Pressurised metered-dose inhalers (pMDIs) are the most widely used devices for delivering inhaled medication because of their effectiveness, low cost and relative simplicity of use.2 Despite possessing a number of advantages, pMDIs also have some inherent limitations. First, the spray from pMDIs comprises large rapidly moving propellant droplets that readily impact in the oropharynx, so that no more than c.20% of the emitted dose reaches the lungs. Second, many patients are unable to use pMDIs correctly despite adequate instruction.3 Crompton4 has estimated that as many as half of the adult patients and a greater proportion of children are getting little or no benefit from using pMDIs because of poor inhalation technique. The most important errors are dys-co-ordination between pMDI actuation and inhalation, and the so-called ‘cold Freon’ effect, which may cause some patients to stop inhaling completely when the cold blast of propellant strikes the back of the throat.3,4 These errors are particularly important because they can result in reduction of aerosol being deposited in the lung and, consequently, reduction in the clinical effect.3

Several inhalation aids have, therefore, been developed to reduce problems of poor inhalation technique with the use of pMDIs.5-7 The term ‘spacer devices’ covers a range of inhalation aids of varying dimension and complexity, often known alternatively as ‘add-on devices’, ‘extension devices’ or ‘holding chambers’. For the purposes of this paper, they will all be described by the term ‘spacer’. Their characteristics and effects on delivery and lung deposition of inhaled medications will be reviewed and the published data evaluating their clinical efficacy in patients with reversible airway obstruction will be discussed.

Characteristics of Spacer Devices
Spacers are extensions to a pMDI with a port at one end to which the pMDI is attached and a mask or mouthpiece fitted at the other end. These devices constitute a volume into which the patient actuates the pMDI and from which the patient inhales without necessarily having to co-ordinate the two manoeuvres. By acting as an aerosol reservoir, these devices slow the aerosol velocity and increase transit time and distance between the pMDI actuator and the patient’s mouth, allowing particle size to decrease.5,6 As a result, the respirable portion of the aerosol increases, thus improving deposition of the aerosol particles to the lung periphery.5,6 Moreover, because spacers trap large particles comprising up to 80% of the aerosol dose, only a small fraction of the dose is deposited in the oropharynx, thereby reducing side effects, such as throat irritation, dysphonia and oral candidiasis, associated with inhaled medications delivered by the pMDI alone.5-7 Some spacers are also equipped with valves that provide audible cues to patients to inhale more slowly; these devices generate a whistling sound when inspiratory flow rates exceed a threshold value, above which turbulent conditions lead to excessive impaction of the aerosol dose in the upper airways.

On the negative side, the spacer devices are generally bulky and difficult to carry around, and the encumbrance of some of them may detract from the appeal of the pMDI to the patients, especially among the paediatric population. Some spacers are designed to fit only a single type of pMDI. Furthermore, spacer devices do not completely obviate errors in pMDI inhalation technique. Indeed, since spacers differ widely in design, it is likely that optimal inhalation technique may differ from one spacer to another. Generally, patients using pMDIs with a spacer still have to be trained to inhale slowly (≤30 litres/minute) and to hold their breath after aerosol inhalation for at least 10 seconds.6 A too-long delay in inhalation after pMDI actuation may lead to excessive loss of the respirable dose within the device.8Some patients tend to discharge multiple doses from a pMDI into a spacer before inhalation. The turbulence created by this practice leads to coalescence of small particles into larger particles and excessive deposition on the walls of the spacer, thus reducing the respirable dose per actuation.9 Static electricity accumulates on many plastic spacers, especially when handled by the patient. This may result in some of the aerosol dose suspended within the device being attracted to the spacer walls, and therefore not being available for inhalation.6 It was found that washing the spacer in soapy water, rinsing in tap water and then allowing to air dry reduced the static charging on spacer surfaces, increasing both lung deposition10 and clinical effects11 of inhaled medications.

Advantages and disadvantages of spacers compared with pMDIs alone are summarised in Table 1. Table 1: Advantages and Disadvantages of Spacer Devices

Several different types of spacers are commercially available. They differ in a number of characteristics, including volume, length, shape, construction material, rigidity (i.e. rigid or collapsible), presence or absence of the valve system, and interface with the airway opening (e.g. mouthpiece, face mask, adaptor to ventilator tubing).

Generally, spacers fall into three categories (see Table 2):

• open tube spacers that simply distance the inhaler mouthpiece from the patient’s oropharynx;
• holding chambers, which include a one-way inhalation valve in the mouthpiece intended to retrain the aerosol within the device until the patient inhales; and
• reverse-flow devices, in which the spray is fired away from the patient either into a collapsible bag or into a small volume through which outside air is entrained.

Table 2: Types of Spacer Devices

The varying characteristics of the different types of spacers may affect the amount of respirable dose delivered from pMDIs to which these spacers are interfaced. Bisgaard et al.12 showed that the dose of budesonide delivered from a pMDI plus spacer differed by up to as much as two-fold, depending on the type of spacer used. A metallic, pear-shaped nonelectrostatic spacer with separate inspiratory and expiratory valves delivered the highest dose, followed in descending order of efficiency by the Babyhaler, a 350ml plastic cylinder spacer with both inspiratory and expiratory valves, the Nebuhaler a 750ml plastic, pear-shaped spacer, and the AeroChamber, a 145ml plastic cylinder with a single one-way valve.12 These differences in dose delivered were likely due to less electrostatic attraction of charged aerosol particles to the walls of the non-electrostatic spacer, as well as to the presence of a separate inspiratory and expiratory valve design of the non-electrostatic spacer. Different spacers may perform differently, depending on the particular pMDI with which they are used. Ahrens et al.13 measured the fine particle dose of β-adrenergic agonists and corticosteroids delivered via the pMDI alone and via the four different holding chambers. They found that the respirable dose delivered from the same pMDI varied with the type of spacer used. These findings suggest the need for further studies to evaluate the interaction between pMDIs and the individual types of spacers with which they are used.

Effects of Spacers on Drug Deposition
Compared with the pMDI alone, spacers, especially the holding chambers, markedly reduce oropharyngeal drug deposition.5 The reduction in oropharyngeal deposition arises because spacer devices have a sizeselective function, retaining larger particles on the spacer walls and allowing smaller particles to pass through to the patient. Thus, a proportion of the particle that would have been deposited in the oropharynx is transferred to the spacer itself.5

Compared with the pMDI alone, lung deposition is generally either increased or unchanged by using spacers.5 Several factors likely account for these variable findings. For instance, the inhalation techniques used, as well as the amount of electrostatic charge present in the spacer, may affect drug delivery and, consequently, lung deposition.5-7 Differences in the radiolabelling methods employed in the studies may also play a role.6 For these reasons, caution should be taken in comparing data derived from lung deposition studies performed with different spacer devices.

Spacers vary widely in their shape and size, with volume ranging from 50ml to 750ml. Although it is not an invariable rule, large-volume spacers appear to increase lung deposition to a greater extent than small-volume tube spacers.5-7 Many spacers have a oneway valve that may influence drug deposition in the lungs.The amount of drug deposited in the lungs depends upon the nature of the aerosol formulation used with a given spacer, or upon the the type of spacer used to deliver a given formulation. For instance, Matthys14 has shown that when a radiolabelled formulation of sodium cromoglycate was given via three different spacers, the drug dose deposited in the devices, oropharynx and lungs varied widely between the three spacers. Conversely, administration of three different drug formulations delivered via the same spacer resulted in significantly different values of lung deposition.14

Effects of Spacers on Clinical Responses
Despite the large numbers of clinical trials performed with a variety of spacers in patients with obstructive airway diseases, there are still difficulties in demonstrating differences in the clinical responses between spacers and other inhalation devices.15 Part of the confusion stems from the fact that the inhalation techniques used in some studies are inadequately controlled or inadequetely described. Generally, if a patient is using the pMDI alone with adequate technique, spacers do not add great, additional benefits, whereas if someone is using the pMDI ineffectively, a spacer may make the difference between a good and poor therapeutic effect. König15 described this situation by referring to spacers as neither a ‘gimmick’ nor a ‘breakthrough’, but as having a role somewhere between these two extremes. Some studies have failed to show differences in the clinical response between spacers and other inhalation devices, possibly because these studies had insufficient power to detect a difference of clinical significance, or because they are conducted close to the plateau of the dose-response curve.5-7 Even if a spacer is found to be more efficacious than other inhalation devices in a well designed clinical trial, it should be remembered that subjects who agree to take part in such trials may have received extensive coaching in spacer use. As such, they may not be typical of the general population. In addition, changing from one spacer to another may be of scarce importance with some drugs but critical for others, leading to over-treatment or treatment failure. For these reasons, clinicians should be aware that data about a spacer derived from clinical studies with one drug may not apply to others.

Spacers Compared with Nebulisers
Several clinical studies2,5,16 have shown that spacers are at least as effective as nebulisers in the treatment of severe acute asthma attacks. However, advantages of spacers over nebulisers include improved delivery efficiency, greater convenience, an inherently low risk of pulmonary infection, greater speed of administration and cost-effectiveness. Holding chambers, such as the Babyhaler, equipped with facemasks are a useful alternative to nebulisers in delivering inhaled medications for long-term treatment of infants and children with asthma.5 In these patients the use of holding chambers rather than nebulisers for delivering inhaled medications results in a more rapid discharge from the hospital and in a reduction in drug-related costs.17,18

Spacers Compared with pMDIs Alone
Several studies5,15 have investigated the clinical efficacy of spacers compared with that of pMDIs alone. In terms of bronchodilation, some studies19,20 suggest that spacers do not confer any additional benefit when pMDIs alone are correctly used; in contrast, other investigations21,22 show that, compared with pMDIs alone, spacers may actually enhance bronchodilation. Several reasons may account for the discrepancy. It is likely that the favourable results obtained with spacers in some studies may be due to inclusion of patients with poor inhalation technique. Furthermore, detection of the additional bronchodilator effect exerted by spacers may be, at least partially, impeded by other factors such as the respiratory manoeuvres required for assessing bronchodilation, the method used to quantify it, and differences in the level of patients’ baseline airway calibre. Recently, the effects of administration of a β2-adrenergic bronchodilator through a pMDI alone and two different spacers (the Volumatic large-volume spacer, and the Jet smallvolume spacer) on the magnitude and velocity of large and small airway bronchodilator response have been compared in asthma patients who correctly operate a pMDI.23 It was found that, even in patients with good inhalation technique, both spacers enhanced bronchodilation compared with the pMDI alone. Furthermore, compared with both the Jet and the pMDI alone, the Volumatic allowed faster and larger small airway dilation with less than half the dose of the bronchodilator drug.23

With regards to inhaled steroids, it has been shown that in severe asthma patients treated with a high dose of beclomethasone dipropionate, the addition of a spacer to the pMDI not only markedly reduced the incidence of oral candidiasis but also resulted in a continuing trend of improvement in airflow obstruction over three to six months, which did not occur in patients using the pMDI alone.24 Of note, British Asthma Guidelines25 recommend the use of large-volume spacers for delivering high doses of inhaled corticosteroids (ICS) (>1000μg/day for beclomethasone, >500μg/day for fluticasone) in asthma patients.

Spacers Versus Dry Powder Inhalers
As for the comparative studies between spacers and pMDIs alone, the results of studies aimed at ascertaining whether differences exist in the clinical response to administration of inhaled medication via a pMDI plus spacer or via DPIs have yielded conflicting results.16 For instance, a recent study26 performed in asthma patients suggests that the magnitude of bronchodilation following salbutamol administered via a spacer is greater than that obtained by using two different DPIs; however, the differences are minimal and, in the authors’ view, of no clinical significance.26 Other studies27,28 performed in asthmatic children suggest that terbutaline is equally efficacious when administered via a spacers or via a DPI, the Turbohaler, at the same nominal dose. In contrast, studies with ICS29,30 support the equivalence of budesonide administered via a spacer or via a Turbohaler, but the latter at half of the nominal dose for the spacer. Dissimilarities in the types of inhalation devices, the inhalation methods used, and the characteristics of patients studied may account for these conflicting results. Recently, the authors have undertaken a study to compare the magnitude and time course of changes in lung function and dyspnoea intensity following different salbutamol doses inhaled via a DPI, the Diskus, or via the Volumatic spacer in asthma patients.31 This study was carried out in patients with induced, rather than spontaneous, bronchoconstriction to obtain a standardised level of reduction in baseline airway calibre, thus avoiding the confounding effects related to different degrees ofspontaneous bronchoconstriction. It was found that the magnitude of salbutamol-induced changes in forced expiratory volume in one minute (FEV1) and dyspnoea intensity score was not affected by either the salbutamol dose or inhalation devices, possibly because, even with the lower salbutamol dose, the responses had already reached the flat part of the doseresponse curves.31 However, increases in small airway patency and lung volumes induced by salbutamol were markedly higher in Volumatic than Diskus trials.31 The same inhalation devices have been used in a subsequent study32 aimed at evaluating the speed ofthe bronchodilator response following salbutamol administered via these devices in asthma patients. It was found that salbutamol via the Volumatic provided faster reversal of induced bronchoconstriction thanvia the Diskus.32 Furthermore, twice the salbutamol dose administered via the Diskus was needed to obtain a velocity of bronchodilation similar to that obtained when salbutamol was administered via the Volumatic spacer.32

Conclusion
More than 20 years ago, König15 posed the question whether spacers represented a ‘breakthrough’ or a ‘gimmick’, and concluded that they were neither a breakthrough of such magnitude that they should be made mandatory for all pMDI users, nor a useless gimmick, but that they had a value somewhere between these extremes. Essentially, this seems to be the situation still pertaining today. However, recent data from the authors’ laboratory23,31,32 suggest that, compared with both pMDIs alone and DPIs, spacers may increase the response to short-acting ®- adrenergic bronchodilators, even in patients with correct inhalation technique. Furthermore, spacers are recommended for delivering high doses of ICS, and may permit a lower maintenance dose to be used.25 Thus, based on these considerations, we believe that every pMDI may be routinely fitted with a spacer, especially in situations where correct pMDI use is unlikely.