What the pulmonary specialist should know about the new inhalation therapies

B.L. Laube; H.M. Janssens; F.H.C. de Jongh; S.G. Devadason; R. Dhand; P. Diot; M.L. Everard; I. Horvath; P. Navalesi; T. Voshaar; H. Chrystyn

doi:10.1183/09031936.00166410

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Tables

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Figure 1–
The International Commission on Radiological Protection model showing the relationship between aerodynamic diameter and lung deposition. Data from [14].
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Figure 2–
The relationship between dose emission from a dry powder inhaler (DPI) and the patient's inhalation. Reproduced and modified from [64] with permission from the publisher.

Tables

Figures

Table 1– Definitions of commonly used terms that describe an aerosol

Term	Abbreviation	Definition
Labelled dose or nominal dose^#		The mass of drug that is available within the aerosol generator per actuation. This is the dose that is metered.
Total emitted dose or delivered dose^#	TED	The mass of drug emitted per actuation that is actually available for inhalation at the mouth.
Fine-particle dose	FPD	The mass of particles <5 μm in size within the total emitted dose.
Fine-particle fraction	FPF	The fine particle dose divided by the total emitted dose.
Aerodynamic equivalent diameter	d_ae	The diameter of a fictitious sphere of unit density (1 g·cm⁻³) that has the same gravitational (settling) velocity in the same gas as the actual particle.
Mass median aerodynamic diameter	d_ae,μm or MMAD	The MMAD divides the aerosol size distribution in half. It is the diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller.
Geometric standard deviation	σ_g or GSD	The GSD measures the dispersion of particle diameter and is defined as the ratio of the median diameter to the diameter at ±1 sd (σ) from the median diameter. In a cumulative distribution plot of the aerodynamic diameter and mass of particles, the GSD is calculated as the ratio of the median diameter to the diameter at 15.9% of the probability scale, or the ratio of the diameter at 84.1% on the probability scale to the median diameter. Aerosols with a GSD ≥1.22 are considered polydisperse. Most therapeutic aerosols are polydisperse and have GSDs in the range of 2–3.

^#: lung deposition can be presented as a percentage of the nominal or emitted dose. Note that these two parameters are not the same.

Table 2– Devices currently available for delivery of commonly prescribed brand-name drugs by pressurised metered-dose inhalers (pMDI), breath actuated (BA)-pMDIs, nebulisers, soft mist inhalers and dry powder inhalers (DPI)

Drug class	Drug/device (brand name)^#	Dose available		Comments^¶
Drug class	Drug/device (brand name)^#	Nominal	Emitted
pMDIs⁺
Anticholinergics	Ipratropium bromide (Atrovent®)	21 μg
β₂-adrenergic agonists	Formoterol (Atimos® or Foradil®)	12 μg		Atimos® emits extra-fine particles. Discard Atimos® 12 weeks after dispensing.
	Salbutamol	100 μg		Airomir®, Proventil® and ProAir® contain a small amount of alcohol. In some countries, Ventolin® has a dose counter. In some countries, some generic versions are formulated with CFC products.
	Salmeterol (Serevent®)	25 μg
	Levalbuterol (r-salbutamol) (Xopenex®)	45 μg		Contains a small amount of alcohol.
Corticosteroids	Beclomethasone (QVAR®)	50 and 100 μg		QVAR® aerosol inhaler and Alvesco® inhaler emit extra-fine particles.
	Ciclesonide (Alvesco®)		40, 80 and 160 μg	Due to greater lung deposition, the prescribed dose of QVAR® is half that of the traditional beclomethasone dose. Licensed with the Aerochamber®, in some countries.
	Beclomethasone (Clenil®)	50, 100, 200 and 250 μg		Formulated with HFA propellants but has particle size characteristics that are similar to CFC-beclomethasone. Licensed with the Aerochamber®, or the Volumatic®, in some countries.
	Beclomethasone (Beclazone®)	50, 100 and 250 μg		Formulated with CFC propellant, but will be discontinued in the near future.
	Budesonide (Pulmicort®)	50 μg		Currently formulated with CFC propellants.
	Fluticasone (Flixotide®, Flovent®)	50, 125 and 250 μg
	Flunisolide HFA (Aerospan®)	80 μg
Combinations	Beclomethasone/formoterol (Foster®). In some countries, this product is known as Fostair®, Fostex® or Innovair®.	100/6 μg		Beclomethasone and formoterol in this combination product are formulated as extra-fine particles.
	Budesonide/formoterol (Symbicort®)		80/4.5 μg, 160/4.5 μg	Should be discarded 12 weeks after dispensing. Has a dose counter.
	Fluticasone/salmeterol (Seretide®)	50/25, 125/25 and 250/25 μg		Has a dose counter. Licensed with the Volumatic®, or Aerochamber®, in some countries.
	Ipratropium bromide/salbutamol (Combivent®)	18/100 μg		Formulated with CFC propellant, but will be discontinued in the near future.
Cromones	Nedocromil sodium (Tilade®)	2 mg		Has been discontinued in many countries.
	Sodium cromoglycate (Intal®)	1 mg and5 mg		Formulated with CFC propellant, but will be discontinued in the near future.
BA-pMDIs⁺
β₂-adrenergic agonists	Salbutamol	100 μg		Easi-Breathe® Inhaler and Airomir® Autohaler.
	Pirbuterol	200 μg		Maxair® Autohaler; discontinued after December 31, 2010.
Corticosteroids	Beclomethasone (QVAR®)	50 and 100 μg		QVAR® Autohaler® and QVAR® Easi-Breathe® Inhaler. Beclomethasone formulated as extra-fine particles.
Nebulisers
β₂-adrenergic agonists	Formoterol fumarate inhalation solution (Perforomist®)	20 μg/2 mL
	Salbutamol inhalation solution	0.083%		Vials do not require dilution.
		Vials with 1, 2 and 5 mg·mL⁻¹		Add saline until 4-mL total for jet nebuliser.
	Arformoterol tartrate (r-formoterol) inhalation solution	15 μg
	Levalbuterol (r-salbutamol) inhalation solution	0.31 mg/3 mL, 0.63 mg/3 mL and 1.25 mg/3 mL		Store in foil pouch. Once pouch is opened, use vials within 2 weeks.
	Metaproterenol sulfate (Alupent®)	0.5, 0.6 and 5%
Nonsteroidal anti-inflammatories	Cromolyn sodium	20 mg		Can be mixed with salbutamol inhalation solution in nebuliser.
Antibiotics	Tobramycin inhalation solution	300 mg/5 mL (TOBI®)		Licensed for use with PARI LC® Plus nebuliser and Devilbiss® Pulmo-Aide® compressor.
		300 mg/4 mL (Bramitob®)		Licensed for use with PARI LC® Plus and PARI TURBO Boy® compressor.
	Colistin inhalation solution (Promixin®)	Vial with powder: 1 million units (80 mg) with water and saline for solution (3 mL)		Licensed for use with jet nebuliser (PARI LC® Plus or similar nebuliser) with appropriate compressor. Licensed for use with the I-neb® adaptive aerosol delivery system, in some countries.
	Aztreonam inhalation solution (Cayston®)	75 mg/2 mL		Licensed for use with the eFlow®, in some countries.
Corticosteroids	Budesonide inhalation suspension	0.25, 0.5 and 1 mg (Pulmicort Respules®)		Licensed for use with jet-nebulisers.
		0.25 and 0.5 mg (generic)		Not for use with ultrasonic nebuliser.
	Fluticasone inhalation suspension	0.50 mg/2 mL; 2 mg/2 mL (Flixotide®)
Mucolytics	Recombinant human DNase (Pulmozyme®)	2.5 mg/2.5 mL		Licensed for use with many nebulisers (see text for details). Should not be used with ultrasonic nebulisers. Fluid should not be diluted or mixed with other drugs.
	Hypertonic saline inhalation solution			Studied with jet nebulisers and breath-enhanced nebulisers with appropriate compressors.
	Hyper-Sal™	3.5%/4 mL and 7%/4 mL
	MucoClear®	6%/4 mL
	Hyaneb™	7%/5 mL		Also contains sodium hyaluronate 0.1%.
Prostacyclin	Iloprost (Ventavis®)	2.5 μg per ampule and 5 μg per ampule		Licensed for use with I-neb® adaptive aerosol delivery system.
Anticholinergics	Ipratropium bromide (Atrovent®)	500/vial		Can be combined with salbutamol, or metaproterenol, solutions.
Anti-infective	Pentamidine (NebuPent®)	0.02%, 300 mg		Licensed with Respigard II nebuliser.

Soft mist inhalers
Anticholinergics	Tiotropium bromide	2.5 μg		Respimat®
Combinations	Fenoterol/ipratropium bromide	50/20 μg		Respimat®
DPIs
Aerolizer®	Budesonide	200 μg		Capsule, low resistance.
	Formoterol	12 μg
Diskhaler®	Beclomethasone	100, 200 and 400 μg		Capsule (8 or 4), low resistance.
	Fluticasone	100, 250 and 500 μg
	Salmeterol	50 μg
	Zanamivir (antiviral)	5 mg
Diskus (Accuhaler® in the UK)	Fluticasone	50, 100, 250 and 500 μg		Individual doses in a blister inside the device, medium resistance.
	Salbutamol	200 μg
	Salmeterol	50 μg
	Fluticasone/salmeterol	100/50, 250/50 and 500/50 μg
Clickhaler®	Beclomethasone	50, 100 and 250 μg		Multi-dose reservoir, medium/high resistance.
	Budesonide	100, 200 and 400 μg
	Formoterol	12 μg
	Salbutamol	114 μg
Cyclohaler®	Beclomethasone	100, 200 and 400 μg		Capsule, low resistance.
	Budesonide	200 and 400 μg
	Salbutamol	200 μg
Easyhaler®	Beclomethasone	100, 200 and 400 μg		Multi-dose reservoir, high resistance.
	Budesonide	100, 200 and 400 μg
	Formoterol	12 μg
	Salbutamol	100 and 200 μg
Handihaler®	Tiotropium	18 μg		Capsule, high resistance.
Maghaler®	Budesonide	200 μg		Multi-dose reservoir.
Novolizer®	Budesonide	200 μg		Multi-dose reservoir, medium resistance.
	Formoterol	12 μg
	Salbutamol	100 μg
Pulvinal®	Beclomethasone	100, 200 and 400 μg		Multi-dose reservoir, medium/high resistance.
	Salbutamol	200 μg
Spinhaler®	Sodium cromoglycate	20 mg		Capsule, low resistance.
Spiromax®	Budesonide	100, 200 and 400 μg		Multi-dose reservoir, medium/high resistance.
Turbuhaler®	Budesonide	100, 200 and 400 μg; 90 and 180 μg (in USA)		Multi-dose reservoir, medium/high resistance.
	Formoterol	6 and 12 μg
	Terbutaline	500 μg
	Budesonide/formoterol	100/6, 200/6 and 400/12 μg
Twisthaler®	Mometasone	200 and 400 μg; 220 and 110 μg (in US.)		Multi-dose reservoir, high resistance.

^#: not all drugs/devices are available in all countries. ^¶: for all drugs, patients should be monitored for side-effects. ⁺: pMDIs and BA-MDIs formulated with hydrofluoroalkane (HFA) propellant unless otherwise stated in the comments column. The dose of reformulated product is the same as the chlorofluorocarbon (CFC) version unless specified. See Appendix for all product/drug manufacturer details.

Table 3– How to choose the right aerosol delivery device for patients with good and poor actuation–inhalation coordination

Good actuation–inhalation coordination		Poor actuation–inhalation coordination
Inspiratory flow^# ≥30 L·min⁻¹	Inspiratory flow^# <30 L·min⁻¹	Inspiratory flow^# ≥30 L·min⁻¹	Inspiratory flow^# <30 L·min⁻¹
pMDI	pMDI	pMDI+spacer	pMDI+spacer
BA-pMDI		BA-pMDI
DPI		DPI
Nebuliser	Nebuliser	Nebuliser	Nebuliser

pMDI: pressurised metered-dose inhaler; BA-pMDI: breath actuated-pMDI; DPI: dry powder inhaler. ^#: inspiratory flow can be determined from the flow–volume curve generated during spirometry measurements, or by using devices like the IN-Check Dial®. See Appendix for all product/drug manufacturer details. Reproduced and modified from [34].

Table 4– Detailed instructions on how to use pressurised metered-dose inhalers (pMDIs), breath-actuated (BA)-pMDIs, pMDIs with spacers, dry powder inhalers (DPIs), nebulisers and soft mist inhalers

pMDIs: for patients with good actuation–inhalation coordination

1) Shake four or five times if suspension formulation.

2) Take the cap off.

3) Prime the inhaler (refer to the PIL for specific instructions).

4) Exhale slowly, as far as comfortable (to empty the lungs).

5) Hold the inhaler in an upright position.

6) Immediately place the inhaler in the mouth between the teeth, with the tongue flat under the mouthpiece.

7) Ensure that the lips have formed a good seal with the mouthpiece.

8) Start to inhale slowly, through the mouth and at the same time press the canister to actuate a dose.

9) Maintain a slow and deep inhalation, through the mouth, until the lungs are full of air. This should take an adult 4–5 s.

10) At the end of the inhalation, take the inhaler out of the mouth and close the lips.

11) Continue to hold the breath for as long as possible, or up to 10 s before breathing out.

12) Breathe normally.

13) If another dose is required, repeat steps 4–12.

BA-pMDIs: for patients ≥6 yrs old

1–7) Same as above for pMDIs alone.

8) Start to inhale slowly, through the mouth. The patient should sense that a dose has been released, either by taste or a noise when the dose is released (the noise is quiet for the Easi-Breathe®).

9) Maintain a slow and deep inhalation, through the mouth, until the lungs are full of air. This should take a child ∼2–3 s and an adult 4–5 s.

10–13) Same as above for pMDIs alone.

pMDI + spacer with facemask: for patients ≤3 yrs old or anyone who cannot breathe consciously through the mouth

1–3) Same as above for pMDIs alone.

4) Insert the mouthpiece of the pMDI into the open end of the spacer and ensure a tight fit. If a reverse flow spacer is used (table 6), insert the valve stem of the pMDI into the port on the mouthpiece of the spacer.

5) Place the facemask over the nose and mouth and be sure the fit is tight to the face.

6) Actuate one dose into the chamber of the spacer.

7) The patient should inhale and exhale normally into the spacer at least 10 times.

8) Take the facemask off the patient's face.

9) If another dose is required, repeat steps 1–8.

pMDI + spacer with mouthpiece: for patients ≥3 yrs old (caregiver should determine if child can perform this technique correctly)

1–4) Same as above for spacer with facemask.

5) Place the mouthpiece of the spacer in the patient's mouth with the teeth over the mouthpiece and the lips sealed around it.

6) Actuate one dose into the chamber of the spacer.

7) Instruct the patient to inhale and exhale using normal (tidal) breaths into the spacer at least 5 times. With some spacers, the inhalations and exhalations can be monitored by observing the movement of the valves.

8) If another dose is required, repeat steps 4–7.

9) If ICSs are used, rinse mouth afterwards.

pMDI + spacer with mouthpiece: for patients ≥6 yrs old (caregiver should determine if child can perform this technique correctly)

1–4) Same as above for spacer with facemask.

5) Place the mouthpiece of the spacer in the patient's mouth with the teeth over the mouthpiece and the lips sealed around it.

6) Instruct the child to exhale slowly, as far as comfortable (to empty their lungs).

7) Actuate one dose into the chamber of the spacer and start to inhale slowly through the mouthpiece. Some spacers will make a whistling noise if inspiration is too fast.

8) Maintain a slow and deep inhalation through the mouth, until the lungs are full of air. This should take a child 2–3 s and an adult 5 s.

9) At the end of the inhalation, take the inhaler out of the mouth and close the lips.

10) Continue to hold the breath for as long as possible for up to 10 s before breathing out.

11) Breathe normally.

12) If another dose is required, repeat steps 1–11.

13) If ICSs are used, rinse mouth afterwards.

DPIs: for patients ≥5–6 yrs old (caregiver should determine if child can perform this technique correctly)

1) Take the cap off (some do not have a cap).

2) Follow the dose preparation instructions in the PIL.

3) Do not point the mouthpiece downwards once a dose has been prepared for inhalation because the dose could fall out.

4) Exhale slowly, as far as comfortable (to empty the lungs). Do not exhale into the DPI.

5) Start to inhale forcefully through the mouth from the very beginning. Do not gradually build up the speed of inhalation.

6) Continue inhaling until the lungs are full.

7) At the end of the inhalation take the inhaler out of the mouth and close the lips. Continue to hold the breath for as long as possible, or up to 10 s.

8) Breathe normally.

9) If another dose is required, repeat steps 1–8.

Jet nebulisers: for patients of any age who cannot use a pMDI with a valved holding chamber, with or without a facemask, or if the drug is only available as nebuliser liquid

1) Assemble the tubing, nebuliser cup and mouthpiece (or mask).

2) Pour the medication solution into the nebuliser cup.

3) Do not exceed the fill volume recommended by the manufacturer.

4) Connect to power source; flow of 6–8 L·min⁻¹, or compressor.

5) Place the mouthpiece in the mouth and close the lips around it (or cover the nose and mouth with an appropriate facemask).

6) Keep the nebuliser vertical during treatment.

7) Inhale and exhale using normal (tidal) breaths, with occasional deep breaths, until the nebuliser starts to sputter or no more aerosol is produced.

8) If the treatment must be interrupted, turn off the unit to avoid waste.

9) At the completion of the treatment, take the mouthpiece out of the mouth.

10) Dismantle and clean nebuliser following manufacturer's instructions.

11) With technology that differs from that of a traditional jet nebuliser, clinicians should thoroughly review operating instructions prior to patient use and instruction.

Mesh nebulisers: for use with drugs licensed with this type of nebuliser

1) Assemble the device according to the manufacturer's instructions.

2) Follow manufacturer's instructions to test the nebuliser function prior to the first use of a new device and after each cleaning to verify proper operation.

3) Pour the medication solution into the medication reservoir. Do not exceed the volume recommended by the manufacturer.

4) Turn on the power.

5) Hold the nebuliser in the position recommended by the manufacturer.

6) Put the mouthpiece into the mouth and close the lips around it.

7) Inhale and exhale using normal (tidal) breaths, with occasional deep breaths.

8) At the completion of the treatment, take the mouthpiece out of the mouth.

9) Clean nebuliser following the manufacturer's instructions.

Soft mist inhalers

Assemble and use the device according to the manufacturer's instructions.

PIL: patient information leaflet; ICSs: inhaled corticosteroids. See Appendix for all product/drug manufacturer details.

Table 5– Advantages and disadvantages of pressurised metered-dose inhalers (pMDIs), pMDIs with spacers, breath actuated (BA)-pMDIs, nebulisers and dry powder inhalers (DPIs)

Type	Advantages	Disadvantages
HFA-pMDIs (suspension and solution)	Portable and compact.	Coordination of actuation and inhalation needed.
	Short treatment time.	Most patients inhale too fast.
	No contamination risk.	Low lung deposition and high oropharyngeal deposition.
	High reproducibility between doses.	Important to prime before use if new or not used in some time.
		Must be kept upright during inhalation.
		With most devices, the number of doses remaining is difficult to determine. Only one β₂-adrenergic agonist device has a dose counter (Ventolin®) and it is only available in the USA. Seretide® and Symbicort® (combination drug devices) have dose counters. Symbicort® is only available in the USA.
		Few drugs available as breath-actuated pMDIs.
HFA-pMDIs (extra-fine particles)	As above for pMDIs.	Important to prime before use if new, or not used in some time.
	Higher lung deposition and lower oropharyngeal deposition, compared with pMDIs that are used alone.
	Good for inhaled corticosteroids. When using QVAR®, the corticosteroid dose can be half of that prescribed for patients using traditional corticosteroid pMDI products.	Only two corticosteroid products available (QVAR® and Alvesco®). Only one combination product available (Foster®).
pMDI+spacers	Less need for coordination of actuation and inhalation compared with a pMDI alone.	More expensive and less portable than a pMDI alone.
	Reduced oropharyngeal deposition compared with a pMDI alone.	Prone to reduced or inconsistent dosing because of electrostatic charge associated with plastic spacers.
	Improves lung deposition if this is poor with pMDI alone.	Special washing instructions.
	Useful for maintaining efficient drug delivery during acute exacerbations.	Steps in administering drug with a spacer are crucial. Mistakes can lead to reduced, or no drug being inhaled (i.e. multiple actuations into spacer before inhalation, and delay of inhalation after actuation).
	Can use tidal breathing if the spacer has a valve.
	Some spacers make a noise to indicate that the inhalation flow is too fast.	Some children like to make the noise and if they do they will be inhaling too fast.
BA-pMDIs	May be useful for patients who cannot coordinate inhalation and actuation; may be useful for the elderly.	Patients sometimes stop inhaling once actuation occurs.
	Should not be used with a spacer or VHC.
		Breath-actuation does not control inspiratory flow rate, so patients need to be instructed to inhale slowly.
		Can only be used with a drug that is dispensed with the device; no substitutions.
DPIs	Portable and compact. Many are multi-dose.
	Some are single-dose with doses kept separately in sealed packages.	Single-dose devices require repeat loading, which can lead to error. Two separate inhalations are required for each dose.
	Breath-actuated, so no outside energy source, or propellant, is needed. With no propellant needed, it avoids the possible damaging effects of CFCs to Earth's ozone layer. Also, there is no need to coordinate actuation and inhalation, which is required with a pMDI.	DPI delivery can result in high oropharyngeal deposition because a forceful inhalation is needed to aerosolise the particles.
		Flow-dependent dose emission for some designs. Poor quality (or no) dose emitted if inspiratory flow is too slow.
		Patients need to exhale into the room to functional residual capacity before inhaling from the DPI. Patients should not exhale into the device once the dose has been prepared for inhalation, or the dose could be blown out of the device.
	Most multi-dose devices have a dose counter.	Patients need to inhale forcefully from the beginning. They should not gradually increase their speed of inhalation.
	Short treatment time.	Uncertainty of emitted dose during acute exacerbations.
		More expensive than pMDIs.
		Must be upright when preparing the dose for inhalation. Must be kept upright or turned horizontally during inhalation.
		Needs to be stored in a cool and dry place.
Nebulisers	May be used at any age.	Pneumatic jet devices require an outside energy source and compressor.
	Vibrating mesh nebulisers are portable and do not require an outside energy source.
	Patient coordination not required.	Treatment times can be long.
	May be used to dispense drugs that are not available for delivery by pMDI or DPI.	Suspensions do not nebulise well.
	No propellant needed.	Performance (i.e. emitted dose and particle size) varies significantly between devices.
	Breath-enhanced nebulisers, dosimetric nebulisers and vibrating mesh nebulisers are much less wasteful of drug than pneumatic jet nebulisers.	With pneumatic jet nebulisers, drug can be lost to the surrounding environment during exhalation, exposing caregivers and other personnel to the drug.
	Dosimetric nebulisers deliver aerosol during inhalation only, over a proscribed time period, and turn off when dosing is complete.	Many pneumatic jet nebulisers are wasteful since a certain volume of solution cannot be aerosolised (i.e. dead volume).
		There may be a risk of bacterial contamination if the device is not properly cleaned.
		Newer devices (i.e. vibrating mesh nebulisers) are expensive.

HFA: hydrofluoroalkane; VHC: valved holding chamber; CFC: chlorofluorocarbon. See Appendix for all product/drug manufacturer details. Reproduced and modified from [9], with permission from the publisher.

Table 6– Characteristics of commonly used spacers

Spacer^#	Type	Valved	Anti-static
Aerochamber Plus®	Small volume	Yes	No
Aerochamber Max®	Small volume	Yes	Yes
Optichamber® (Breathatec® in Australia)	Small volume	Yes	No
Vortex®	Small volume	Yes	Yes
Volumatic®	Large volume	Yes	No
Babyhaler®	Large volume	Yes	No
Ace®	Large volume/reverse flow	Yes	No
Optihaler®	Large volume/reverse flow	No	No
InspirEase®	Opaque reservoir/reverse flow	No	No
Microspacer®	Extension device	No	No
Synchro-Breathe®	Extension device	No	No