Spacers and Valved Holding Chambers

Introduction

The use of standard pressurized metered-dose inhalers (pMDIs) alone has a number of disadvantages. Due to the high velocity at which drug particles are emitted from the pMDI, patients must consistently be able to closely coordinate the actuation of the pMDI with the start of inhalation to minimize oropharyngeal impaction and improve therapeutic efficiency. This can be difficult for many patients, particularly children ¹ and the elderly, ² and for parents ³ or caregivers attempting to administer therapy via pMDI to patients. In those patients who are able to utilize the pMDI alone effectively, a significant amount of the actuated drug will still be impacted in the oropharynx instead of depositing in the lungs. ⁴ Non-pulmonary impaction of drug may be reduced if the patient can be trained to take a slow, deep inhalation after actuation, but irrespective of technique, significant oropharyngeal impaction is still likely to occur. ⁵

Spacers, both valved and non-valved holding chambers, were developed to address the problems of coordination and extrapulmonary drug deposition. A review of the history of spacer development makes interesting reading. ⁶ Spacers are accessory devices placed between the pMDI and the patient's mouth. The pMDI is actuated into the spacer and the patient inhales the drug available as an aerosol cloud within the spacer. While spacers are less convenient and portable than the use of pMDIs alone, there are multiple advantages to spacer use: 1) reducing the need for coordinating actuation with inhalation, since the actuated drug is held within the chamber and is available for inhalation for a short time post-actuation; 2) the high velocity at which the drug is emitted from the pMDI actuator is reduced due to the increased distance/time between actuation and entry into the patient's mouth; and 3) the larger particles which have the greatest inertia at high velocity and which are most likely to impact in the mouth or throat, impact or sediment out in the spacer instead, while the” respirable” drug is still available to be inhaled and deposited in the lungs.

Non-valved spacers may be used by patients who can be trained to take a single slow, deep inhalation after actuation, but valved spacers (VHCs or valved holding chambers) would normally be recommended for inhalation with tidal breathing, so that the exhaled breath is vented away from the spacer chamber. However, homemade (unvalved) spacers made from plastic bottles or even styrofoam coffee cups have been tested. A spacer made from a 500 ml soft drink bottle has been shown to be efficacious and may be a low-cost alternative in developing countries.^7,8 Small unvalved extension devices such as the Microspacer®, which increase the distance between the point of aerosol emission and the back of the patient's throat, have also been commercially developed. These devices must also be used with a single maximal inhalation rather than tidal breathing.

The aerosol dose available for inhalation (i.e. the amount of drug emitted from the spacer mouthpiece) is reduced when spacers are used. Arguably, the majority of the drug loss occurs in the particle size range that would normally deposit in the oropharynx, rather than in the lungs. The magnitude of the drug loss, and the proportion of it that would come from the” respirable” fraction that is most likely to deposit in the lungs, depends on several factors shown in Table 1.

Despite these variable factors, the efficacy of pMDI-spacer use is indicated by the fact that this combination has replaced the use of nebulizers for bronchodilator treatment of acute, severe asthma exacerbations in emergency departments in many countries. Increased lung delivery of bronchodilator has been shown with pMDI-spacers compared with nebulizers, ⁹ and equivalent or increased clinical efficacy has been found using pMDI-spacers compared with nebulizers in adults and children.^10–13

When reviewing the published literature in this field, it is important to distinguish between drug delivery from the pMDI-spacer combination, which is determined by a combination of device characteristics and administration technique (Table 1), and drug deposition, which is determined by a combination of all the factors described in Table 1. Drug delivery is generally an in vitro assessment, measuring the amount of drug emitted from the mouthpiece of the chamber, which can be equated to the dose which would be delivered to the patient's mouth or the total body dose. Drug deposition is a much more complex assessment which measures the amount of drug depositing in the patient's lungs as well as quantifying extrapulmonary deposition.

Spacer Design Characteristics

It is difficult to study the individual spacer design factors in isolation, because each spacer comes as a package which incorporates a given volume, valve design and construction material. Studies with earlier spacer designs produced data indicating that larger spacer volumes tended to result in increased lung delivery. ¹⁴ The Volumatic™, Nebuhaler® and Fisonair® are examples of large volume spacers (>700 ml in volume) available at that time—of these, only the Volumatic™ is still available commercially these days.

Research conducted on spacers in the early days indicated that accumulation of electrostatic charge on the inner surface of plastic spacers could markedly reduce the amount of drug available for inhalation.^15,16 These effects have been minimized in the past by the use of an ionic detergent coating on the inner surface of the spacer ¹⁷ or by the use of metallic spacers. ¹⁸ “Priming” or coating the inner spacer surface with multiple pMDI actuations was also a method recommended to minimize electrostatic charge; ¹⁹ however, the effectiveness of this method may be dependent on the pMDI formulation used.

Nowadays, major advances in valve design and low or anti-static construction materials over time have resulted in the development of a variety of more efficient small volume spacers that appear to offset the effect of spacer volume, such that modern small volume spacers produce equivalent or better drug delivery than the older large volume spacers. ²⁰ The AeroChamber Plus® Flow-Vu® (135 ml) and Optichamber Diamond (140 ml) are examples of modern anti-static small volume spacers. Patient preferences for smaller, more portable devices have meant that developmental advances in this area have focused on smaller volume spacers, and almost all large volume spacers are no longer commercially available.

pMDI Formulations

The effect of pMDI formulation on efficiency of drug delivery has been covered in other sections of the textbook. One fact that is worth highlighting in this section is the use of spacers with extrafine pMDI formulations. The reduced particle size emitted from the pMDI together with a slower emission velocity can result in increased lung deposition with reduced oropharyngeal impaction,^4,21 making the use of a spacer potentially less critical. Additionally, the impact of miscoordination and errors in inhalation technique on lung deposition is potentially reduced. ²²

Face Mask Versus Mouthpiece

Spacers may be used with a mouthpiece or face mask. Face masks must be used for infants and young children, and the age at which advice is given to change to a mouthpiece is variable in different countries. Traditionally, it is assumed that drug delivery and lung deposition is much lower when using a face mask than with a mouthpiece, primarily due to studies such as the nebulizer deposition study published by Chua and colleagues. ²³ The inefficiency of nasal inhalation of conventional-sized aerosol particles combined with the lack of a good seal of the face mask to the face in many cases contributes to this advice. However, recent advances in face mask design and construction material, with improved flexibility potentially resulting in a better fit of the mask to the face, have increased the efficiency of drug delivery with these devices. ²⁴ While it is still probable that mouthpiece delivery would still be more efficient, in patients with poor inhalation compliance it is questionable whether a mouthpiece would deliver more drug than a face mask. ²⁵ ERS-ISAM recommendations are to use a face mask in children under 3 years of age and to transition to a mouthpiece in children aged 3-6 years. ²⁶

Device Use Parameters

Factors such as the effect of multiple actuations into the spacer prior to inhalation and varying delays between actuation and” inhalation” were elegantly characterized in a series of in vitro studies by Barry and O’Callaghan in the 1990s.^15,16 There have been many developments since then in pMDI formulations (including the development of extrafine formulations) as well as improvements to spacer design and construction. However, until evidence is shown to the contrary, their recommendations to minimize the delay between actuation and inhalation and only introduce a single actuation into the spacer prior to each patient inhalation should be adhered to.

Spacers may be used with tidal breathing or slow maximal inhalations. There is evidence to indicate that the maximal inhalation technique increases lung deposition ²⁷ but tidal breathing must be used in infants and very young children. ERS-ISAM guidelines recommend tidal breathing in children under 6 years with either facemask (<3 years) or mouthpiece (3–6 years), whereas children aged 6 years and older should be trained to use a single, slow maximal inhalation with a mouthpiece. ²⁶ Lower lung deposition is achieved when aerosol is delivered to crying or struggling infants and children.^28–31

Patient-Related Physiological and Cognitive Factors

Factors relating to patient groups of different ages as well as differing disease conditions are covered in detail in other sections of this textbook. Despite the fact that the pMDI-spacer is the recommended choice of device in many countries for infants and preschool children with asthma, lung deposition in this age group is lower ²⁸ than that seen in the other age groups. ³² There is little published data on lung deposition from spacers in the elderly, but it has been shown that older patients exhibited more inhaler use errors and found it more difficult to simultaneously coordinate actuation of a pMDI used without a spacer, with inhalation. In addition, older patients were more likely to continue to use pMDIs incorrectly after training, ³³ indicating that the spacer use may be indicated in this age group also.