How to choose delivery devices for asthma
The inhalation route has many advantages in the treatment of diseases of the respiratory tract. Medication may be delivered directly to its site of action, giving a faster onset and allowing smaller doses of drug to be administered. Systemic absorption of the drug is diminished, reducing systemic side effects. The drug treatment regimen for the vast majority of patients with asthma is straightforward and is documented in recent guidelines.1The choice of which drug delivery device to use is less clear. Rather than being spoilt for choice, we are more frequently confused by the ever increasing number of devices available. What guidance may be given to the paediatrician selecting an inhalation drug delivery device for a patient? The choice depends on the device, the patient, and the drug. Our current practice is outlined in table1.
Spacer devices, used with facemasks for children unable to breathe reliably through a mouthpiece, are the first choice of device for children younger than 5 years. Nebulised delivery of bronchodilator and prophylactic medications is inefficient and expensive, and nebulisers should be reserved for those unable or unwilling to use metered dose inhalers and spacers. The use of metered dose inhalers alone, breath actuated devices, and dry powder inhalers should be discouraged in this age group. It is important to read studies pertaining to this age group with care, as conclusions of a device's suitability may be generated across a wide age range, despite inclusion of a small number of subjects younger than 5 years chosen for their ability to undertake advanced respiratory manoeuvres.
For children older than 5 years, bronchodilators may be given via a breath actuated metered dose inhaler or a dry powder inhaler. We recommend a spacer device for the administration of inhaled steroids at any age. These are normally given twice a day, for instance on waking and retiring, so arguments that the spacer is not portable are not relevant. However, for low dose steroids, if the child is unwilling to use a spacer, breath actuated or dry powder devices may be chosen in preference to the metered dose inhaler alone. There is no evidence that changing to these devices improves compliance.
Drug delivery device
There are three main types of inhalation drug delivery device, grouped by the drug dispersion method that they use: pressurised metered dose inhalers, containing a mixture of propellant and drug under pressure; dry powder inhalers, utilising the patient's inspiratory effort to disperse medication; and nebulisers, using compressed gas or the vibration of a piezo electric crystal to aerosolise liquids. Adjuncts—such as spacers or holding chambers—may also be used to improve inhalation treatment.
PRESSURISED METERED DOSE INHALERS
Pressurised metered dose inhalers are easy to actuate, but difficult to use properly. Drug is emitted at high speed and most impacts in the oropharynx. Many adults and most children use their metered dose inhalers incorrectly,2 and the necessity to coordinate inhalation with metered dose inhaler actuation means that they are not suitable for use on their own for most children.
Metered dose inhalers with extended mouthpieces, such as the Spacehaler (Evans Medical, Leatherhead, UK), are designed to reduce the speed of the emitted aerosol, reducing oropharyngeal deposition. There are no published studies of this device used by children.
Breath actuated metered dose inhalers incorporate a trigger that is activated during inhalation. In theory, this reduces the need for the patient or carer to coordinate metered dose inhaler actuation with inhalation.3 However, patients may stop breathing when the metered dose inhaler is actuated (the “cold freon effect”) or have suboptimal inspiration.4 Evaluation of their efficacy in children under the age of 6 years is limited,5 and their use should be restricted to older children and adults. Oropharyngeal deposition of steroids using these devices is still very high, and some devices incorporate a short open tube spacer. This addition may be expected to reduce extrathoracic drug deposition, although there are no published evaluations of its use.
Spacer devices were developed to overcome some of the problems of metered dose inhalers. There are two main types.
Valved holding chambers (for example, Volumatic (GlaxoWellcome, Uxbridge, UK), Nebuhaler (AstraZeneca, Kings Langley, UK), Babyhaler (GlaxoWellcome), Aerochamber (Trudell Medical, Ontario, Canada) are what most practitioners refer to as spacer devices. They allow the patient to breathe tidally from a reservoir of drug. Facemasks allow spacers to be used by infants and children too young to use a mouthpiece. However, delivery of drug by a mouthpiece is more efficient, and patients should use this in preference to a facemask as early as possible.
Extension devices may be used with pressurised metered dose inhalers. They provide a “space” between the inhaler and the patient, allowing the aerosol to slow and propellants to evaporate, reducing the size of drug particles from metered dose inhalers, and trapping large particles in the spacer. Examples include the Integra for becloforte, the Optihaler, and ACE spacer. Coordination is still required for optimal drug delivery. Because of this, these devices are not suitable for young children and may be inappropriate for the large number of patients, of any age, who have difficulty in coordinating actuation of a metered dose inhaler and inhalation.
The size of the spacer may also affect the amount of drug available for inhalation, and this will vary with the drug prescribed.6-8 The clinician should be aware that data about a spacer derived from studies with one drug might not apply to others. Similarly changing from one spacer to another may be unimportant with some drugs, but be critical for others, leading to overtreatment or treatment failure. Output from spacer devices may vary greatly depending on static charge. Drug output from a spacer lined with an antistatic agent may increase by a factor of 3 or more. Static charge of polycarbonate spacers will vary greatly depending on the washing procedure used and the use of the spacer. Although non-electrostatic spacers should overcome this variability they are not currently available in the UK.
DRY POWDER INHALERS
Dry powder devices do not have the associated problem of coordination difficulties experienced when a metered dose inhaler is used. However, oropharyngeal deposition of inhaled drug is high, and spacer devices are still advocated for patients requiring higher doses of inhaled steroids. In the UK, the Accuhaler (Discus (GlaxoWellcome))9 and the Turbohaler (AstraZeneca)10 are the most popular. Comparative studies of these two multidose devices are confusing. The Accuhaler is twice11 or equally10 efficient at delivering medication as the Turbohaler. In vitro studies suggest that the Accuhaler is more consistent in the dose delivered at different flow rates, although it has a reduced fine particle mass and emits more large particles than the Turbohaler.12 Again the number of dry powder inhalers are continuing to increase. The Clickhaler device (Medeva, Leatherhead, UK) is designed to look similar to a metered dose inhaler, even mimicking the press down action of a metered dose inhaler to load a unit dose for inhalation.
Nebulisers are mentioned only briefly because of their decreasing role in asthma management. Many new designs have been introduced without formal information on the output of drugs such as steroids being available. This is of concern as recent laboratory studies have shown that the amount of budesonide a child is likely to inhale from different devices may vary by up to 400%.13Most of the prescribed medication for nebulisers never reaches the lungs. Of the dose placed in the nebuliser chamber, perhaps two thirds remains there at the end of nebulisation. Two thirds of the dose released from the nebuliser may be released during expiration and passes into the surrounding air. With many nebulisers, less than 10% of the prescribed dose reaches the lung. The nebuliser does not rely on patient cooperation or coordination to work, although deposition is improved by the use of a mouthpiece rather than a facemask, by holding the facemask close to the patient,14 and by the patient breathing quietly, rather than crying or rapid breathing.15
The Halo-lite (Medicaid, Pagham UK) is the only nebuliser currently able to release a predetermined dose with accuracy.16 It monitors the breathing pattern of the patient, generates pulses of aerosol during early inspiration only, and allows titration of the inhaled drug dose. As the patient's breathing pattern is known to affect the delivery of drug from nebulisers, this type of device may prove more efficient and reliable than conventional nebulisers, although no published studies have examined this device when used by children. The inclusion of electronic devices used to monitor compliance, currently used in research trials, would be of great help in monitoring asthma patients who are responding poorly to treatment.
Dose variability with age
The patients' breathing pattern will affect the dose of drug delivered from a nebuliser or spacer device.15 The amount of drug delivered from a polycarbonate spacer increases with tidal volume,17 and more drug may be delivered from small rather than large volume spacers when these are used by infants and young children.18
From nebulisers, the inhaled dose increases with age up to the point where inspiratory flow exceeds nebuliser output,19 and the dose inhaled per kilogram is constant up to 6 months of age, declining after this. Only infants will inspire with a lower flow than that of the nebuliser output, and only then will the dose received be affected by the child's size. The importance of this observation has been highlighted in relation to bronchoprovocation studies in infants and young children.20 Data from Salmon et al suggests that up to 1.5% of the dose of nebulised sodium cromoglycate will be deposited in the lungs of children from 6–36 months of age.21 Assuming approximately 10% of a nebulised dose is deposited in the lungs of an adult, the dose per kilogram body weight can be calculated. For example, a 70 kg adult will receive 0.14%/kg (10% ÷ 70), whereas, using Salmon's data, young children will receive up to 0.15%/kg (1.5% in a 10 kg infant). This suggests that although there may be poor drug deposition in infant lungs, this is compensated for by their small size, so that the final dose reaching the lungs per kilogram body weight may be very similar to that of an adult.
There have been few clinical studies of lung deposition of nebulised aerosols in children. Alderson et al found that lung deposition increased with age,22 whereas others23 24 have found no relation between age and total lung deposition of nebulised aerosols.
The most effective inhaler for any given patient is the one that the patient will use on a regular basis and in an effective manner. Patient compliance with inhaled medication is poor. In studies using electronic timer devices attached to metered dose inhalers, where subjects knew that compliance was being monitored, on only half of the study days was the prescribed medication taken, whether this was self administered by adults or children25 26 or where administration was supervised by a parent.27 Poorly compliant patients are at increased risk of exacerbations.28 Although there is no evidence that compliance is improved by changing to a different inhaler device, small, unobtrusive devices are often marketed on the basis that they are more acceptable to the patient, and will therefore be used more. There is increasing interest in drug delivery devices that can both monitor and prompt patient use.
Age and drug specific recommendations can be made (table 1), and are a useful starting point. At present clinical management should be based on prescribing a device that the patient will use, and encouraging adherence to prescribed treatment. Clinicians should be aware of the limitations of each type of device, and the optimum methods of use for each. They should then pick one or two of each type of device for use in their practice and become completely familiar with these, using table 1 as a guide. When considering new devices, clinicians should ask how the devices were tested, and whether the tests are appropriate to estimate lung deposition. Whichever device is used the dose of drugs, such as corticosteroids, should be titrated to the lowest dose required to control symptoms.