Adults
Inhalation of bronchodilators and glucocorticosteroids results in faster onset of action with fewer systemic side-effects than taking the same drugs orally or parenterally.1
To be effective, an inhalation device must produce an aerosol of medication with a significant dose of particles in the so-called respirable range that enters the lower airways. Inhalation devices should also minimize local (oropharyngeal) and systemic side-effects of the drug and should be simple to use, portable, durable, unobtrusive and cost effective.2 Because the efficacy and side-effects of inhaled medications are highly dependent on the device, drug and user, the response to a drug delivered from a specific inhaler may differ from the response to different drugs of the same class delivered by the same inhaler or the same drug delivered by a different device. Caregivers must be familiar with the characteristics of the devices they prescribe and dispense,3 and they must ensure that their patients are able to use the prescribed devices properly.
Pressurized metered-dose inhalers
The pressurized metered-dose inhaler (pMDI) is the most widely used delivery system. As in other delivery systems, even when used correctly, only about 10%-20% of the nominal per puff dose reaches the targeted airways.4 Fortunately, only a small amount of drug is needed to produce a useful clinical effect. There is general agreement on the technique for optimum use of the pMDI (Table 1).
The so-called "open-mouth" technique is most often recommended because it is believed that this method provides a space in which the aerosol cloud is "conditioned," that is, the velocity of the aerosol cloud slows and aerosol particle size decreases so that drug deposition in the distal airways is enhanced. However, many get good results from a pMDI using a "closed-mouth" technique, in which the inhaler mouthpiece is inserted in the mouth, as long as the tongue is not obstructing it.
Most recommendations suggest that patients should not exhale forcefully and completely to residual volume before inhaling from a pMDI for fear that bronchospasm may result in patients with marked airway irritability. However, for most patients, this is not a concern, and a slow complete exhalation to residual volume may be followed by slightly better drug delivery to the lung than incomplete exhalation. Another common recommendation is that at least 30 seconds elapse between pMDI actuations to allow recharging and reconditioning of the next dose. The clinical importance of this between-dose delay is not known but is likely minimal.
Approximately 40% of patients first assessed in a specialized respiratory care centre or pulmonary function laboratory will not use their pMDIs in the best manner.5-7 Whether this is true of alternative inhalation devices is not clear. The most common difficulties are failure to coordinate actuation of the device with inhalation (the "aim-shoot-breathe" manoeuvre) and an involuntary cessation of inhalation when cold aerosol particles reach the soft palate. If inhaler technique can be improved and maintained, clinical improvement is likely. For some patients, this may require adding a spacer to the pMDI or switching to a breath-activated device such as a dry-powder inhaler (DPI). If technique with a pMDI is good, the patient is satisfied with the device and the disease is well controlled, little or no increase in clinical efficacy is gained by switching to a DPI or adding a spacer.8
Until recently, all pressurized aerosol inhalers used chlorofluorocarbon (CFC) propellants. These substances are now known to be damaging to stratospheric ozone levels and are being withdrawn from industrial, domestic and medical uses under an international agreement (the Montreal protocol).9 In the next few years, CFC-containing inhalers will be withdrawn as alternatives, such as hydrofluoroalkane (HFA), become available.
HFA-driven inhalers are effective and safe, but caregivers must be aware of slight differences in characteristics between CFC and non-CFC driven inhalers.10 For example, patients switching to a non-CFC inhaler must be warned to expect a different taste and a different aerosol sensation.11 Alternative-propellant inhalers may also have deposition characteristics and, therefore, clinical efficacy that differs slightly from the comparable CFC inhaler.12 Therefore, caregivers must treat the shift from CFC to non-CFC aerosol inhalers as they would any other change in inhaler format; that is, they must titrate the inhaler dose to the least amount of medication needed to achieve the desired clinical effect.
Metered-dose inhalers with spacers
The use of add-on "holding chambers" or "spacers" has increased recently. There are 2 reasons to consider using a spacer with a pMDI or DPI: inability to use the pMDI or DPI correctly; or persistent local oropharyngeal side-effects associated with inhaled glucocorticosteroids. The addition of a spacer to the pMDI can usually ensure aerosol delivery to the airways for most patients who are having difficulty.
Several types of spacers are available. Those with one-way valves can hold the aerosol discharged from the pMDI in suspension for 2-3 seconds, thereby easing coordination problems and permitting time for the patient to inhale slowly. It is possible to misuse a pMDI with a spacer and miss the dose, although the prevalence of this problem is not known. Common mistakes with the pMDI and spacer combination include inhaling from the spacer before actuating the pMDI and waiting too long after actuation before inhaling.13 (See Table 2 for the recommended technique.) When multiple puffs from a pMDI are required, each dose should be inhaled separately from the pMDI and spacer combination because charging the spacer with multiple puffs is associated with reduced dosing to the airways compared with inhaling each puff separately.13,14
The use of a CFC-driven pMDI with spacer produces a clinical effect at least equivalent (and generally superior) to that of a correctly used pMDI alone. In some instances it may increase the amount of drug deposited in the airways, possibly because spacer devices act to condition the aerosol, slowing the jet of medication and allowing the propellant to evaporate. This influences particle size in favour of finer more respirable particles. Increased drug deposition is more likely when patients who have normal tidal volumes use a large-volume (e.g., 750 mL), valved spacer, although there is little evidence that such spacers offer any significant clinical advantage over smaller (e.g., 150 mL) valved spacer devices. However, when tidal volumes are very low (e.g., in children and the elderly), spacer volume may have an inverse relation to airway drug deposition due to dilution of the drug in larger spacers, coupled with low-volume inspirations. Whether this theoretical concern is clinically significant is not yet known.
As a cost-saving measure, caregivers or patients sometimes construct homemade holding chambers. Although devices made from recycled plastic containers or Styrofoam hot beverage cups may work, their delivery characteristics are untested and must be regarded as unreliable. If careful prescribing and monitoring of inhaled medication indicates that the patient is best served by a spacer, a commercially manufactured and validated device should be purchased; third-party reimbursement agencies such as insurance companies and provincial formularies ought to reimburse for these devices on the same basis as for the drugs they deliver.
By removing large aerosol particles that are not useful for therapy, spacer devices can reduce oropharyngeal deposition of glucocorticosteroid and, thus, help to reduce or prevent local oropharyngeal side-effects such as thrush and dysphonia. Rinsing the mouth after a dose of inhaled glucocorticosteroids can also significantly reduce the incidence of local side-effects, regardless of the inhalation device used.
Several potential problems with spacer devices have not been addressed adequately by clinical research and appropriate education of caregiver or patient. For example, the reduction in deposition of large particles in the oropharynx is often perceived by patients as a reduction in drug delivery and is apparently a reason for noncompliance with the device. Compliance with the caregiver's recommendation to use a spacer has never been quantified and the rate of compliance may be low.
Data suggest that caregivers have little knowledge of optimum spacer use and that this ignorance extends to matters of care and cleaning.15 Holding chambers should be replaced when damaged or worn. This implies that the chambers should be inspected periodically by the caregiver - every 3-6 months seems reasonable. For plastic devices, an electrostatic charge may be present when the device is new, a problem that can be worsened by inappropriate cleaning, especially if the device is toweled dry. The electrostatic charge can cause aerosol medication to adhere to the sides of the spacer so that total drug delivery and, consequently, lung deposition are reduced.16 In general, plastic holding chambers should be washed in a dilute solution of household detergent. The chamber should not be rinsed after washing and the device should be allowed to air dry without toweling. The thin film of detergent adhering to the walls of the chamber reduces electrostatic build-up.
Dry-powder inhalers
Various DPI devices are available. Currently, all are breath-actuated, effectively eliminating the coordination problem seen with the pMDI alone, and all are free of CFC and HFA propellants. For these and other reasons, the use of DPIs to deliver asthma medications is increasing.
Most adult patients find all DPIs easier to use than a pMDI alone, and switching from a pMDI to a DPI generally results in no loss of therapeutic control. There can be significant differences in lung deposition efficiencies among the various DPIs, but it is not clear whether these differences are clinically important, particularly for bronchodilators that ideally are taken as-needed using a sufficient number of inhalations to achieve clinical relief. Differences in lung and oropharyngeal deposition of inhaled glucocorticosteroids among DPIs may be clinically relevant.
The greatest single problem associated with all DPIs is inadequate inspiratory flow rate.17 In some devices, the powdered medication may clump when the humidity is high, thus reducing effectiveness. Reduced efficacy will result if a patient exhales into the device before inhalation, as the dose will be expelled from the DPI. The next dose may also be affected by the added humidity of the patient's exhaled breath. Additives in some DPIs can cause cough and irritation. Some DPIs cause a slight sensation of drug entering the mouth (in contrast with the pMDI alone), causing some patients to feel that the device is malfunctioning.18 Appropriate patient education is necessary.
The correct way to use a DPI is device specific (Table 3); some come preloaded with multiple doses, whereas others require manual loading of doses or dose packs. In contrast to the pMDI technique, a rapid rather than a slow inhalation is recommended for optimum airway deposition.
Bioequivalence and systemic side-effects of inhaled medications
Systemic bioavailability of inhaled medications is a complex issue. Although there appear to be minimal systemic side-effects when aerosol glucocorticosteroids are used in low doses, high doses of inhaled glucocorticosteroids (e.g., more than 1000 μg/d of beclomethasone, budesonide or equivalent) may create new problems. For example, most systemic side-effects from inhaled medications (e.g., adrenal suppression, altered bone metabolism) appear to be related to absorption via the bronchial circulation of the inhaled portion rather than the swallowed portion of the dose.19,20 The potential for such side-effects is thus modulated, not only by the type of medication, but also be the efficiency of the delivery device used. Although the clinical implications of this phenomenon are not yet known, they could be of particular concern in postmenopausal women and in children in terms of the effects of inhaled glucocorticosteroids on bone metabolism and growth.
Wet nebulization
Wet nebulizers may be subdivided into jet and ultrasonic models and, as for pMDIs and DPIs, drug delivery from these devices also involves a complex interaction among the device, the drug formulation, the patient who inhales the drug and the patient's disease. Wet nebulizers are employed chiefly for the delivery of large bronchodilator doses during acute asthma attacks and, occasionally, for patients unable to use other inhalation devices. The output characteristics of various wet nebulizer systems vary greatly; drug deposition efficiencies can vary at least 10-fold depending such factors as the model of the nebulizer, the fill volume, the flow rate of the driving gas, whether mouthpiece or nose and mouth (mask) breathing is used and whether the nebulizer is operated continuously or intermittently.21
Several limitations and potential problems associated with the use of wet nebulizers should be noted. When the patient's airway disease is stable, the usual wet nebulizer delivery system deposits about 10% of the nominal dose in the lower airway. As the deposition efficiency of these devices when operated continuously depends on the patient's breathing pattern, the high inspiratory flow rates during an acute attack of asthma can reduce deposition dramatically. Many patients have difficulty maintaining nebulizers in clean working order. Wet nebulizers are much more expensive than any other delivery system, are not as portable and require more time to deliver a specific amount of drug compared with DPIs or pMDIs with or without spacers. Currently available ultrasonic devices are more portable, but are expensive. The many disadvantages of wet nebulizer therapy and the ability to achieve equal or better therapeutic effect with a variety of low-cost inhalers means that the wet nebulizer is rarely indicated for treatment of the ambulatory patient.22
Before nebulized medication is considered for maintenance management of asthma,
• The diagnosis of asthma should be reviewed and confirmed.
• The patient's inability to use alternative inhalation devices should be re-examined and confirmed.
• Optimum use of anti-inflammatory therapy should be confirmed.
• The patient's ability to operate the wet nebulizer correctly and to bear the expense of this therapy should be considered.
Following institution of home wet-nebulizer therapy,
• Improved control of asthma symptoms and objective measurements of lung function should be verified.
• The patient's ability to take care of the wet-nebulizer device, including cleaning and accurate drug dosing should be verified.
Inhalation therapy in the acute care setting
The Canadian Association of Emergency Physicians and the Canadian Thoracic Society have published guidelines for the use of various inhalation devices to treat acute asthma in the emergency department.23-26
Children
The type of medication, the delivery device, patient characteristics and the interaction of these factors all play a role in determining the quantity of medication delivered by inhalation to children with asthma. These variables make it difficult to study aerosol delivery in children. Studies in infants are scarce in part because of the difficulties related to their inability to cooperate and ethical considerations surrounding the need for invasive measurements, but also because of a lack of interest of sponsors in such studies. Nevertheless, age-specific recommendations can be made.
MDIs, spacers, DPIs and wet nebulizers can vary greatly in terms of particle distribution characteristics. The health care provider should know the pulmonary and systemic bioavailability of medication delivered by the device used by the patient. This is particularly important in considering the benefits and side-effects of inhaled glucocorticosteroids for various devices and ages.
Nebulizers
Although ultrasonic nebulizers are promising,27 they tend to generate large particles with poor deposition characteristics28 and are not recommended. With jet nebulizers, lung deposition increases with body size in infants,29 but not in older children29-31; thus, dose must be corrected for body size after the age of 1 year.
In children, from 1% to 7% of the nominal dose in a nebulizer is deposited in the lungs, the larger proportion applying to adolescents.32 This must be taken into account when prescribing for this age group. Increasing the relative humidity can significantly increase lung deposition.33,34 Drying chambers can significantly increase the quantity of respirable particles available,35 but they are cumbersome and not readily available. The wet nebulizer device is cumbersome and expensive, and, for the amount of medication delivered, the most costly of all methods of delivery.
Metered-dose inhalers
In MDIs, large droplets emanate from the valve mechanism, but particle size decreases as the propellant evaporates and the aerosol disperses. Deposition in the lung varies from 9% to 26% of the metered dose in adults36-38; deposition rates may be lower in children, whose technique may be less effective than that of adults.39 Depending on the circumstances, breath-activated devices may result in more40 or less41 deposition than standard MDIs.
Spacers
A spacing device or "holding chamber" slows the velocity of the aerosol and allows more time for evaporation, which reduces particle size and, with a valve mechanism, improves coordination of delivery.42 In the school-aged child, inhaling at tidal levels is at least as effective as a slow deep inspiration.43 Holding the breath is not necessary.42,43 However, the only study in infants using radiolabeling demonstrated a very low rate of deposition in the lungs - about 1% of the nominal dose.44 In this study, 2 infants who were crying had the lowest deposition rates.
In adults, lung deposition rate generally doubles with the use of a spacer and gastrointestinal deposition of particles can be reduced from 81% to 17%.45 This can dramatically improve the benefit and reduce the side-effects of inhaled glucocorticosteroids, particularly those with a relatively high gastrointestinal bioavailability such as beclomethasone (about 20% bioavailable46). Even with the new HFA propellant, which markedly increases the pulmonary deposition of the medication, beclomethasone still has high rate of gastrointestinal absorption46 and should not be inhaled without a spacer.
New spacers (e.g., Spacechamber™,47 Optichamber™48) are being developed and tested, and are often associated with improved bioavailability of the medication. Currently, in Canada, the efficacy of a device does not have to be proven for it to be marketable; thus, it is imperative that the delivery characteristics of the chosen device are known by the health care provider.
Dry-powder inhalers
DPIs store medication as fine particle aggregates, either as a pure substance (e.g., budesonide) or with a carrier (e.g., fluticasone) that helps regulate the dose. Some multidose devices, such as the Diskus™, use separately sealed individual doses; in others, like the Turbuhaler™, doses are micronized from a reservoir. If this reservoir is exposed to humidity by being left open or stored in the bathroom, the efficacy of the medication will be reduced.49
The patient's inspiration provides the force that actuates the device, thus eliminating the need for good coordination required with MDIs. The rate of inspiratory flow is critical to delivery of the medication, although the efficiency of the Diskus™ appears to be relatively flow-independent over a wide range.50 In one study,51 3- to 6-year-old children exhibited as much bronchodilatation using the Turbuhaler™ as those using an MDI. However, in another study,52 younger children did not use the Turbuhaler™ as efficiently as older ones; this discrepancy was not seen when an MDI and spacer was used. Goren and colleagues53 found that 79% of 4-year-old children, 92% of 5-year-old children and 100% of 6-year-old children benefited from the Turbuhaler™, although only 43%, 67% and 80%, respectively, used it correctly. Tilting the head backward, holding the breath for 10 seconds or inhaling from residual volume rather than functional residual capacity had no effect on efficacy of the Turbuhaler™.54 A forceful and deep breath is required for optimum output from this device.55
Some DPIs, like the Turbuhaler™, deliver 20%-30% of the nominal dose in adults (about twice that of the MDI),50,56 whereas the Diskhaler™ and Diskus™ appear to deliver 10%-15% of the nominal dose to the lungs.37,57 In children, a dose reduction study of budesonide in a clinical setting58 confirmed the 2:1 superiority of the Turbuhaler™ over the MDI. Although patients have criticized the Turbuhaler™'s high resistance to flow, this characteristic is probably the reason for the associated high bioavailability of the medication.59
A holding chamber, filled using a spring-loaded trigger, has been tested with a breath simulator using tidal volumes of 100 mL (equivalent to that of a 1- to 2-year-old child).60 Of the resulting medication dose, 76% had a aerodynamic diameter <4.7 μm, making this a potentially extremely useful device for infants and young children.
Masks and mouthpieces
Nasal breathing can decrease lung deposition by up to 67%.30 Therefore, inhalation via the oral route, preferably with a mouthpiece rather than a mask, is recommended when the child is old enough.
Propellants
MDI canisters contain propellants, surfactants and the medication, which may be in solution or suspension. These devices have been available for over 40 years, but are undergoing a revolutionary change in design with the conversion from CFC to HFA propellant under the Montreal Protocol.61 The HFA-134a propellant operates at temperatures as low as −20°C,62 which is important in Canada. In addition, alterations in the surfactant and valve mechanism are leading to more consistent dosing and a decrease in the tailing-off of the dose as the canister becomes almost empty.63
Beclomethasone is soluble in the new HFA formulation and has a higher fine-particle mass and bioavailability than in the CFC preparation.64 However, it still has a high rate of gastrointestinal absorption46 and probably should not be inhaled without a spacer. Salbutamol, which is suspended in the HFA formulation, has about the same bioavailability and efficacy as in the CFC preparation.65,66 The problem of the lower availability of salbutamol after the container has been standing for over 1 hour, even with shaking,67 has been rectified in the new canisters; the availability is now independent of the position in which the canister was stored.63 Most of this technical information has not been peer reviewed.
Care of spacers
Electrostatic forces cause particles to adhere to the plastic walls of spacers, considerably lowering the amount of medication delivered to the lungs.68,69 Using a metal spacer,70 lining the plastic spacer with an antistatic spray71 or simply washing it with soap and letting it drip dry72,73 can dramatically improve particle delivery and respirable mass. In addition, the longer the medication remains in the electrostatic spacer, the lower the respirable mass.14 Coating the spacer will also minimize this problem.71 Particle half-life can be increased from 10 seconds to 30 seconds by using a coated spacer.71
Increasing the dead space between the spacer and the infant (mask, valving system) decreases bioavailability of the medication.74 Bisgaard and colleagues75 used an infant breath simulator to study 3 spacers that have different amounts of dead space, antistatic characteristics and volumes. The total dose output from the spacer device ranged from 12% (Aerochamber™) to 20% (Babyhaler™) to 30% (nonelectrostatic device) of the total dose delivered.
Suggestions for future research
• National and international regulations governing inhalation devices must be established.
• DPIs that are spring-loaded, attached to holding chambers and breath-activated by infants should be available.
• Advances in ultrasonic and jet nebulization may make these techniques more useful.
• Dosimeters can greatly enhance the overall output of jet nebulizers by minimizing wastage in the expiratory phase. Perhaps direct targeting of molecules to specific receptors and liposomal formulations will greatly enhance the benefit-side-effect profile of medications.
Recommendations
• Inhaled drug delivery is recommended over oral or parenteral delivery for adrenergic bronchodilators and glucocorticosteroids (level I).
• The inhalation device that best fits the needs of the individual patient should be chosen (level III).
• With adequate teaching, adults and older children can use any of the commercially available hand-held inhalation devices. MDIs with spacers can be considered for all age groups, and specifically MDIs with valved spacer and face mask are advocated for young children and the elderly. Dry-powder inhalers can provide adequate drug delivery for most children by the time they reach age 5 years (level II).
• MDIs that use hydrofluoroalkane propellant are recommended over those using chlorofluorocarbons (level IV).
• Health care professionals must teach correct inhaler technique when devices are prescribed and dispensed (level I).
• Patients' method of using their inhalation device must be reassessed and reinforced periodically (level II).
• Asthma control should be reassessed when changing an aerosol device (level IV).
• Wet nebulizers for home use are rarely indicated in the management of asthma at any age (level III).
• A trial of wet nebulization in infants and children at home may be appropriate if an MDI with a spacer is not effective (level IV).
• When spacers are used, conversion from a mask to a mouthpiece is strongly encouraged as soon as the age and the cooperation of the child permit (level II).
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