivery efficiency increased by standardizing in vitro methods of
`nebulizer performance assessment. Key words: nebuliz‘er, nebulization, aerosol, standard, standard—
`ization, testing, Europe, International Standards Organization, ISO, Comité Européen de Normalisation,
`CEN,
`in vitro assessment.
`[Respir Care 2002;47(12):l445—1455]
`
`Introduction
`
`Although delivering nebulized drugs to the lungs has
`been used for centuries in medical research, and nebulizers
`
`John H Dennis PhD MSC is affiliated with the Department of Environ—
`mental Science, University of Bradford, Bradford, West Yorkshire, United
`Kingdom.
`
`John H Dennis PhD MSc presented a version of this report at the 30th
`RESPIRATORY CARE Journal Conference, Liquid Nebulization: Emerging
`Technologies, held June 28—30, 2002, in Montreal, Quebec, Canada.
`
`Correspondence: John H Dennis PhD MSc, Department of Environmen-
`tal Science, University of Bradford, Bradford, West Yorkshire, United
`Kingdom, BD7 IDP. Eimail: j.h.dennis@bradford.ac.uk.
`
`and nebulizer drugs have been commercially available
`throughout the past century,1 the delivery of nebulized
`drugs is still poorly controlled and poorly understood by
`the clinical community.
`Prescription drugs delivered orally, intravenously, and
`via aerosol inhalation from metered-dose inhalers and dry
`powder inhalers undergo clinical trials to prove the drug’s
`safety and efficacy. This is not the case with the many
`drugs used for nebulization, which are prescribed off—1i—
`cense and bypass regulatory requirements. Nebulizers are
`regarded as cheap and convenient plastic devices that
`readily generate an aerosol (Fig. 1) that will contain what—
`ever drug solutions or suspensions are placed in them for
`delivery to the respiratory tract. Rarely is the nebulizer
`delivery device specified on the prescription. Rather, only
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`STANDARDIZATION ISSUES: IN VITRO ASSESSMENT OF NEBULIZER PERFORMANCE
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`
`
`Fig. 1. A typical jet nebulizer, showing release of aerosol.
`
`the drug solution volume and concentration are specified.
`This leaves open the choice of nebulizer by which to de-
`liver the off—license drug aerosol. The decision of what
`device to use is often left up to the local doctor or nurse,
`and sometimes even a hospital clerk, to choose whatever
`device is either conveniently to hand or has become the
`hospital’s standard nebulizer for that period. The nebulizer
`is often chosen with little or no objective justification other
`than the manufacturer’s performance claims or, more of-
`ten, simply the lower cost of a particular nebulizer. The
`reader should recognize that there is a wide range Of per—
`formance among nebulizers. If, say, 2 mL of a given drug
`solution was placed into all available nebulizers, the dose
`delivered could vary greatly.2 The lack of regulation and
`understanding in matching the prescribed drug with the
`nebulizer implies that the quality, consistency, and control
`of the delivered dose are poor.
`There are 2 main types of nebulizer, jet (or pneumatic)
`and ultrasonic, which have different operating character—
`istics (recently reviewed by Hess3) and can be described in
`terms of their overall performance as either constant—out-
`put, breath—enhanced, or dosimetric.2 Each nebulizer brand
`has specific characteristics that determine its aerosol out—
`put, including total rate of aerosol output, rate of aerosol
`delivered to the patient, dead volume (solution remaining
`in the nebulizer after nebulization has ceased), and particle
`Size characteristics. Some nebulizers are most efficient at
`delivering small droplets to the peripheral lung, some nebu-
`
`lizers are better suited to deliver larger particles in the
`upper airways, and, in my opinion, some nebulizers are not
`suited to drug aerosol delivery at all. But how is the cli-
`nician to know Which nebulizer tO use for which patient?
`What criteria can the clinician use to make an informed
`decision?
`
`Many methods have been described to measure the “per-
`formance” of particular nebulizer designsflv5 For instance,
`measurement of aerosol output using weight loss has been
`undertaken for decades and is still commonly used. How-
`ever, weight loss measures both aerosol output and evap-
`orated solvent, and evaporated solvent typically accounts
`for half of the weight loss over a nebulization period. In
`some particularly inefficient nebulizers, evaporation can
`account for more than 75% of the weight loss.6 Alterna-
`tively, total aerosol output can be estimated by measuring
`the amount of drug solution left in the nebulizer cup. This
`method can provide a measure of the total drug aerosol
`emitted and is not confounded by evaporative losses, but it
`does not reflect the aerosol delivered to the patient, as
`most nebulizers commonly allow inhalation of only
`40—70% of the emitted dose. There is a similar problem
`with methods that collect all emitted aerosol on a filter,
`followed by subsequent analysis of the filtered residue.
`Though all these methods produce data, the results cannot
`reflect the in vivo situation. This, in my opinion, makes
`them weak methods on which to base a nebulizer Standard,
`as the results are divorced from the clinical setting.
`Measuring aerosol particle size is equally confusing.
`Cascade impactors, which are commonly used to measure
`aerosol particle size from metered-dose inhalers and dry
`powder inhalers, can drastically distort the aerosol size by
`causing full evaporation Of the nebulized aerosol. Laser
`diffraction (scattered light) size measurement of aerosol
`droplets cannot take into account droplet evaporation, which
`is inherent in all constant—output aerosol designs. For both
`aerosol output and aerosol droplet size many different re-
`sults are possible from the same nebulizer, depending on
`the measurement method used.
`The relative merits Of the various methods to assess in
`vitro nebulizer performance have been debated in the lit-
`erature for decades, often by individuals or small groups
`with greater or lesser amounts of training in aerosol and
`clinical sciences. From all the different views one common
`message emerges, namely that the method used should
`reflect the amount and droplet size of aerosol received by
`the patient.7 In other words, the in vitro test should reflect
`the in vivo dose delivered. However, though that is a com-
`monly held objective, over the past 50 years researchers
`have not naturally regressed to a commonly accepted neb-
`ulizer test method. And because nebulized drugs have es—
`caped regulatory control, no national or international body
`had been commissioned to examine the science and pro—
`duce standard methods. Or at least that was the situation
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`STANDARDIZATION ISSUES: IN VITRO ASSESSMENT OF NEBULIZER PERFORMANCE
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`until the early 19905, when the United Kingdom’s stan-
`dards body made the first attempt at standardizing test
`methods, by publishing a British Standard“)9 Though the
`British Standard methods had limitations (Table l) the
`existence of the published standard became a focal point
`for debate and progress. In the late 19905 the issue of
`standardizing in vitro methods to assess nebulizer perfor-
`mance was tackled more comprehensively by the Euro—
`pean Standards Organization (Comité Européen de Nor-
`malisation or CEN), culminating in the research and
`development of new nebulizer in vitro test methods pub-
`lished as a European Standard.10
`The present review summarizes standardization issues
`inherent in the in vitro measurement of nebulizer perfor-
`mance, describes the scientific and clinical principles un-
`derlying the European Standard, introduces the principles
`underlying the clinical nebulizer guidelines recently pub-
`lished by the European Respiratory Society, and describes
`how the European Respiratory Society adopted the stan—
`dard testing methods of the European Standard.
`
`Standardization Issues
`
`There may be a perception that “standardization” could
`be interpreted as making things the same: making them a
`standard size, shape, color, or, in the case of nebulizers,
`similar in terms of performance, as measured by aerosol
`output and aerosol droplet size. That is not the intended
`meaning of standardization in this review.
`There are many types, designs, and brands of nebulizer,
`with a great range of aerosol output and droplet size. I
`regard this as a good thing, because different drug solu—
`tions and suspensions are targeted to different parts of the
`airways, in different doses. Therefore different nebulizer
`
`designs are needed for different patients and settings (pe—
`diatric versus adult, intensive care versus home care), with
`different delivered aerosol doses and different droplet sizes
`required for different patients and therapies. Thus a wide
`range of nebulizer designs and performances are needed,
`ideally with each nebulizer medication being matched to a
`particular window of nebulizer performance. However, dif-
`ficulty arises when clinicians are faced with numerous
`devices and manufacturer claims of performance character-
`istics. How should a clinician make the choice of what neb-
`
`ulizer system is best Suited to a particular patient or patient
`group for effective delivery of a particular medicine?
`In choosing the ideal nebulizer to deliver a particular
`drug, the clinician Should take into account the intended
`site of aerosol deposition (upper and/or lower respiratory
`tract), which largely determines the required aerosol drop-
`let size, depending on the patient’s age and disease state,
`desired dose, treatment time, and patient compliance with
`the treatment. In addition, cost constraints can limit the
`choice of nebulizer. At present a major difficulty is that
`information on nebulizer performance is not presented to
`the clinician in any meaningful way.
`Information on nebulizer output and aerosol droplet size
`can be entirely absent or only loosely described in mar-
`keting jargon (cg, “best performing nebulizer,” “clinically
`proven,” “preferred by over 90% of users”) without any
`scientific justification of the claims. Of course not all neb-
`ulizer manufacturers are so vague in describing the per-
`formance of their devices. Many manufacturers actively
`promote, or at least have available, technical literature on
`their devices. However, those performance data can be
`obtained with a wide variety of laboratory methods. HOW—
`ever well-informed the clinician, performance data are very
`dependent on the method by which they were obtained—so
`
`Strengths
`First formal national standard relating to jet nebulizers
`
`Strengths and Weaknesses of British Standard 7711, Part 3, Specification for Gas—powered Nebulizers for the Delivery of Drugs
`Table l.
`Comment
`Focused attention on assessment of nebulizer performance and provided a
`platform for debate and technical research and development.
`Standard practice relied on weight loss, which grossly overestimated true aerosol
`output because of concurrent evaporation to compressed and ambient air.
`
`Adopted a chemical tracer rather than weight loss to
`evaluate nebulizer performance
`
`Weaknesses
`No use of breathing pattern in assessing inhaled
`aerosol
`Does not extend to ultrasonic nebulizers
`
`This is particularly important for assessing the performance of breath—enhanced
`and dosimetric nebulizer designs.
`Modern designs of ultrasonic nebulizers (eg, Omron nebulizer) have solved many
`past technical limitations and are expected to become more common as their
`advantages are recognized in the health care market.
`Laser sizing takes no account of solute concentrating effects, particularly in the
`smaller particles, and provides a volume/size distribution invariably larger than
`the solute size (dry particles) distribution, which is of far greater clinical
`relevance and interest.
`Applies laser diffraction to size a “standing cloud"
`Ncbulizer aerosols rapidly evaporate in ambient air, such as the air entrained over
`
`constant-output nebulizers or through breath-enhanced nebulizers.
`
`Relies on laser diffraction to estimate particle size
`
`
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`STANDARDIZATION ISSUES: IN VITRO ASSESSMENT OF NEBULIZER PERFORMANCE
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`much so that the data may be meaningless, as with aerosol
`output measured by weight loss ‘or solute loss, with or
`without breathing simulation. Yet that is usually the only
`type of information the clinician is expected to use in
`deciding about off—license nebulization of a drug. It is
`difficult if not impossible for the average clinician, who is
`not an expert in nebulizer design and function, to make an
`informed decision on which device is best for which pa—
`tient. For that reason the focus in‘ this review is to persuade
`the reader that some amount of standardization of in vitro
`aerosol measurement methods is desirable. Such standard-
`ization would provide a’ commonly derived data set for all
`nebulizer designs, which would (I) be more easily inter—
`preted than the type of data currently available, (2) help
`clinicians determine the most appropriate nebulizers for
`particular patients and patient groups, and (3) improve
`patient safety and aerosol delivery efficiency.
`At the risk of laboring the point for the need for stan—
`dardizing nebulizer performance testing, consider the fol-
`lowing analogy with the automobile industry. Cars come
`in a range of shapes and sizes and are intended for differ—
`ent purposes. Most car buyers know what basic désign
`they require, but choosing the exact brand and model can
`be difficult. Like nebulizers, the manufacturer’s marketing
`information is invariably biased toward its own product.
`Though this may make interesting reading for the enthu—
`siast, it should not be relied upon for an objective decision.
`We can rely on reviews by experts who offer their opin-
`ions on subtle differences between models, but those views
`are individual and invariably biased by previous preju—
`dices and current affiliations. Consider the information
`available for estimating fuel economy. If this important
`performance criterion were left solely up to the manufac-
`tures to provide,
`they would no doubt as an industrial
`group regress to making the measurement starting from
`the top of a mountain with a tailwind in order to bias the
`fuel economy figure as far as possible. That does not hap-
`pen because standardized test methods for fuel economy
`have been developed to gain more realistic and compara-
`ble data. We must rely on objective information supplied
`by standardized methods to make an objective and fully
`informed decision. For example, data on trunk (called
`“boot” in the United Kingdom) space, acceleration,
`ser—
`vicing costs, and depreciation are independently obtained.
`The methods for obtaining these data are refined to be as
`realistic and repeatable as practicable. Data that prove un—
`realistic are of little use. Methods that cannot be repeated
`are of little value. What is true for the automotive industry
`and marketplace is largely true for the nebulizer industry
`and marketplace.
`To date there has been little, if any, standardization in
`the nebulizer industry and marketplace. I believe the in—
`dustry would welcome standardization, as would most cli-
`nicians and nebulizer Users. Standardization of in vitro
`
`performance measures would improve patient safety and
`aerosol delivery efficiency, and, in the long term, Stan—
`dardization can help provide a more solid foundation for
`develOpment of better nebulizer technologies, because man—
`ufacturers will know that the marketplace is better pre—
`pared to recognize and appreciate the real benefits of new
`technologies. At present if a manufacturer produced a bet»
`ter nebulizer, how would the clinician know? It would just
`be absorbed into the marketplace as yet another “best per—
`formance” nebulizer claim, with perhaps a few supporting
`papers written by individuals with personal bias and affil—
`iation. It is for these reasons that some standardization is
`
`required.
`
`European Nebulizer Standard
`
`The European Standard developed over a period of 6
`years, involving all European national standards bodies
`(eg, United Kingdom’s British Standards Institution, Neth—
`erlands Organization for Applied Scientific Research)
`working within CEN, the European umbrella organization.
`Most scientists and clinicians with a serious interest in
`
`nebulizer testing and clinical application were involved,
`either directly or indirectly. For the first time, a critical
`mass of clinical and scientific experts were brought to—
`gether to focus on how best to standardize the measure-
`ment of nebulizer performance. Though the European Stan-
`dard on nebulizers addresses a number of regulatory issues,
`most are beyond the scope of the present review. What is
`important here is that the European Standard facilitated the
`development of in vitro testing methodologies that were
`thoroughly discussed and evaluated prior to acceptance by
`the European clinical and sCientific aerosol community.
`Aspects of the European Standard have been described
`elsewhere.11 Some of the more important principles are
`introduced and summarized below.
`
`Nebulizer Versus Nebulizer System
`
`The European Standard recognizes that different nebu-
`lizers will deliver different doses of drug to the same pa-
`tient, even if all conditions such as breathing pattern and
`nebulizer fill volume are controlled. This is because some
`
`nebulizers are inherently more efficient than others. For
`example, consider the most common nebulizer design, the
`constant—output nebulizer, which probably accounts for
`more than 70% of the nebulizers in home and hospital use
`today. A constant—output nebulizer emits aerosol at a con-
`stant rate until the volume of drug solution in the nebulizer
`cup is so small that nebulization ceases. The rate of aerosol
`output is constant, regardless of whether the patient is
`inhaling, breath—holdin g, or exhaling. This implies that for
`at least half the duration of operation the nebulizer is emit-
`ting aerosol into the ambient air. Not only is this extremely
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`STANDARDIZATION ISSUES: IN VITRO ASSESSMENT OF NEBULIZER PERFORMANCE
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`wasteful, it is an important source of air pollution. Breath—
`enhanced nebulizers, on the other hand, release more aero-
`sol during patient inhalation than during breath—hold or
`exhalation and thus are inherently more efficient. Dosi-
`metric nebulizers are the most efficient because (at least in
`theory) aerosol is released only during inhalation, so the
`entire emitted dose is delivered to the patient.
`However,
`it is not only the nebulizer design that is
`important in determining the performance of the nebulizer;
`the characteristics of the nebulizer itself can be critically
`important. With a jet nebulizer the greater the flow of
`compressed air through the nebulizer, in general, the greater
`the aerosol output and, usually, the smaller the particle
`Size. So the compressor is an integral part of the nebulizer
`system. Another important aspect of the nebulizer system
`is the design and use of the mouthpiece (eg, whether the
`mouthpiece is valved for exhalation), which can signifi-
`cantly influence the quantity and quality of aerosol deliv—
`ered to the patient. Alternatively, the mouthpiece might be
`replaced by a face mask, which can greatly reduce the
`amount of drug effectively delivered to the patient.
`The European Standard recognizes the importance of
`the nebulizer system rather than simply the nebulizer itself.
`For this reason the European Standard Specifies that neb—
`ulizer manufacturers should test performance of the neb-
`ulizer system as they intend it to be used. So, for example,
`if a nebulizer manufacturer sells a nebulizer sometimes
`
`with a mouthpiece and sometimes with a face mask, both
`of those 2 nebulizer systems need to be tested for aerosol
`output and size. Similarly if the nebulizer is recommended
`for use with various compressed air flows, the manufac-
`turer is required to test each nebulizer system with the
`range of recommended air flows—the minimum, maxi—
`mum, and typical average flow. This requirement to test
`each permutation can impose a substantial range of testing
`variables, but each permutation relates to a specific clini—
`cal condition of use to which the manufacturer is targeting
`the nebulizer product. Adoption of a nebulizer system con-
`cept will dissuade manufacturers or researchers from pub-
`lishing performance information without also making ref-
`erence to the system in which it was tested.
`The European Standard does not require testing all neb-
`ulizer designs for their ability to nebulize all drugs. Most
`commonly prescribed nebulizer drugs are in aqueous so-
`lutions that also contain excipients and usually some con—
`centration of sodium chloride. Some formulations are sus-
`
`pensions, with small, nearly colloidal solid particles within
`an aqueous solution, usually with excipients and sodium
`chloride. Most formulations intended for nebulization (by
`design or prescribed off-license) behave much like a Sim:
`ple salt solution, though admittedly a few drug solutions
`and suspensions do not because they are either extremely
`viscous, froth, or foam during nebulization, or have some
`other physical characteristic that causes atypical behavior.
`
`However, those are the exception. The European Standard
`recognizes that testing all forms of drug solutions and
`suspensions with all of the nebulizer systems combina-
`tions would be unreasonably burdensome. The practice
`adopted within the European Standard was to use a single
`test solution for all nebulizer system permutations. The
`solution adopted was a low concentration of sodium flu—
`oride, which was chosen because: it has similar properties
`to sodium chloride, which is commonly used in nebulizer
`drug formulations; it is relatively rare in most laboratory
`environments, so contamination from other sources is min-
`imized; and electrochemical analysis of sodium fluoride
`concentration (using a method similar to pH measurement)
`is relatively simple, low~cost, and sufficiently analytically
`sensitive.
`
`Measuring Aerosol Output and Aerosol Droplet Size
`Using the Methods in the European Standard
`
`In vitro assessment of nebulizer output has been poorly
`understood and characterized, and numerous methods have
`been described to estimate output. Recently, a European
`Standard was published and is believed to contain methods
`for reproducible and robust in vitro measurement of neb-
`ulizer aerosol output and droplet size.
`
`Aerosol Output
`
`Figure 2 illustrates the European Standard methodology
`for measuring aerosol output. The nebulizer system is at—
`tached to a breathing simulation device. A low-resistance
`electrostatic filter (Simulating the patient) is placed be—
`tween the breathing Simulation device and the nebulizer
`system. The intention is that aerosol collected on that filter
`represents aerosol delivered to the patient under clinical
`conditions. The standard breathing cycle is a simple sinus
`flow pattern of 15 cycles per minute and 500 mL per cycle.
`This pattern was adopted because it is relatively simple to
`simulate and reproduce. Other breathing patterns were con-
`sidered (eg, square waves, various inspiratory/expiratory
`ratios), but none was thought more appropriate as a single
`measure than the simple sinus flow pattern. Though this
`pattern is Specifically defined in the European Standard,
`the methods used can be adapted to virtually any other
`breathing pattern. Whatever the breathing pattern, the neb-
`ulizer is filled with a volume of test liquid that contains a
`trace amount (1%) of sodium fluoride. With the breath
`simulation device running and an electrostatic filter in place,
`any aerosol generated by the nebulizer system that is drawn
`into the breathing system (the analogy of being inhaled by
`a patient) is collected on the filter. The fluoride residue on
`the filter can then be quantified.
`
`
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`aerosol wasted
`
`aerosol inhaled
`
`
`
`Fig. 2. Schematic of Comité Européen de Normalisation (CEN) methodology to measure nebulizer aerosol output. Aerosol output is
`subjected to sinus flow breathing simulation, and the aerosol is collected onto low—resistance electrostatic filters. The aerosol contains trace
`concentrations of sodium fluoride, which is quantified electrochemically. rpm 2 respirations per minute. (Adapted from Reference 12.)
`
`entrained _..,
`air
`
`Suction Pump
`V}?-
`
`13 Umin
`555'
`
`15 [1min
`
`
`
`
`
`Nebuljser
`
`Containing
`
`2.5% NaF
`
`solutions
`
`
`Aerosol
`Size
`
`Compresgd
`gas
`
`Pump 2 L/min
`
`Fig. 3. Schematic of Comité Européen de Normalisation (GEN) methodology to measure nebulizer aerosol particle size. A constant inhalation
`of 15 L/min is drawn over (or through) the nebulizer. The nebulized solution contains sodium fluoride (NaF). The aerosol mixes with the
`entrained air. A 2 L/min flow is drawn off into a low—flow cascade impactor to sample the aerosol. The aerosol captured in the cascade
`impactor is analyzed for each size fraction, from which the normative and cumulative particle size distributions are derived. (Adapted from
`Reference 12.)
`
`Aerosol Particle Size
`
`Figure 3 illustrates the European Standard methodology
`for measuring aerosol particle size. A low-flow cascade
`impactor is placed in line with the nebulizer system. The
`nebulized fluid contains a trace (2.5%) of sodium fluoride.
`Instead of using the dynamic air flow pattern of a breath—
`
`ing machine, a constant simulated inhalation flow of 15
`L/min is applied, which is thought to represent a typical
`mid—inhalation flow rate. The cascade impactor samples a
`2 L/min (2/15) fraction of the total flow. The aerosol drop-
`lets deposit according to size in the stages of the cascade
`impactor, and the amount of fluoride residue on each stage
`is quantified. Table 2 presents a sample set of cascade
`
`1450
`
`RESPIRATORY CARE 0 DECEMBER 2002 VOL 47 No 12
`
`
`
`h,_.—-————-—__ 7 ______
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`__—_ _
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`_
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`_ _ .—__( _A_sf_4_l
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`IPR2021-00406
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`United Therapeutics EX2030
`Page 7 of 15
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`IPR2021-00406
`United Therapeutics EX2030
`Page 7 of 15
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`

`

`STANDARDIZATION ISSUES: IN VITRO ASSESSMENT OF NEBULIZER PERFORMANCE
`
`353.55%?338
`HHNoofgflix—rom
`
`g E g 3 g ”'Q 3 g 3 O
`°‘°‘°‘°°°"‘
`
`N N g g 2 g e v Ln 0
`J 2 E :- a. :3- 0: g 2 g e
`
`impactor data, from which are derived cumulative and nor—
`mative size distributions such as those depicted in Figure 4.
`
`Clinical Relevance of the European Standard
`inVitroMethods
`
`It is not known how well the currently drafted CEN test
`conditions will predict clinical performance. This can only
`be established once an appropriate study has compared in
`vitro output and droplet size measurements against in vivo
`lung deposition with a variety of nebulizers. However, the
`European Standard in vitro methods were developed with
`the agreement of a number of leading nebulizer aerosol
`scientists and clinicians in Europe and were tailored to
`meet the needs of type testing within a European Standard
`and to be as clinically relevant as practicable. Preliminary
`work13 relating draft in vitro methods in the European
`Standard to in vivo measures of aerosol deposition seem
`promising (Fig. 5), though more research is needed. If the
`European Standard in vitro methodology provides good
`estimates of in vivo deposition, then the in vitro methods
`could be used to guide clinicians in choosing the nebulizer
`system best suited for a specific patient group. If the in
`vitro/in vivo correlation is poor, then the in vitro methods
`can be exarmned and modified in subsequent standards to
`prov1de a more clinically representative measure of neb-
`ulizer output.
`
`European Respiratory Society Guidelines
`on the Use of Nebulizers
`
`i
`The in vitro methods in the European Standard are al—
`ready being used to improve clinical practice. To appre-
`ciate the advantages of standardizing in vitro measurement
`of nebulizer performance, the following section introduces
`and describes basrc prinCIples underlying the clinical nebi
`ulizer guidelines recently introduced by the European Re—
`spiratory Society (ERS).
`The ERS commissioned a task force in the mid-19905 to
`review the scientific and clinical principles of nebulizer
`therapy and to produce a set of guidelines (evidence-based
`whenever possible) to improve clinical nebulizer use
`throughout Europe. The task force held 3 interactive work-
`shops, each with some 25 invited experts from throughout
`the nebulizer field, and the ERS Guidelines were pub-
`lished in 2001.12
`The most important aim of the guidelines was to in—
`ff
`and atie tsafet
`b
`recommendin s
`s—
`creasee icacy
`p
`n
`y y
`g y
`terns by which nebulizers could be chosen and used. The
`guidelines were aimed at a wide variety of health care
`professionals practicrng in very different health care sys-
`tems throughout Europe. Though the immediate target an—
`
`
`
`
`
`2
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`ii,
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`3
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`f; E g
`3
`g g E
`
`g.
`g5
`§
`E E E
`EEEEE
`83;»0
`
`3'55 3% E
`f” E 13% E
`U E“; E E»
`E 3 3 g E
`
`”Ii/gig
`3039
`go‘éfin
`3333‘
`T
`E03 = 7:11,
`E 275 I
`3%. :37. '52 393i 3.3.3. "'3.
`E <1 51 Pg"
`gfimw OOOOOHHOOOT
`magi;
`E ‘5 "D 5
`0
`5