A GUIDE TO
`
`
`
`hmmmmlubuationwlththu
`mmmmhnfuwmmm
`
`Whymmmlgnm ‘—-—--"'.r-='-"'—'--
`Minimum.
`RESPIRONICS
`
`IPR2021-00406
`
`United Therapeutics EX2029
`Page 1 of 48
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 1 of 48
`
`

`

`|PR2021-00406
`
`United Therapeutics EX2029
`Page 2 of 48
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 2 of 48
`
`

`

`A Guide to Aerosol Delivery Devices
`
`for Respiratory Therapists
`
`Dean R Hess PhD RRT FAARC
`
`Timothy R Myers BS RRT-NPS
`
`Joseph L Rau PhD RRT FAARC
`
`With a Foreword by
`
`Sam Giordano, Executive Director
`
`American Association for Respiratory Care
`
`Produced in collaboration with the American Association for Respiratory Care
`
`Supported by an educational grant from Respironics, Inc.
`
`© Copyright May 2007, American Association for Respiratory Care
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 3 of 48
`
`

`

`FOREWORD
`
`iii
`
`Aerosol therapy is both an art and a science. And for respiratory therapists, who are the experts in
`aerosol therapy, the terms “ art” and “ science” take on a practical meaning. Respiratory therapists are
`the only health care providers who receive extensive formal education in aerosol therapy and who
`are tested for competency in aerosol therapy. In fact, administration of prescription drugs via the
`lungs is a major component of the scope of practice for all respiratory therapists. Respiratory thera-
`pists are the experts when it comes to the art and science of aerosol therapy.
`How does art combine with science in the context of aerosol therapy? “ Science” includes phar-
`macology, cardiopulmonary anatomy and physiology, physics, and mathematics. In order to claim
`expertise in aerosol therapy and optimize its many uses, one must have a thorough understanding of
`the drug formulation, know its mode of action, and understand the conditions where it is effective.
`One must also know the contraindications to avoid harm and to in uence decisions related to effec-
`tive use of aerosols. The same 5 rights that apply to all medication delivery apply also to aerosol
`therapy: the right patient, the right medication, the right time, the right route, and the right dose.
`For aerosol therapy, the right dose is technique-dependent. One can select the right drug and fail
`to administer the right dose because the medication was not delivered using correct technique. Here
`is where “ art” comes into play. There is ample scienti c evidence of ineffective use of aerosols when
`they are self-administered because the patient lacks knowledge about proper technique. Aerosol
`therapy is not a “
`re and forget” clinical intervention. Many patients bene t from aerosol therapy,
`especially in hospitals, because it is administered by respiratory therapists. Many millions of other
`patients, however, do not receive optimum (or sometimes any) bene t from their prescribed
`metered-dose inhalers, dry powder inhalers, and nebulizers simply because they are not adequately
`trained to use them.
`There is a critical juncture where science intersects with art. For aerosol therapy to be effective,
`the appropriate delivery system for the medication must be matched to the patient’s ability to use it
`correctly. The art of aerosol therapy does indeed arise from the science. First, we must identify the
`appropriate medication, based on physician diagnosis. Next, we must assess the patient’s ability to
`correctly use the aerosol delivery device. That assessment should be done by a respiratory therapist,
`as well as physicians and nurses who interact with the patient. This assessment should not be limited
`to respiratory function since other factors also contribute to effective use of aerosol delivery systems.
`For example, all too often patients are prescribed the appropriate inhaled medication but do not
`receive the prescribed dose because the patient cannot use the delivery system appropriately.
`While respiratory therapists are best able to demonstrate complete and correct knowledge of
`aerosol delivery devices, there remains room for improvement. Because aerosol therapy is integral to
`our scope of practice, and because we are considered the experts in this area, we have a professional
`obligation to continue our learning in this area. Respiratory therapists have an opportunity to rein-
`force their value by updating their knowledge of aerosol delivery systems and combining that
`knowledge with effective assessment of patients requiring this therapy. Recommending an appropri-
`ate delivery system tailored speci cally to the patient’s abilities is part of that assessment.
`This booklet provides detailed and comprehensive information that, when combined with your
`dedication and commitment to be the professional experts in this important area, will empower you
`to provide guidance to your physician, nurse, and pharmacist colleagues, but, most importantly, to
`your patients.
`With a widening array of effective inhaled medications and with billions of dollars spent on
`aerosol medications, you can have a profound impact on bringing about the appropriate match of
`medications and device delivery to your patients. You’ll not only improve the patient’s condition, but
`also contribute to more cost-effective use of health care system resources.
`Here’s your opportunity to improve your expertise in this area. Accept the challenge and realize
`your potential as a respiratory therapist.
`
`Sam Giordano MBA RRT FAARC
`Executive Director
`American Association for Respiratory Care
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 4 of 48
`
`

`

`As part of your membership bene ts in the American Association for Respiratory Care (AARC),
`the association…
`
`(cid:129)
`(cid:129)
`(cid:129)
`
`provides you with continuing education opportunities;
`keeps track of all the CRCE hours you earn from CRCE-approved programs; and
`allows you to print online a transcript of your CRCE records.
`
`These services are available to you 24 hours a day, 7 days a week, on the AARC website
`(www.AARC.org).
`
`The proceedings from the symposium contained in this book are approved for 4 CRCE contact
`hours, and as an AARC member, there is no charge to you. To earn those CRCE contact hours,
`please go to the AARC website at:
`
`http://www.AARC.org/aerosol_delivery
`
`Further instructions will be given on that website, including…
`
`(cid:129)
`(cid:129)
`
`how you register to take an examination to assess your mastery of course objectives;
`how to update your email address so that registration con rmations can be sent to you.
`
`You should expect to learn the following as you read this book.
`
`Learning Objectives
`
`1.
`
`2.
`3.
`4.
`5.
`6.
`7
`8.
`9.
`
`State approximate amount of aerosol deposited in the lower respiratory tract for nebulizers,
`metered-dose inhalers, and dry powder inhalers.
`List advantages and disadvantages of inhalation compared to other routes of drug administration.
`Compare the principle of operation of a jet nebulizer, mesh nebulizer, and ultrasonic nebulizer.
`Describe methods that are used to decrease aerosol loss from a nebulizer during exhalation.
`List advantages and disadvantages of nebulizers for aerosol delivery.
`Describe the basic components of a metered-dose inhaler.
`List advantages and disadvantages of metered-dose inhalers.
`Compare HFA and CFC propellants in metered-dose inhalers.
`Explain the importance of priming and tracking the number of doses for a metered-dose
`inhaler.
`10. Compare the design of holding chambers and spacers.
`11. Describe factors that affect dose delivery from a holding chamber/spacer.
`12. List advantages and disadvantages of dry powder inhalers.
`13. Describe the principle of operation of various commercially available dry powder inhalers.
`14. List the correct steps for use of a nebulizer, metered-dose inhaler, metered-dose inhaler with
`holding chamber/spacer, and dry powder inhaler.
`15. Describe the proper technique of cleaning aerosol delivery devices.
`16. Discuss criteria to assist clinicians in selecting an aerosol delivery device.
`17. List common problems and errors with each type of inhaler.
`
`Continuing Respiratory Care Education (CRCE)
`
`iv
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 5 of 48
`
`

`

`Table o
`
`f Contents
`
`FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii
`
`THE SCIENCE OF AEROSOL DRUG DELIVERY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Types of Aerosol Inhalers
`Terminology
`Where Does an Inhaled Aerosol Drug Go?
`Equivalence of Aerosol Device Types
`Advantages & Disadvantages with Inhaled Aerosol Drugs
`Mechanisms of Aerosol Deposition and Particle Sizes
`Currently Available Aerosol Drug Formulations
`Age Guidelines for Use of Aerosol Devices
`
`SMALL VOLUME NEBULIZERS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`Pneumatic Jet Nebulizers
`Designs to Decrease Aerosol Waste During Exhalation
`Mesh Nebulizers
`Ultrasonic Nebulizers
`Nebulizers for Speci c Applications
`Continuous Aerosol Delivery
`Cleaning and Disinfection of Nebulizers
`
`METERED-DOSE INHALERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`Propellants
`MDI Preparation for Use
`Proper Technique
`Cleaning the MDI
`Dose Counting
`Breath-Actuated MDI
`
`METERED-DOSE INHALER ACCESSORY DEVICES . . . . . . . . . . . . . . . . . . . . . . . . 24
`Spacers
`Valved Holding Chambers
`Drug Delivery and Technique
`Care and Cleaning
`
`DRY POWDER INHALERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
`Principle of Operation
`Currently Available DPI Formulations and Designs
`Major Limitations with Dry Powder Inhalers
`Correct Use of a Dry Powder Inhaler
`
`CRITERIA TO SELECT AN AEROSOL DELIVERY DEVICE . . . . . . . . . . . . . . . . . . . 33
`
`EDUCATING PATIENTS IN CORRECT USE OF AEROSOL DEVICES . . . . . . . . . . 34
`Patient Adherence
`Common Patient Errors with MDIs
`Common Patient Errors with Holding Chambers/Spacers
`Common Patient Errors with Dry Powder Inhalers
`Common Patient Errors with Small Volume Nebulizers
`Instructing and Evaluating Patients in the Use of Inhaler Devices
`
`SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
`
`REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
`
`ADDITIONAL READING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 6 of 48
`
`

`

`The Science of Aerosol Drug Delivery
`
`Types of Aerosol Inhalers
`There are 3 common types of aerosol generators for inhaled drug delivery: the small
`volume nebulizer (SVN), the metered-dose inhaler (MDI), and the dry powder inhaler
`(DPI). Because of high medication loss in the oropharynx and hand-breath coordination
`dif culty with MDIs, holding chambers and spacers are often used as ancillary devices
`with an MDI.
`
`Terminology
`In everyday clinical usage the term ‘aerosol’ often denotes use of a nebulizer, whereas
`the term ‘inhaler’ is often taken to mean an MDI, with or without a holding
`chamber/spacer. In correct context, all 3 device types are aerosol inhalers. An ‘aerosol’ is a
`suspension of liquid (nebulizer or MDI) or solid particles (MDI or DPI) in a carrier gas,
`and not necessarily a liquid spray only. We suggest that speci c, correct terminology be
`used, such as ‘nebulizer’ or ‘metered-dose inhaler’ or ‘dry powder inhaler’ when referring
`to an aerosol drug delivery system or device. The term ‘aerosol’ should be used to refer to
`the plume of particles produced by the aerosol generator.
`
`Where Does an Inhaled Aerosol Drug Go?
`Lung deposition is 10-20% for most aerosol systems.1-4 For example, of 200 micrograms
`( g) of albuterol in two actuations or puffs from an MDI, only about 20-40 g reach the
`lungs with correct technique. The remaining drug is lost in the oropharynx, the device,
`the exhaled breath, and the environment. Figure 1 shows drug disposition for different
`aerosol systems, showing that oropharyngeal loss, device loss, and exhalation/ambient loss
`differ among aerosol device types, while lung deposition is similar.
`
`Figure 1. Drug disposition with 3 common aerosol inhaler devices, including an
`MDI with a spacer attached, showing similar lung deposition with varying
`amounts of loss in the oropharynx, device, and exhaled breath. MDI – metered-
`dose inhaler; SVN – small volume nebulizer; DPI – dry powder inhaler. (Modified,
`with permission, from Respir Care 2005; 50(3):367-382).
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists 1
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 7 of 48
`
`

`

`It is important to realize that different types of aerosol devices deposit the same approxi-
`mate fraction of the total dose (also termed ‘nominal’ dose) in the lungs. However different
`types of aerosol device, eg, a nebulizer and an MDI, do not have the same nominal dose.
`Using albuterol as an example, the typical MDI nominal dose is 2 actuations, or about 200
`g, while the typical nebulizer nominal dose is 2.5 mg, or 12 times more drug. If the same
`percentage reaches the lungs, and the MDI has a smaller nominal dose than a nebulizer for
`the drug, more drug will be deposited in the lungs with the nebulizer. Table 1 lists both the
`MDI and nebulizer nominal doses for several drugs, showing this difference.
`
`Table 1. Difference in nominal (total) dose between a metered-dose inhaler
`(MDI) and a nebulizer (SVN) for several drug formulations.
`
`DRUG
`Albuterol
`Ipratropium
`Cromolyn
`
`MDI NOMINAL DOSE
`0.2 mg (200 g)
`0.04 mg (40 g)
`2 mg
`
`SVN NOMINAL DOSE
`2.5 mg
`0.5 mg
`20 mg
`
`Equivalence of Aerosol Device Types
`Clinically it is often thought that nebulizers may be more effective than MDIs, especially
`for short-acting bronchodilators in acute exacerbations of air ow obstruction. A number of
`studies have established that either device can be equally effective, if the lower nominal dose with
`an MDI is offset by increasing the number of actuations (“ puffs” ) to lung dose equivalence.
`Data in Figure 2 show that the lower-dose MDI can achieve the same clinical effect as the
`higher-dose nebulizer by increasing the number of MDI puffs.5 Other studies have shown
`equivalent clinical results whether an MDI, a nebulizer, or a DPI is used, provided that the
`patient can use the device correctly.6 For bronchodilators, the same clinical response is often
`achieved with the labeled dose from the MDI or nebulizer, despite the higher nominal dose
`for the nebulizer.
`
`Figure 2. Mean change in FEV1 versus cumulative dose from a
`metered-dose inhaler (MDI) and small volume nebulizer. Five puffs
`from the MDI (1.25 mg) of terbutaline gave an effect equivalent to
`the usual 2.5 mg dose from the nebulizer. (From Reference 5, with permission.)
`
`2
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 8 of 48
`
`

`

`Newer aerosol devices and drug formulations are increasing the ef ciency of lung deposi-
`tion compared to the traditional devices commonly used. For example, lung deposition for
`HFA-beclomethasone dipropionate (QVAR) is in the range of 40 - 50% of the nominal
`dose using an MDI formulation with hydro uoroalkane (HFA) propellant to replace the
`older chloro uorocarbon (CFC) propellants. Investigational devices such as the Respimat
`nebulizer and the Spiros DPI also have shown lung depositions of 40% or better.
`
`Advantages & Disadvantages with Inhaled Aerosol Drugs
`There are a number of advantages with inhalation of drugs to treat pulmonary disease
`(Table 2). There are also disadvantages to the use of inhaled aerosol delivery, and clinicians
`should be realistic about these, including the relatively low lung deposition fraction of all
`aerosol delivery devices. The primary advantage of inhaled aerosol therapy is treating the
`
`Table 2. Advantages and disadvantages of the inhalation route of administration
`with aerosolized drugs in treating pulmonary diseases. MDI – metered-dose
`inhaler; SVN – small volume nebulizer; HPA – hypothalamic-pituitary-adrenal.
`
`Advantages
`Aerosol doses are generally smaller than systemic doses; eg, oral albuterol is
`2 to 4 mg; inhaled albuterol is 0.2 mg (MDI) to 2.5 mg (SVN).
`Onset of effect with inhaled drugs is faster than with oral dosing; eg, oral
`albuterol is (cid:148) 30 min; inhaled albuterol is ~ 5 min.
`Drug is delivered directly to the target organ (lung), with minimal sys-
`temic exposure.
`Systemic side effects are less frequent and severe with inhalation compared
`to systemic delivery (injection, oral); eg, less muscle tremor, tachycardia
`with 2-agonists; lower HPA suppression with corticosteroids.
`Inhaled drug therapy is less painful and relatively comfortable.
`
`Disadvantages
`Lung deposition is a relatively low fraction of the total aerosol dose.
`A number of variables (correct breathing pattern, use of device) can affect
`lung deposition and dose reproducibility.
`Dif culty coordinating hand action and inhalation with MDIs.
`Lack of knowledge of correct or optimal use of aerosol devices by patients
`and clinicians.
`The number and variability of device types confuses patients and clinicians.
`Lack of standardized technical information on inhalers for clinicians.
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists 3
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 9 of 48
`
`

`

`lung directly with smaller doses, resulting in fewer side effects than with oral delivery.7 As
`seen in Figure 3, inhalation of terbutaline, a short-acting 2-agonist, from an MDI resulted
`in better air ow than with a much larger oral dose, or even with a subcutaneous injection
`of drug.
`
`Figure 3. Changes in FEV1 for three different routes of administration with
`terbutaline. Greater clinical effect was seen with drug delivered as inhaled
`aerosol from a metered-dose inhaler, compared to similar or larger doses
`delivered orally or by subcutaneous injection. (From Reference 7, with permission.)
`
`Mechanisms of Aerosol Deposition and Particle Si es
`There are 3 mechanisms usually cited by which an aerosol particle can deposit: inertial
`impaction, gravitational settling (sedimentation) and diffusion. Inertial impaction occurs with
`larger, fast-moving particles. Gravitational settling is a function of particle size and time, with
`the rate of settling proportional to particle size. Diffusion occurs with particles smaller than 1
`m. These mechanisms come into play as aerosol particles are inhaled orally or through the
`nose. Larger particles > 10 m are
`ltered in the nose and/or oropharynx, most likely by
`inertial impaction; particles of 5-10 m generally reach the proximal generations of the
`lower respiratory tract, and particles of 1-5 m reach the lung periphery (Fig. 4).8
`
`4
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 10 of 48
`
`

`

`Figure 4. A simplified view of the effect of aerosol particle size on the
`site of preferential deposition in the airways (From Reference 8, with permission.)
`
`Particle size plays an important role in lung deposition, along with particle velocity and
`settling time.9 As particle size increases above 3 m, there is a shift in aerosol deposition
`from the periphery to the conducting airways. Oropharyngeal deposition also increases as
`particle sizes increase above 6 m. Exhaled loss is high with very small particles of 1 m or
`less. These data support the view that particle sizes of 1-5 m are best for reaching the lung
`periphery, while 5-10 m particles deposit preferentially in the conducting airways.
`Aerosol devices in clinical use produce heterodisperse (also termed polydisperse) particle
`sizes, meaning that there is a mix of sizes in the aerosol. This is contrasted with monodisperse
`aerosols, which consist of a single particle size. A measure that can be useful in describing a
`polydisperse aerosol is the mass median diameter (MMD), which is de ned as the particle size
`(in m) above and below which 50% of the mass of the particles is contained. This is the
`particle size that evenly divides the mass, or amount of the drug in the particle size distribu-
`tion. This is usually given as the mass median aerodynamic diameter, or MMAD, due to the
`way sizes are measured. The higher the MMAD, the more particle sizes are of larger diame-
`ters.
`
`Currently Available Aerosol Drug Formulations
`Some aerosol drugs are available in more than one formulation, and others (often newer
`drugs) are only available in a single formulation. Table 3 lists current aerosol drugs and their
`FDA-approved aerosol delivery devices. As the CFC propellants used in MDIs are phased
`out, some older aerosol drugs are being transitioned to the newer HFA propelled MDI for-
`mulations. New aerosol drugs are either formulated as an HFA-MDI (eg, MDI-levalbuterol)
`or, more commonly, as DPIs (eg, formoterol, tiotropium, mometasone).
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists 5
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 11 of 48
`
`

`

`Table 3. Common aerosol drug formulations with corresponding inhaler devices available for use in the
`United States in 2005. CFC – chlorofluorocarbon; HFA – hydrofluoroalkane; MDI – metered-dose inhaler;
`SVN – small volume nebulizer; DPI – dry powder inhaler. Cost information from www.drugstore.com.
`
`Drug
`Short-acting Bronchodilators
`Albuterol
`
`Pirbuterol
`
`Levalbuterol
`
`Ipratropium
`
`Ipratropium & albuterol
`
`Long-acting Bronchodilators
`Salmeterol
`Formoterol
`Arformoterol
`Tiotropium
`Corticosteroids
`Beclomethasone
`
`Triamcinolone
`Flunisolide
`
`Fluticasone
`
`Budesonide
`
`Mometasone
`uticasone/salmeterol
`
`Budesonide/formoterol
`Others
`Cromolyn
`
`Nedocromil
`Acetylcysteine
`
`Dornase alfa
`Tobramycin
`
`Device
`
`Cost
`
`CFC-MDI
`
`HFA-MDI
`
`SVN
`
`$10.99/inhaler (generic) (200 actuations); $0.05/puff
`$30.19 – $35.99 (brand name) (200 actuations);
`$0.15 - $0.18/puff
`$30.18 (generic)
`$37.63 - $39.61 (brand name)
`$15.00 for 20 mL bottle of 0.5%; $0.38 per 0.5 mL (usual dose)
`$18.99 for 25 3-mL vials of 0.083%; $0.76/vial
`Breath-actuated $94.76 MDI (400 actuations); $0.24/puff
`CFC-MDI
`HFA-MDI
`SVN
`
`$48.99 (200 actuations); $0.24/puff
`$79.50 for 24 vials (0.31mg/3mL); $3.31/vial
`$70.84 for 24 vials (0.63mg/3mL); $2.95/vial
`$71.25 for 24 vials (1.25mg/3mL); $2.97/vial
`$81.75 (200 actuations); $0.41/puff
`$77.32 for 25 vials (0.02% in 2.5mL); $3.09/vial
`$91.99 (200 actuations); $0.46/puff
`$123.73 for 60 3-mL vials; $2.06/vial
`
`HFA-MDI
`SVN
`CFC-MDI
`SVN
`
`$111.94 for 60 doses; $1.87/dose
`DPI (Diskus)
`$108.17 for 60 capsules; $1.80/capsule
`DPI (Aerolizer)
`(Available in 2007)
`SVN
`DPI (HandiHaler) $129.55 for 30 capsules; $4.32/capsule
`
`HFA-MDI
`
`CFC-MDI
`CFC-MDI
`HFA-MDI
`HFA-MDI
`
`$60.84 40 mcg/puff (100 actuations); $0.61/puff
`$73.57 80 mcg/puff (100 actuations); $0.74/puff
`$105.99 100 mcg/puff (240 actuations); $0.44/puff
`$77.55 250 mcg/puff (100 actuations); $0.78/puff
`(Available in 2007)
`$78.24 44 mcg/puff (120 actuations); $0.65/puff
`$104.74 110 mcg/puff (120 actuations); $0.87/puff
`$170.82 220 mcg/puff (120 actuations); $1.42/puff
`$149.35 for 30 vials of 0.25 mg/2 mL; $4.98/vial
`$165.80 for 30 vials of 0.5 mg/2 mL; $5.53/vial
`DPI (Turbuhaler) $152.56 (200 inhalations); $0.76/dose
`DPI (Twisthaler) $143.62 (120 doses); $1.20/dose
`DPI (Diskus)
`$146.47 for 100/50 mcg/dose (60 inhalations); $2.44/inhalation
`$166.99 for 250/50 mcg/dose (60 inhalations); $2.82/inhalation
`$229.87 for 500/50 mcg/dose (60 inhalations); $3.83/inhalation
`DPI (Turbuhaler) (Available in 2007)
`
`SVN
`
`CFC-MDI
`
`SVN
`CFC-MDI
`SVN
`
`SVN
`SVN
`
`$107.89 (200 actuations); $0.54/puff
`$71.28 (112 actuations); $0.64/puff
`$46.61 for 60 vials (20 mg/2mL); $0.78/vial
`$81.43 (104 actuations); $0.78/puff
`$7.99 for 10 ml vial of 10% Solution
`$14.99 for 10 ml vial of 20% Solution
`$7.99 for 10 ml vial of 20% Solution
`$1,589.32 for 30 2.5-mL vials; $52.98/vial
`$3,391.92 for 56 5-mL vials; $60.57/vial
`
`6
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 12 of 48
`
`

`

`Age Guidelines for Use of Aerosol Devices
`The 1997 National Asthma Education and Prevention Program (NAEPP) guidelines have
`recommended age limits for effective use of the different types of aerosol inhaler devices.10
`These are given in Table 4. Such guidelines are general suggestions only, representing
`expected maturity and physical coordination at a given age. Patient use of an aerosol deliv-
`ery device at any age needs to be properly evaluated for optimal technique, and tailored to
`the patient’s ability to use the device correctly.
`
`Table 4. Age guidelines for use of aerosol delivery device types. Based on
`NAEPP guidelines.10
`
`Aerosol System
`Small volume nebulizer
`Metered-dose inhaler
`MDI with holding chamber/spacer
`MDI with holding chamber/spacer and mask
`Breath-actuated MDI
`(eg, Autohaler)
`DPI
`
`Age
`≤ 2 years
`> 5 years
`> 4 years
`≤ 4 years
`> 5 years
`
`≥ 5 years
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists 7
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 13 of 48
`
`

`

`Nebulizers convert solutions or suspensions into aerosols of a size that can be inhaled into
`the lower respiratory tract. Pneumatic jet nebulizers are the oldest form of aerosol genera-
`tor, and their basic design and performance have changed little in the past 30 years.
`Ultrasonic nebulizers, which have been available for many years but are not commonly used
`for inhaled drug delivery, use electricity to convert a liquid into respirable droplets. The
`newest generation of nebulizers uses mesh technology. General advantages and disadvantages
`with use of small volume nebulizers are listed in Table 5.
`
`Table 5. Advantages and Disadvantages of Small Volume Nebulizers.
`
`ADVANTAGES
`Ability to aerosolize many drug solutions
`Ability to aerosolize drug mixtures (>1 drug), if drugs
`are compatibile
`Normal breathing patterns can be used
`Useful in very young, very old, debilitated, or distressed patients
`An inspiratory pause (breath-hold) is not required for ef cacy
`Drug concentrations can be modi ed
`
`DISADVANTAGES
`Treatment times are lengthy for pneumatically-powered nebulizers
`Equipment required may be large and cumbersome
`Need for power source (electricity, battery, compressed gas)
`Variability in performance characteristics among different brands
`Possible contamination with inadequate cleaning
`Wet, cold spray with facemask delivery
`Potential for drug delivery into the eyes with facemask delivery
`
`Pneumatic Jet Nebuli ers
`A pneumatic nebulizer delivers compressed gas through a jet, causing a region of negative
`pressure (Fig. 5). The solution to be aerosolized is entrained into the gas stream and is
`sheared into a liquid
`lm. This
`lm is unstable and breaks into droplets due to surface ten-
`sion forces. A baf e in the aerosol stream produces smaller particles. The aerosol is further
`
`Small Volume Nebulizers
`
`Figure 5. Cartoon illustration of the function of a pneumatic jet nebulizer.
`
`8
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 14 of 48
`
`

`

`conditioned by environmental factors such as the relative humidity of the carrier gas.
`Nebulizer performance is affected by both technical and patient-related factors (Table 6).
`
`Table 6. Factors affecting penetration and deposition of therapeutic aerosols delivered by jet
`nebulizers.
`
`Technical Factors
`Manufacturer of nebulizer
`Flow used to power nebulizer
`Fill volume of nebulizer
`Solution characteristics
`Composition of driving gas
`Designs to enhance nebulizer output
`Continuous versus breath-actuated
`
`Patient Factors
`Breathing pattern
`Nose versus mouth breathing
`Composition of inspired gas
`Airway obstruction
`Positive pressure delivery
`Arti cial airway and mechanical ventilation
`
`Dead volume refers to the solution that is trapped inside the nebulizer and is thus not
`made available for inhalation. Dead volume is typically in the range of 0.5-1 mL. In an
`attempt to reduce medication loss due to dead volume, clinicians and patients tap the nebu-
`lizer periodically during therapy in an effort to increase nebulizer output. Therapy may also
`be continued past the point of sputtering in an attempt to deliver medication from the dead
`volume, but this is unproductive and not recommended. Due to evaporative losses within
`the nebulizer, the solution becomes increasingly concentrated and cools during nebuliza-
`tion. Solution temperature affects nebulizer output, with output and droplet size varying
`directly with temperature.
`The most important characteristic of nebulizer performance is the respirable dose provid-
`ed for the patient. The respirable dose is sometimes reported as respirable mass, which is the
`output of droplets from a nebulizer in the respirable range (1-5 (cid:77)m). Other important char-
`acteristics of nebulizer performance include nebulization time, ease of use, ease of cleaning
`and sterilization, and cost. Duration of nebulization is important for patient compliance in
`the outpatient setting and clinician supervision for hospitalized patients. A short nebuliza-
`tion time that delivers an effective dose is desirable. Many nebulizers are low cost, mass pro-
`duced, single-patient-use devices. Newer more ef cient nebulizers, however, are more
`expensive (Table 7).
`
`Table 7. Approximate costs of nebulizers.
`
`Device
`Single patient use pneumatic nebulizer
`Reusable nebulizer with compressor
`Nebulizer with
`lter for pentamadine
`Nebulizer with reservoir bag
`Reusable breath-enhanced nebulizer
`Breath-actuated nebulizer
`Mesh nebulizer
`Ultrasonic nebulizer
`
`Approximate Cost
`$1 - $3
`$50 - $150
`$10 - $12
`$5 - $6
`$15 - $20
`$4 - $5
`$250 - $350
`$100 - $150
`
`A Guide to Aerosol Delivery Devices For Respiratory Therapists 9
`
`IPR2021-00406
`United Therapeutics EX2029
`Page 15 of 48
`
`

`

`A ll volume of 4-5 mL is recommended11 unless the nebulizer is speci cally designed for a
`smaller ll volume. The volume of some unit dose medications is suboptimal. Ideally, saline should
`be added to the nebulizer to bring the ll volume to 4-5 mL, but this might not be practical. The
`increased nebulization time with a greater ll volume can be reduced by increasing the ow used
`to power the nebulizer. Increased ow also decreases the droplet size produced by nebulizers; 6-8
`L/min is recommended.11 The ow from many compressors is unfortunately too low for optimal
`nebulizer performance. Several studies have reported performance differences between nebulizers
`of different manufacturers and among nebulizers of the same manufacturer. Due to cost consider-
`ations, disposable single-patient-use nebulizers are typically used for many treatments. Pneumatic
`nebulizers have been reported to function correctly for repeated uses provided that they are
`washed, rinsed, and air dried after each use. TECHNIQUE BOX 1 lists generic steps in correct
`use of pneumatic nebulizers. Since newer nebulizer designs are entering the clinical market, respi-
`ratory therapists should modify these instructions by following manufacturers’ recommendations.
`
`TECHNIQUE BOX 1. Steps for correct use of nebulizers.
`
`Jet nebuli er technique
`1. Assemble tubing, nebulizer cup, and mouthpiece (or mask).
`2. Place medicine into the nebulizer cup; use
`ll volume of 4-5 mL.
`3. The patient should be seated in an upright position.
`4. Connect to power source; ow of 6-8 L/min or compressor.
`5. Breathe normally with occasional deep breaths until sputter or no more aerosol is produced.
`6. Keep nebulizer vertical during treatment.
`7. Rinse nebulizer with sterile or distilled water and allow to air dry.
`
`With technology that differs from that of a traditional jet nebulizer, clinicians should thoroughly
`review operating instructions prior to patient use and instruction.
`
`Cleaning the jet nebulizer (home use)
`After each use:
`1. Remove the tubing from the compressor and set it aside – this tubing should not be
`washed or rinsed.
`2. Shake remaining solution from the nebulizer cup.
`3. Disassemble the equipment and rinse nebulizer cup and mouthpiece with either sterile
`water or distilled water.
`4. Shake off excess water and air dry on an absorbent towel.
`5. Store the the nebulizer cup in a ziplock bag.
`Once or twice a week:
`1. Disassemble the nebulizer and wash it in a mixture of warm soapy tap water.
`2. Soak the nebulizer cup and mouthpiece for 1 hour in a solution that is one part distilled
`white vinegar (5%) and three parts hot water (1.25% acetic acid). An alternative is to use
`quaternary ammomium compound (QAC) at a dilution of one ounce to one gallon of ster-
`ile or distilled water for at least 10 minutes.
`3. Discard the vinegar solution after use. QAC can be reused for up to o