General considerations

An ideal inhaler device should deliver a predetermined dose of drug to the lungs, in an easy-to-use, reproducible and cost-effective manner, with minimal deposition of drug in other sites. Factors to do with both the patient and the inhaler device can affect drug delivery.

The patient may, because of their age or physical or cognitive disability, be unable to use certain devices. For instance, they may be unable to co-ordinate actuation and inspiration precisely enough to use a pressurised metered dose inhaler (MDI), or to inhale forcefully enough when wheezy to use a dry powder inhaler (DPI), or they may simply find a device too cumbersome or too fiddly. It is therefore important at the outset to choose a device that the patient can use correctly. Once taught, inhaler technique needs to be checked regularly, and any difficulties identified and, where possible, corrected or the patient offered an inhaler they find easier to use. Where asthma appears poorly controlled, both inhaler technique and adherence to the prescribed treatment should be checked. Many patients underuse asthma treatments.1 Acceptability of the prescribed device is likely to influence adherence to treatment, but little is known about this; promotional material often suggests that patients prefer small, unobtrusive devices, but there is no clear proof that they use them more reliably.

The inhaler must emit the drug in a particle size that can reach the lungs and deposit in the airways. Deposition in the airways is probably maximal with particles of 1-3µm diameter, and most therapeutic aerosols are formulated to produce particles of 1-5µm diameter. Particles of 10µm diameter or greater deposit mainly in the mouth and throat, or are prevented from entering the lungs by abrupt changes in airflow in the upper airway, and the cough reflex. The design of the inhaler (e.g. how it stores, releases and disperses the drug) determines how much of the dose is delivered as respirable and non-respirable particles, and the extent to which delivery will depend on precise co-ordination or adequate inspiratory flow. There are three main methods of dispersing medication into an aerosol for inhalation: by pressurised MDI, by dry powder inhaler or by using a nebuliser.

Pressurised metered dose inhalers

In a pressurised MDI, the drug is dissolved or suspended in a propellant under pressure and, when activated, a valve system releases a metered volume of drug and propellant. The propellant provides the force to propel and disaggregate particles. Pressurised MDIs may be manually actuated or breath-actuated. They can be used alone or in combination with various devices or adaptations (e.g. spacers, extended mouthpieces) designed to slow the aerosol cloud, reduce oropharyngeal deposition and promote ease of use. Hitherto, all pressurised MDIs contained chlorofluorocarbon (CFC) propellants, but because CFCs damage the earth's ozone layer2 their use will be phased out over the next 3 years or so. We are therefore now in a transition period, as CFC-MDIs are gradually being replaced by MDIs containing non-ozone-depleting propellants such as hydrofluorocarbons (HFCs).3^,4

Manually actuated pressurised MDIs

These devices have been in use for around 40 years. They are familiar to many patients, convenient to carry, quick to actuate, and generally inexpensive. However, for optimum drug delivery, they require good co-ordination and psychomotor skills to ensure that actuation, inhalation and breath-holding occur in precise sequence. Common failings are not shaking the canister before use, inhaling too rapidly or 'jerkily', or not holding the breath long enough at the end of inspiration. Another problem is that some patients stop inhaling when the high-velocity aerosol hits the back of the throat ('cold Freon effect'). In one study in general practices with a special interest in asthma, 30% of adults with asthma had clearly inadequate MDI technique.5 Drug delivery to the lower respiratory tract varies from around 7-20% depending on the patient's technique;6^,7 about 80% of the dose deposits in the oropharynx.8

It is increasingly accepted that a pressurised MDI alone (i.e. without a spacer) is not a suitable choice for most children under about 12 years old,9 or for many physically or cognitively impaired adults.10^,11 On the other hand, even with imperfect technique, most adults gain good relief from β₂-agonists in the doses delivered from MDIs, which are high up the dose-response curve. On grounds of cost and convenience, most of our consultants still recommend that, in adults with the required co-ordinating skills, a pressurised MDI should usually be tried first for the delivery of bronchodilator therapy.

Breath-actuated MDIs

Breath-actuated MDIs (e.g. Autohaler; Easi-Breathe) incorporate a mechanism which is activated during inhalation (at a flow of around 30L/min) and triggers the MDI. This reduces the need to co-ordinate actuation and inhalation precisely, and, for example, makes the devices easier for elderly, physically impaired patients to use than a conventional MDI.10 In one study, lung deposition of salbutamol was significantly greater in patients using a breath-actuated MDI than in patients using a conventional MDI with poor technique; in those with good technique, a breath-actuated inhaler offered no advantage.7 In general, use of a breath-actuated MDI should be reserved for older children and adults. There are few data on their use in young children. In a small study, all but one of 51 wheezy children could fire a salbutamol Autohaler, but how much drug was delivered in those under 6 years old is unclear since peak expiratory flow improved in only half.12 Moreover, we know of no efficacy trials of the devices for administration of corticosteroids.

Breath-actuated MDIs are bulkier and less portable than conventional MDIs. As with ordinary MDIs, the cold Freon effect is sometimes a problem and oropharyngeal deposition of corticosteroids is high; it can be reduced by use of a short 'open tube' spacer (the 'Optimiser') which comes free with Easi-breathe beclometasone and cromoglycate inhalers.13

Spacer devices

Spacer devices are used with pressurised MDIs and are of two main types - extension devices and holding chambers.

An extension device (e.g. the Integra, used with Becloforte MDI) increases the distance the aerosolised drug has to travel before it is inhaled, slowing the aerosol and allowing the propellants to evaporate; this reduces the size of the aerosol droplets, and traps large (non-respirable) particles within the spacer, thereby reducing oropharyngeal impaction of drug. Extension devices do not have a valve, and still require good co-ordination, making them unsuitable for young children and patients who have difficulty co-ordinating actuation and inhalation. The spacehaler uses the same canister as a conventional MDI but has an extended mouthpiece to slow the aerosol cloud. In adults it delivers salbutamol as effectively as a large-volume holding chamber,14 and is more compact, but we know of no published studies of its use in children, nor for delivery of inhaled corticosteroids.

Holding chambers provide a reservoir of drug from which the patient breathes. Holding chambers share the properties of extension devices, but in addition they reduce the need for co-ordination between MDI actuation and inhalation, and are generally easier for children9 and older, frailer patients11 to use than a conventional MDI alone. Valved holding chambers (e.g. Volumatic, Nebuhaler, AeroChamber, Babyhaler, Fisonair) allow the patient to breathe tidally from the reservoir of drug and are especially helpful for children. The availability of face masks for use with holding chambers has markedly improved the opportunities for the treatment of very young children with asthma. The Volumatic, Nebuhaler and AeroChamber (infant, child, or standard) are all now prescribable with a compatible mask on the NHS, although drug delivery is more efficient via a mouthpiece if the patient can use one.

By reducing oropharyngeal deposition, use of a large-volume spacer lowers the incidence of local unwanted effects of inhaled corticosteroids, such as oropharyngeal candidiasis, and reduces the amount of drug available for absorption from the alimentary tract.8^,15 This is especially important for beclometasone dipropionate (BDP), because a significant proportion of drug absorbed from the gut survives passage through the liver and contributes to systemic activity.8 Use of an MDI plus a large-volume spacer is recommended for the administration of inhaled corticosteroids in children,16 or for giving high doses in adults.17 We also recommend it for giving bronchodilator therapy in children under 6 years old, and it is often a good choice in any patient with difficulty co-ordinating actuation of the MDI and inhalation. In the emergency room setting, administration of bronchodilators by MDI plus spacer relieves acute asthma at least as effectively as administration from a nebuliser, and, for children, has less effect on heart rate and reduces the amount of time spent in the emergency room.18

Drugs should be administered as single actuations into the spacer, and inhaled with minimum delay after each puff, repeating until all the prescribed dose has been given.15 Multiple actuations, fired into the spacer before inhaling, reduce the overall respirable dose. The canister should be shaken between actuations. Either a single slow, deep inspiration or a series of smaller breaths appears equally effective.19 The spacer valve should be checked to see that it opens and closes with breathing and does not stick. In infants, it has been recommended that the spacer and face mask be tilted to about 60 degrees above horizontal, which, in the case of some large-volume spacers, helps to keep the valve open and may make it easier for the baby to inhale the drug.

Static charge accumulates on the walls of most currently available spacers (made from plastic and polycarbonate). This attracts drug particles and reduces the output of medication from such spacers in vitro.20 Washing the spacer in washing-up liquid, and allowing it to dry in air without rinsing or wiping, reduces the static charge for at least 4 weeks and increases delivery of salbutamol to the lungs, compared to new and untreated, or water-rinsed and air-dried, spacers.21 Washing the spacer in this way is advisable before first use of a spacer and once monthly.

Unfortunately, the many different spacers now available vary widely in the dose of drug they emit.15 The amount of drug reaching the lungs is affected by the size and shape of the spacer, mask design, ease of opening of the valve, the breathing pattern, the drug being given and the speed and volume of the MDI aerosol.22–24 Data about a particular holding chamber for one drug may not apply to other spacer devices and other drugs. Many spacers are marketed with little laboratory information and sometimes no published clinical data to support their use. Action is needed from the Medical Devices Agency to rectify this.

The transition to CFC-free MDIs

With the gradual phasing out of CFC-containing MDIs, manufacturers have not only had to develop non-ozone-depleting propellants, such as HFCs, but also redesign MDIs to ensure compatibility with the new propellants. Three CFC-free formulations of salbutamol are now available in the UK as manually actuated pressurised MDIs (Airomir; Salbulin; ▼Evohaler), and one (Airomir Autohaler) as a breath-actuated MDI. Only one CFC-free inhaled corticosteroid, a formulation of BDP (▼Qvar), is licensed as a manually or breath-actuated MDI for use in patients aged 12 years or over.

Complete equivalence between CFC inhalers and their HFC replacements cannot be assumed in every situation. For example, the new HFC salbutamol MDI, Airomir, delivers the same particle size and dose as a CFC-containing Ventolin MDI when used alone, but not when used with a spacer device.25 Only spacers specified in the SPC for a particular CFC-free MDI should be used with that inhaler.4 Qvar emits BDP in much smaller particles than the old CFC-MDI, which results in higher deposition in the lung periphery;26 control of asthma appears to require about half the dose of Qvar as BDP from a conventional MDI.27 Therefore, when switching from a CFC-containing formulation of BDP or budesonide to Qvar, the total daily dose prescribed should be halved.26 If switching from fluticasone propionate, the prescribed dose should remain the same.26 The dose of Qvar may need to be further readjusted according to the clinical response and unwanted effects.

CFC-formulations will still be prescribable until a choice of CFC-free alternatives is available for all patient groups at an adequate range of doses and has undergone a year's post-marketing surveillance. The timetable for the transition will vary for different drugs and drug categories. It is important that the changeover is carefully managed and accompanied by education schemes so that patients understand the reasons for the change and are not switched back and forth between CFC-containing and CFC-free inhalers.4 Good communication between hospital doctors, GPs, practice nurses, pharmacists and patients is essential during the transition: prescribers will need to specify the brand, or state clearly whether a CFC-containing or CFC-free inhaler is intended. The changeover will provide a useful opportunity to check inhaler technique and titrate the dose of inhaled corticosteroid to the lowest needed for effective control of asthma. Patients need to be advised that the aerosol from some HFC-MDIs may feel warmer and less dense than that from CFC inhalers, and may taste different.3^,4

Dry powder inhalers

DPIs do not require propellants, but rely on the patient's inspiratory effort to disperse the drug into small particles and deliver it to the lungs. The devices differ in how inspiratory flow affects particle size and, hence, delivery to the lungs, how the drug is stored and the dose metered, and in the presence of dose counters or 'device empty' warnings. In general, DPIs are unsuitable for children under 6 years old, because too few children of this age can reliably generate the inspiratory flow of 30L/min needed to work the most efficient DPIs.28 However, nearly all adults can achieve this, even when wheezy, and there is evidence that those unable to use an MDI alone find it easier to use a DPI, because it avoids the problems of co-ordination of actuation and inspiration.29 Oropharyngeal deposition remains high (around 60% of the delivered dose) with DPIs, and patients should be advised to rinse the mouth with water after inhaling from a DPI, which minimises local unwanted effects.8^,30

Older DPIs, such as Spinhaler and Rotahaler, use single doses packaged in a gelatine capsule. Each capsule is loaded and opened individually. Problems include loss of powder before inhalation, insufficient inspiratory flow, and deterioration of the capsule in damp or humid conditions.

The Diskhaler is a multidose DPI used for delivering salbutamol, salmeterol, BDP or fluticasone propionate. Four or eight pre-metered doses are sealed in individual foil blisters (protecting against damp) around the edge of the Disk, and opened by the device immediately before inhalation. A lactose carrier means that the patient can taste the dose, which some prefer. With optimal use, the Diskhaler gives similar lung deposition to that from a correctly used MDI (without a spacer).29

The Accuhaler is used for delivering salbutamol, salmeterol, fluticasone propionate, or the combination product, salmeterol plus fluticasone propionate. The device contains 60 doses in blisters on a foil strip, and has a dose counter which locks when the device is empty. The Accuhaler was designed to deliver a similar dose to that received from a correctly used MDI without a spacer. In vitro, the dose delivered, and the respirable fraction (16-21%), were well maintained at inspiratory flows of 30-90L/min throughout the life of the device.31

The Turbohaler, which delivers terbutaline, eformoterol or budesonide, has a single powder reservoir sufficient for 50, 100 or 200 individual doses, dispensed by a volumetric metering system each time the device is used. The Turbohaler is primed before each dose by holding it upright and twisting the base. A window on the device turns red when only a few doses are left. The pure drug powder has no taste. The device should be stored in a dry place. The Turbohaler has high resistance and patients should be told to inhale forcefully and deeply.32 At an inspiratory flow of 60L/min (average for an adult), lung deposition of drug delivered from a Turbohaler is twice that of the same nominal dose inhaled correctly from an MDI,33 and in children aged 5-15 years, control of asthma required half the daily dose of budesonide when given from a Turbohaler as when given by MDI plus spacer.34 However, the dose of drug delivered, and the amount reaching the lungs, falls by 50% at inspiratory flow rates of 30-40L/min32 and the dose that can be inhaled by children up to 8 years old varies widely.35

Direct comparisons of the efficacy of budesonide via Turbohaler with fluticasone propionate via Accuhaler or Diskhaler have given conflicting results, as have evaluations of patient preference for the devices.36^,37

The Clickhaler is a relatively new DPI used for the delivery of salbutamol or BDP. It resembles a conventional MDI and uses a similar 'press down' action to load the dose for inhalation. At inspiratory flows of 15, 30 and 60L/min, the Clickhaler delivered salbutamol as effectively, in one small study, as a correctly used MDI.38 The Clickhaler has a dose counter and a warning appears near the end of its 200 doses. The device locks when empty. It should be kept dry and shaken before use.

Nebulisers

Nebulisers generate an aerosol either by means of a flow of gas, provided by an electrical compressor or compressed gas, passing through a solution or suspension of the drug in a nebulising chamber (jet nebulisers), or by means of ultrasonic vibrations produced in the fluid by a piezoelectrical crystal (ultrasonic nebulisers). Jet nebulisers are cheaper and more robust than ultrasonic nebulisers and are generally more suitable for use in the community.39^,40 Nebulisers do not rely on patient co-operation or co-ordination, but deliver more drug to the lungs when used with a mouthpiece rather than a face mask, and during quiet breathing, rather than rapid breathing or crying. Indications for nebulised treatment in asthma have declined, especially in the community setting.39 The main indication remains the treatment of acute severe asthma in adults and children too ill to use an MDI with a spacer, and needing urgent bronchodilator therapy.17^,39

To deliver a therapeutic dose of drug over 5-15 minutes, nebulisers should provide a drug output with about 50% of particles below 5µm diameter.40 In practice, nebulisers vary greatly in the amount of drug delivered in the respirable range (by eightfold in one study),41 and with many nebulisers, less than 10% of the prescribed dose reaches the lungs. The correct combination of nebuliser chamber and compressor is important in determining whether the nebuliser achieves an adequate output of respirable drug particles. Characteristics of several currently available nebuliser/compressor combinations have been published, but there is a need for more widely available and helpful information.40

A new generation of nebulisers has been developed to overcome some of the inefficiencies of older devices. 'Open vent' nebulisers (e.g.Sidestream), breath-enhanced, open vent nebulisers (e.g. Ventstream; Pari LC Plus), and intelligent dosimetric nebulisers (e.g. Halo-lite) are examples of new devices which incorporate special features to enhance nebuliser output and/or shorten nebulisation time.39^,40

Comment

It is clear that the delivery of drugs in particles of respirable size varies widely from device to device. This has important clinical implications, especially where the therapeutic effect (or lack of effect) may not be immediately apparent (e.g. inhaled corticosteroids), or when a patient needs to change to a different type of device. Changing the device may influence the effectiveness of treatment and the likelihood of unwanted local or systemic effects, yet few data exist to guide prescribers on dose adjustments when switching between devices.

Differences in drug delivery can also make it difficult to interpret data from clinical trials as it is frequently difficult to know the actual dose of drug that patients have inhaled. It is therefore essential that trials report clearly the method of drug delivery, and how the patient's inhaler technique was taught and checked. Trials should not be grouped together in meta-analyses without considering differences in the delivery devices and the patients' inhaler technique.

From both the prescriber's point of view, and for the interpretation of clinical trials, it would help greatly if doses could be expressed in terms of the amount of drug expected to reach the lungs when an inhaler is used correctly, not simply the total dose emitted. Although this is some way off in practice, the European Agency for Evaluation of Medicinal Products (EMEA) has argued for a 'fine powder' dose (the dose in particles of less than 5µm diameter) for DPIs, based on standard laboratory tests, instead of the traditional metered dose.42 It should be borne in mind, however, that neither in-vitro tests of lung delivery, nor studies in healthy volunteers, necessarily reflect actual lung delivery in patients with asthma.

Data from laboratory studies of inhaled asthma treatments depend critically on the measurement techniques used, so require expert interpretation. Such studies should be published in full in peer-reviewed journals. Tests should be standardised and clinically relevant. The manufacturers of nebulisers have made some progress towards the adoption of agreed British and European Standards, but in other areas reported differences (e.g. between DPIs) appear to owe more to inconsistencies in the methods of testing than to clinically important differences between the devices.

Conclusion

A plethora of different devices has been introduced to aid inhaled drug delivery in patients with asthma. This, and the competing claims of manufacturers, often makes it difficult for prescribers to choose the best devices for different patients and circumstances. Doctors and practice asthma nurses need to know the general advantages and limitations of each type of device, and should be fully familiar with perhaps two of each type in order to select appropriately for individual patients. The choice will depend on many factors including the patient's age and the presence of physical or cognitive impairment.

Although it has drawbacks for a significant proportion of patients, a conventional pressurised metered dose inhaler (MDI), used alone, remains a suitable delivery system for bronchodilator therapy for many adults and is convenient and inexpensive. When combined with a spacer (plus a mask in young children), the use of an MDI can be extended to include patients with poor co-ordination and is recommended for administering corticosteroids to children, or to adults who require high doses. Breath-actuated MDIs and dry powder devices require less co-ordination than a conventional MDI, and offer a less cumbersome alternative to a spacer for patients old enough (generally 6 years and over) to use them. Whichever device is used, the treatment regimen (especially for inhaled corticosteroids) should be titrated to the lowest dose required for effective control of symptoms. The switch to chlorofluorocarbon-free MDIs needs careful management, but provides a good opportunity to optimise the patient's dose of inhaled corticosteroids.

When assessing a new device, clinicians need to know how it has been tested, and whether the tests were appropriate for estimating lung deposition in patients like those in the clinician's practice. At present, it is possible to release devices such as spacers or nebulisers on to the market without adequate information on the amount of drug delivered from the device, and promotion is often based on information held 'on file' or published only in abstracts, without peer review. This is unsatisfactory: we believe that the Medical Devices Agency and Medicines Control Agency should require stricter and, preferably, independent assessment of drug delivery devices.