LEADING ARTICLE

JIACM 2004; 5(2): 114-23

Aerosol Therapy
GC Khilnani*, Amit Banga**
Aerosol therapy constitutes delivery of drug to the body via the airways by converting it into an aerosolised form. Although aerosolised drug may be intended for systemic use by absorption through the vast surface area provided by the respiratory tract, overwhelming majority of the aerosolised medications are meant for topical use. Evidence of use of aerosol therapy during the days of Hippocrates has been found1. He used hot vapours for the management of respiratory diseases. Major evolution in the field of aerosol therapeutics has been the development of newer devices and modalities for the conversion of drugs into aerosols and their delivery to the airways. This form of therapy has revolutionised the management of patients with obstructive airway disease by comprehensively changing the route of drug delivery in these patients. More and more bronchodilators and anti-inflammatory agents are becoming available for use as aerosol therapy. Besides airway diseases, aerosol therapy is also being employed for various other diseases. This review summarises the basic principles of aerosol therapy, equipments used for generation of aerosols, as also the clinical uses and limitations of such therapy. onset of action after the drug is inhaled as compared to other modes of delivery. Certain other drugs such as antibiotics may also be used for local effect in the lung parenchyma in patients with infectious diseases such as Pneumocystis carinii pneumonia (see below). Before dwelling upon the various devices available for this form of therapy it is imperative to understand the factors involved in the delivery of aerosolised drugs. Physical properties especially the droplet size of the aerosol, and host factors including the pattern of ventilation as well as status of the airways and lung mechanics, play a major role in determining the eventual fraction of drug delivered at the desired site of action. Physical characteristics of an aerosol Droplet size is perhaps the most important factor in the delivery of the aerosolised drug to the lungs. Size of the aerosol droplets is generally characterised by mass median aerodynamic diameter (MMAD). Any droplet with MMAD larger than 5 is likely to be filtered out in the upper airways and fail to reach even the larger airways2. Aerosol particles less than 5 in size readily reach the distal areas of the respiratory tract. This relationship holds true upto a droplet size of 0.6 beyond which the smaller particles are likely to be exhaled. A particle size less than 2 is ideal and is able to percolate right upto the peripheral airways. In fact, most of the available nebulisers produce droplets of roughly this size3. Chemical and physical properties of the drug may also play an important role in deciding the penetration of the aerosol. For example, aerosols containing drugs with hygroscopic properties are likely to increase in size in humid conditions, which may have a significant impact on the drug delivery. Another characteristic that may modify the penetration of the drug is the shape of aerosol where a more aerodynamically shaped droplet is likely to be associated with better penetration. Finally, aerosols generated at very high velocity are associated with significant upper airway

Rationale of aerosol therapy

Aerosol therapy offers the advantage of delivery of high concentration of drug directly at the site of action without causing any significant systemic effects. This helps to achieve equivalent therapeutic response by using lower doses of a drug than would be required if it was to be given orally or parenterally. Overwhelming majority of drugs used by this route consist of bronchodilators or antiinflammatory agents used for asthma and chronic obstructive pulmonary disease (COPD). Efficacy results from their local effects in the airways2. Achieving a high local concentration of these agents in the lung maximises their intended effects and minimises their systemic absorption and potential adverse actions. Another advantage of this mode of drug delivery is the rapidity of

* Associate Professor, **Senior Resident, Department of Medicine, All India Institute of Medical Science, Ansari Nagar, New Delhi-110 029.

deposition and consequently lower distal deposition. Metered-dose inhaler (MDI) is a typical example of a generator that produces aerosols at a high velocity, which are in the range of 10-100 m/s. On the other hand, dry powder and nebulisers produce aerosols with relatively low velocities4. Slower flow minimises oropharyngeal and upper airway deposition and enhances distal delivery and deposition4. Host factors Host factors can be considered under two headings: factors related to ventilation and those related to airway status. Among ventilation factors those shown to be important are : i) inspired volume, ii) inspiratory time, iii) breath-holding duration, and iv) timing of aerosol delivery during inspiration. Inspired volume plays a critical role in the delivery of the aerosolised drug. With increasing volume of inhalation, particles are likely to be carried further into the lungs. Because of this fact, patients are instructed to take a deep breath with the actuation of aerosol delivery device. They are also instructed to exhale to functional residual capacity before initiating inspiration. But forced exhalation to residual volume prior to inhalation is not recommended since this may lead to temporary collapse of some airways and reduce delivery of the aerosol. It has been shown that breath-holding is important in maximising the drug delivery. Duration of breath-hold is important and studies have shown that a 4 second hold is extremely helpful whereas a longer duration may not help5. Breath-holding increases the penetration as well as number of particles deposited in the lungs. The mechanism of increase in penetration of aerosol particle is not fully understood. To elucidate the role of breath hold, Darquenne and collegues6 compared the penetration of aerosol bolus inhalations of 1 m diameter particles with a period of breath hold on the ground with penetration of similar aerosol particles under conditions of microgravity (to eliminate the effect of gravity). It was demonstrated that deposition was independent of breathholding time in microgravity, whereas, on the ground, deposition increased with increasing breath-holding time. This provided an indirect evidence of role of gravitational sedimentation as the main mechanism of deposition and

dispersion of aerosol during breath-holds. Finally, while using a MDI, it is imperative to coordinate the inspiration with the actuation of inhaler. An uncoordinated actuation may lead to loss of most of the drug. This is not a major factor while using aerosol generated by other equipment such as nebulisers. Ideal technique of using MDI shall be discussed later. Airway status and lung pathology do not affect the total amount of drug delivered to the airways, but may play a major role in deciding the fraction of dose reaching the desired site. For example, the increased airway resistance seen in patients with obstructive airway disease leads to the aerosol particles being deposited in predominantly proximal locations7,8. In fact, even asymptomatic smokers also show a similar tendency of localising aerosol particles centrally, which may be due to goblet cell hypertrophy and increased mucous production seen in these subjects9. This may result in poor response to inhaled drugs in smokers as compared to non-smokers with similar severity of the disease. Chalmers and co-workers9 reported that in mild asthmatics, response to inhaled steroids (fluticasone) was much better in non-smokers as compared to patients who continued to smoke while on therapy. This lack of response could be secondary to poor distal deposition of aerosol particles in smokers. But these problems have been shown to be overcome by using certain techniques that improve delivery of aerosol particles to the peripheral locations within the airway. The rate at which patients inspire, the timing of inhalation, and the period of breathholding can be suitably modified to increase the fraction of aerosol entering the lungs at the desired locations. Schiller-Scotland et al10 compared the deposition of aerosol particles in the size range between 1 and 3 in patients with obstructive lung disease and in normal people. They showed that a breath holding interval of 6 seconds after inhalation reduced the difference in the deposition of aerosol particles between the two groups, and thereby compensated for differences in airway resistance and lung mechanics.

Aerosol devices
The devices available for generation of aerosols can be broadly divided into three categories: metered dose inhaler (MDI), dry powder inhaler (DPI), and nebuliser. Two

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types of nebulisers namely, jet nebuliser and ultrasonic nebuliser are available for use as aerosol generators. We shall now discuss the respective advantages and disadvantages of the various devices.

Metered dose inhaler (Fig.1)

Metered-dose inhalers are the most commonly used devices for generation of aerosol. They consist of a micronised form of drug in a propellant under pressure with surfactants to prevent clumping of drug crystals. Lubricants for the valve mechanism and other solvents are the other constituents. When the device is actuated, propellant gets exposed to atmospheric pressure, which leads to aerosolisation of the drug. As it travels through the air, the aerosol warms, leading to evaporation of the propellant that reduces the particle size to the desirable range. Propellants used for aerosol generation in MDIs have generated some controversy. The conventional propellant used in these devices has been chlorofluorocarbon (CFC). In the year 1987, all substances that could deplete the ozone layer were banned. CFC is also known to cause this

effect and hence came under the imposed ban. Although products used for medical use were exempted from the ban, newer propellants have been developed. Already, MDI using newer propellant like hydrofluoroalkane (HFA) have become available for routine use. Substitution of HFA for CFC has resulted in critical changes in the pharmacokinetic profiles of drugs such as beclomethasone used for aerosol therapy11. The major conclusion to come out of this study comparing the two different propellant based MDI was that only 50% of the usual dose used in CFC MDIs was required to produce the equivalent clinical effect. Other differences between CFC and HFA based MDIs are compared in table I. MDIs have been used widely because of ease of usage, small and compact size, and relative cost-effectiveness. On the other hand, commonest pitfall in the usage of MDI is the lack of coordination between the actuation of device and the initiation of inspiration. Many other problems can be associated with the use of MDI. The physician who prescribes these devices should keep these things in mind and the same should be conveyed to the patient as well : a. Even with the best technique, only 10-20% of the total drug makes it to the large airways and only 5% of the drug reaches the small airways12.

b. Various additives and the cold propellant in MDIs may cause airway irritation, which may lead to cough or occasionally bronchospasm. Since drug contained is usually a bronchodilator this effect may not be revealed clinically and may manifest as a poor response to the treatment. c. The medication is held in a suspension with the propellant in the canister. To prevent undesirable layering of the medication, it is imperative to shake the canister between each puff.

Fig. 1 : A metered dose inhaler available for use with many aerosolised medications.

d. It is important to keep in mind that MDI may continue to deliver aerosol even after the drug is finished. This aerosol only consists of the propellant at this time. This tends to occur commonly in patients who do not adequately shake the canister as a routine. Such problems can be taken care of by noting the manufacturers recommended number of actuations and marking the estimated completion date.

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e.

Each actuation of the aerosol device leads to cooling of its contents temporally. A 30- to 60-second pause between actuations is recommended so as to allow the device to rewarm as the predictability of the aerosol produced is poor when the contents are cool.

Ideal use of MDI comprises of following steps: 1. Shake the canister 2. Hold the canister upright 3. Exhale to functional residual capacity (do not exhale to residual volume) 4. Place the mouth-piece in mouth, between teeth, and close lips, or keep mouth-piece 5 cm in front with mouth open 5. With initiation of inhalation, actuate the canister 6. Slowly Inhale upto maximum capacity (i.e. total lung capacity) 7. Hold breath for 10 seconds or as long as possible 8. Wait 30 seconds before the next puff.
Fig. 2 : A spacer with an attached metered dose inhaler.

discharged into the chamber and only a single actuation should be discharged into the chamber for each inhalation. Following this, patient should be instructed to

Table I : Differences in pharmacokinetic profile of CFC and HFA propellant based MDI for beclomethasone. CFC propellant based Physical state of the drug Particle size Type of spray Velocity of spray Oropharyngeal drug deposition Delivery to the lower airways Equivalent dose for clinical effect Toxicity profile Valved holding chambers/spacers To overcome the major problem related to coordination, a valved holding chamber is used as an adjunct to MDI (Figure 2). It is also useful for old patients and those who are unable to hold their breath. This adjunct has many advantages, including improved coordination with the inspiratory flow of the patient. When MDIs are used with spacer devices, reduction in the overall particle size of the inhaled aerosol occurs, as larger particles tend to stick to the chamber walls/valves. This also leads to reduction in particle velocity leading to reduction in upper airway deposition. It should be explained to the patient that aerosol must be inhaled immediately after the MDI is Suspension 1-10 Harder 10-100 m/s Significant 5-10% No major toxicity HFA propellant based Solution Finer Softer Slower Lesser Double 50% Similar

breathe in and out for at least 2 min before actuating another discharge of MDI. Inspite of all these advantages, it has been shown that no extra benefit is achieved by using a spacer device by patients who follow the correct technique with MDI alone13. Holding chambers are not totally free of problems. Electrostatic charge develops on the inside of the chamber due to regular washing and drying that affects delivery of larger particles. Patients should be instructed to dry the chamber using a non-static cloth or to let it air dry. Another drawback of using holding chamber is that new HFA based MDIs have not been evaluated with presently available chambers. Because of difference in the physical

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characteristics of the particles generated by HFA based MDI drug delivered to the patient may be different.

Dry powder inhalers (Fig. 3 A and B)

Dry powder inhalers (DPI) consist of pharmacologically active powder as aggregate of fine micronised particles in an inhalation chamber. These aggregates are converted into an aerosol by airflow through the inhaler and all currently available DPIs require the patients own inspiratory effort for the drug delivery to occur. This basic fact excludes the problem of coordination between the delivery of drug and initiation of inspiration. But the very same fact also makes it unsuitable for patients who are unable to generate high flow rates. No requirement of propellant as well as breath-holding are the other advantages of DPIs over MDIs. Fraction of the drug delivered to the site of action by DPI varies from 9% to 30% and varies between the various products available in the market12-14. DPI fail to work in patients who cannot generate moderateto-high inspiratory flow rates, since unlike the MDI, they

are driven by the patients own effort. Flow rate required to be generated varies among various internationally available DPIs but a flow rate of 60-90 L/min is usually required. This makes use of DPI unsuitable for elderly as well as paediatric patients and those with severe bronchospasm.

Nebulisers
Two types of nebulisers are available for use as aersosol generators: jet nebuliser and ultrasonic nebuliser. Both work on different principles but have many things in common. They are non-propellant based, do not require patient coordination, and can be used to deliver high doses of a particular drug in a short time such as during acute exacerbations of obstructive airway diseases in emergency setting. Continuous small-volume nebulisation of beta-2 agonists can be employed for patients with acute asthma not responding to intermittent treatment. This method demands more careful monitoring, but supplies higher dosing and more consistent biological levels.

Fig. 3 A and B : A commonly used aerosol generator available for dry powder inhalation.

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Table II : Characteristics of the aerosol generators. MDI Technique of generation of aerosol Particle size Drug deposition Oro-pharyngeal deposition Patient coordination Breath-holding Patient generation of flow Amount of drug Contamination Use for chronic therapy Use for emergency management Use for intubated patient Cost Propellant based 1-10 5-10% Significant Required Required Not required Small doses only No Y es No Preferred Cheap DPI Patient driven flow 1-10 9-30% Variable Not applicable Not required Required Small doses only No Y es No No Cheap Nebuliser Bernoullis principle/ piezoelectric crystal Variable 2-10% Insignificant Not required Not required Not required Large doses possible Possible Rarely Y es Second choice Expensive

Jet nebuliser works on the Bernoullis principle where a high velocity gas (oxygen or air) is passed through a constriction that draws up liquid medication due to the relative vacuum. The result is an aerosol that breaks up into small particles by hitting the inner surface of the apparatus. Smaller particles pass through the tubing to the patient, whereas larger particles are left behind in the jet apparatus to be re-aerosolised. Size of the aerosol particle is directly proportional to the compressed gas flow and the size of the nozzle. It has been shown that systems that deliver 8 L/min of flow produce ideal-sized particles. Also, an intermittent rather than continuous inhalation system leads to lesser loss of medication15. Ultrasonic nebuliser works by creating a fountain by ultrasonic energy. Aerosol is generated by means of a piezoelectric crystal that functions by converting electrical current into high frequency vibration. These intense vibrations pass through the drug to be aerosolised, and result in formation of droplets. Frequency of vibration determines the size of droplets. Clinical studies have indicated that size of the aerosol particles generated by ultrasonic nebuliser is larger as compared to those from a jet nebuliser16,17. Because of this fact, drug deposition in the upper airways may be higher than that with jet nebuliser.

The major disadvantage of the nebuliser is the cost factor. The equipment is expensive and a lot of drug is wasted. The cost of aerosol therapy is a major concern, as usually patients have to take these medications on a long-term basis. It has been demonstrated that in a controlled setting18,19 the efficacy of MDI and nebuliser was comparable for home use as well as for hospitalised patients. Also, cost of using MDI is much lower than the nebuliser. Hence, wherever feasible, MDI should be used with or without a holding chamber. However, there are definite clinical situations where use of nebulisers is warranted.

Choice of aerosol generation device

It is well established that MDI and DPI delivery systems are the most convenient and cost effective and should be the first choice of clinicians for patients with obstructive airway disease. In situations where the patient cannot demonstrate acceptable hand-breath coordination, and whenever pharyngeal deposition is a concern such as with inhaled steroids, a valved holding chamber should be used with the MDI. The nebuliser might be used if a high drug dose or large volume is to be given. Nebuliser may also be indicated if the drug is only available as a solution or MDI/DPI are not effective. Patient preference should be

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considered when selecting an aerosol delivery device. Many patients might prefer nebuliser to MDI/DPI because of better response, but most of the times it is a consequence of higher drug dose being used during use of nebulisation. In such cases, increasing the total daily dose provided by MDI/DPI might be useful and may help to convince the patient to continue using the inhalers.

Aerosol therapy in intubated patients

Intubated patients frequently require aerosolised drugs for various indications and a vast majority of these are bronchodilators. Many patients with obstructive airway diseases require ventilatory support during episodes of exacerbations of their disease. All such patients require inhaled bronchodilator therapy. The mechanics of aerosol therapy are remarkably different in patients who are intubated. This is largely due to the presence of an artificial airway through which aerosol particles have to transmit before reaching lower airways. Aerosol particles have a strong tendency to stick to the walls of the airways and this results in significant reduction in the fraction of the total drug reaching the lower airways. To avoid this, it has been suggested that endotracheal tube (ETT) could be bypassed by using a long catheter that attaches to the nozzle of MDI and release the drug distally in the airways31. Other factors which result in poor delivery of the aerosol particles to the distal airways are heating and humidification32,33 of the inhaled gas, which results in almost 40% reduction in the fraction of drug reaching the distal airways. Density of the inhaled gas also affects the delivery because denser gas is more prone to turbulence and this results in a higher fraction of drug sticking to the artificial airway. This can be circumvented to an extent by using a less dense gas such as oxygen and helium. Use of this mixture for ventilation has been shown to improve aerosol delivery34. Among the generators, MDIs have been found to be more effective than nebulisers35. The technique of connecting the generator to ETT is also an important factor that affects drug delivery. It has been shown that attaching a spacer between the generator and the ETT36, as well as coordinating the actuation with the inspiration 37, results in better delivery of aerosol particles. Several studies have shown that the fraction of delivered dose is almost four times when using a combination of a MDI and a chamber device as compared to that achieved by directly attaching the MDI directly to the ETT38-40. For our setting, a MDI with an attached spacer device with due care of the factors discussed above is the most cost-effective modality for aerosolised bronchodilator therapy for intubated patients.

Clinical uses of aerosol therapy

A majority of drugs available for use as aerosolised medications are used for obstructive airway diseases. Table III enlists these drugs with their dosages and the type of aerosol generator available with each drug. In addition, a few antibiotics and mucolytic agents are available for aerosol therapy. Use of inhaled tobramycin is now well established in patients with cystic fibrosis. Many studies20,21 have shown improvement in lung function by use of aerosolised tobramycin in patients with cystic fibrosis. This improvement in lung function is attributed to clearing of colonised Pseudomonas aerugenosa, which causes recurrent episodes of pneumonia in these patients. Other antibiotics that have been used in aerosolised mode are pentamidine for Pneumocystis carinii pneumonia prophylaxis, colistin in cystic fibrosis22, amphotericin B for bronchopulmonary fungal infections in lung transplant recipients23 and amikacin for E.coli pneumonia24. Mucolytics that have been investigated are N-acetyl cysteine25, recombinant human deoxyribonuclease26 and Nacystelyn27 in cystic fibrosis, and mercapto-ethane sulfonate (Mesna) in patients with COPD28. All the above discussed drugs act through local action in the airways. But a few drugs have been developed or are in the process of development, which are supposed to be delivered through the airways for systemic absorption. Major steps have been taken in the direction of developing aerosolised insulin, which could be used for diabetic patients in place of daily injections29,30. Such a formulation is likely to become available in the near future. In addition, airways as a route of drug delivery is being explored for many novel therapies including gene therapy, antiproteases and oxidative peptides that may change the paradigm of treatment for many diseases in the years to come.

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Table III : Inhaled drugs used for obstructive airway diseases. Drug Type of aerosol generator Salbutamol Salbutamol sulphate Salbutamol sulphate Terbutaline sulphate Terbutaline sulphate Salmeterol xinafoate Salmeterol xinafoate Formoterol fumarate Formoterol fumarate Ipratropium bromide Ipratropium bromide Ipratropium bromide Tiotropium Sodium cromoglycate Sodium cromoglycate Sodium cromoglycate Beclomethasone dipropionate Beclomethasone dipropionate Budesonide Budesonide Fluticasone propionate Fluticasone propionate MDI DPI Solution for nebuliser MDI Solution for nebuliser MDI DPI MDI DPI MDI DPI Solution for nebuliser DPI MDI DPI Solution for nebuliser MDI DPI MDI DPI MDI DPI

Dose 100-200 g 4-6 times/day 200-400 g qid 2.5-5 mg 250-500 g qid 10-20 mg 50 g bid 50 g bid 12-24 g bid 12-24 g bid 20-40 g qid 20-40 g qid 100-500 g 18 g/day 5 mg qid 20 mg qid 20 mg qid 100-400 g 2-4 times/day 200-400 g 2-4 times/day 100-400 g bid 200-400 g bid 100-1000 g bid 100-1000 g bid

MDI : pressurised metered dose inhaler, DPI: dry powder inhaler.

Safety of aerosol therapy

Although drugs delivered as aerosols have been mostly found to be extremely safe, certain clinical situations may require caution on the part of the clinician. Paradoxical bronchospasm is known to occur with DPI formulations of anticholinergic drugs. High doses of beta-2 agonists administered through the nebuliser have been reported in rare cases to lead to arrhythmias. Inhaled corticosteroids in large doses may lead to suppression of hypothalamuspituitary-adrenal axis and must be used cautiously in growing children41. Risk of cross-infection with use of nebuliser in hospital patients is also well known and various methods for decontamination of nebulisers have been described42.

the site of action still remains small. MDI with or without a valved spacer have emerged as the preferred agents for aerosol generation. This holds true for in-hospital patients as well as chronic therapy of patients with obstructive airway diseases. Nebulisers are the generators of choice in an emergency setting. Many new drugs, including insulin, are in the process of development to be used as aerosols that are likely to revolutionise the management strategies of various diseases.

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Conclusion
Many advances have been made in the field of aerosol therapy. Better aerosol generators are now available, although the fraction of total drug eventually making to

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adults: an in vitro study. Chest 1992; 102: 924-30. 39. Bishop MJ, Larson RP, Buschman DL. Metered dose inhaler aerosol characteristics are affected by the endotracheal tube actuator/adapter used. Anesthesiology 1990; 73: 1263-5. 40. Fuller HD, Dolovich MB, Turpie FH, Newhouse MT. Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients:

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