Review Article

Aerosol Therapy
G.C. Khilnani and Amit Banga

Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT

Aerosol therapy has revolutionised the treatment of several respiratory diseases including obstructive airway diseases. This
form of therapy refers to delivery of the drug directly into the lower airways for either topical or systemic effect. The greatest
advantage of this from of therapy is the use of smaller doses and thus, minimal systemic adverse effects, besides giving a
rapid response. Aerosol therapy is now also being used for systemic delivery of certain medications, such as insulin. The
particle size (expressed as mass median aerodynamic diameter) is of critical importance as the drug delivery depends on
the same to a major extent. Several devices such as metered dose inhaler (MDI), dry powder inhaler (DPI) and nebulisers
are available. Each of these devices have advantages and disadvantages that needs to be understood for optimising the
benefit. Aerosol therapy is also used in patients on mechanical ventilation for bronchodilator therapy, anti-inflammatory
medication and at times for instillation of antibiotics and mucolytics. A knowledge of principles and applications of aerosol
therapy is essential for its effective use in various conditions. [Indian J Chest Dis Allied Sci 2008; 50: 209-219]

Key words: Lung, Obstructive airway disease, Asthma, Bronchodilators, Aerosol therapy.

delivery of high local concentrations of the drug directly

INTRODUCTION
Aerosol therapy refers to the delivery of a drug to the
body via the airways by delivering it in an aerosolised
form. Whereas the aerosolised drug may be intended
for systemic use utilising the vast surface area for
absorption provided by the respiratory tract, the
overwhelming majority of the aerosols are meant for
topical use. Evidence of use of aerosol therapy has been
found during the days of Hippocrates1 who utilised hot
vapours for the management of respiratory diseases.
However, the modern era of aerosol therapy began with
the introduction of the Medihaler Epi in 1956.2 The last
few years have seen a major evolution in our
understanding of aerosol delivery to the human
subjects. Modern technology along with increasing
understanding of human pulmonary physiology has
aided the development of improved systems of aerosol
delivery. This form of therapy has revolutionised the
management of patients with various pulmonary
diseases. More and more bronchodilators and anti-
inflammatory agents are becoming available for use as
aerosol therapy. We attempt to summarise the basic
principles of aerosol therapy and the equipments used
for generation of aerosols, their clinical uses and
limitations.
PRINCIPLES OF AEROSOL THERAPY
The basic advantage of aerosol therapy lies in the
[Received: March 8, 2007; accepted after revision: October 24, 2007]
Correspondence and reprint requests: Dr G.C. Khilnani, Professor, Department of Medicine, All India Institute of Medical
Sciences, New Delhi-110 029, India; Fax: 91-11-26588663; E-mail: gckhil@hotmail.com.
to the site of action with minimised risks of systemic
effects. This is achieved with a much lower dose
compared to what may be required for systemic
administration for equivalent therapeutic response. The
commonest aerosolised drugs are the bronchodilators
and anti-inflammatory agents used for obstructive
airway diseases, such as asthma and chronic obstructive
pulmonary disease (COPD). Their efficiency results
from local effects in the airways. 3 High local
concentration of these agents in the lung maximises
their intended effects and minimises systemic
absorption and the potential adverse reactions. Another
advantage of this mode of drug delivery is the rapidity
of onset of action after the drug is inhaled as compared
to other modes of delivery. Centain 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.
An understanding of factors affecting delivery of
aerosols is essential before using them. The pulmonary
deposition of aerosol is achieved by way of three key
mechanisms, namely inertial impaction, sedimentation
and diffusion. These three mechanisms operate in
different combinations for different aerosol drugs at
different sites in the pulmonary tree. Whereas inertial
impaction is the predominant process in the oropharynx
and the larger airways for aerosols with relatively large
particle size (>3µ), diffusion by way of Brownian
motion is the dominant mechanism for the smaller sized
210
aerosols (<0.5µ).4 Aerosols with the particle size in the
range of 1-3µ are subject to gravitational sedimentation
in the small airways and the same tends to be enhanced
by breath holding. The fraction of drug eventually
delivered at the desired site of action also depends on
the physical properties of the aerosol and also the host
factors that include pattern of ventilation, status of the
airways and lung mechanics (Table 1).
Table 1. Factors affecting delivery of aerosolised drugs to the
lungs
Physical Characteristics of the Aerosol Particle
Size (mass median aerodynamic diameter)
Density
Electrical charge
Hygroscopy
Shape
Velocity of the aerosol particles
Host Factors
Inspired volume
Inspiratory time
Inspiratory flow
Breath-hold duration
Timing of aerosol delivery during inspiration (with metered
dose inhaler)
Physical Characteristics of Aerosol
Physical characteristics of aerosol particles including the
size (diameter), density, electrical charge, hygroscopy,
shape and the velocity of the aerosol have an impact on
the deposition of the aerosol.5,6 These characteristics are
dependent on several factors, namely the drug being
used, its formulation and the device or the aerosol
generator. For example, a solution based formulation of
an aerosol generates much smaller sized particles (~2µ)
as compared to suspension based formulations where
particles size is in the range of 4µ are generated.7 These
characteristics become pertinent since among the
various physical characteristics, droplet size of the
aerosol is the most important factor in the delivery of
the drug to the lungs. Size of the aerosol droplets is
generally characterised by mass median aerodynamic
diameter (MMAD). The MMAD of an aerosol refers to
the particle diameter that has 50% of the aerosol mass
residing above and 50% of its mass below it. Any
droplet with MMAD larger than 5µ is likely to be
filtered out in the upper airways and fail to reach even
the larger airways.2 Aerosol particles less than 5µ in size
readily reach the distal areas of the respiratory tract.
This relationship holds true up to a droplet size of 0.6µ
beyond which the smaller particles tend to be exhaled
out. A particle size less than 2µ is ideal and is able to
percolate right up to the peripheral airways. Therefore,
it is no surprise that most of the commercially available
nebulisers produce droplets of roughly this size. 8
Chemical and physical properties of the drug may also
play an important role in determining the penetration of
the aerosol. Aerosols containing drugs with hygroscopic
Aerosol Therapy G.C. Khilnani and A. Banga
properties are likely to increase in size in humid
conditions that may adversely impact the delivery of
the drug.
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 greater penetration. Finally, the velocity
at which the aerosol is generated also affects the fraction
delivered to the lower airways. Those aerosols that are
generated at a very high velocity tend to get deposited
in the upper airways and consequently the delivery to
the lower airways is compromised. An 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 nebulizers produce
aerosols with relatively low velocities.9 Slower flow
minimises oropharyngeal and upper airway deposition
and enhances distal delivery and depositin.9
Host Factors
Host factors comprise of those related to the ventilatory
and the airway status of the patient. Among ventilatory
factors that have been shown to be important are: (i)
inspired volume, (ii) inspiratory time, (iii) breath-hold
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 more likely to be
carried further into the lungs. Hence, instructions are
given to patients to take a deep breath with the
actuation of aerosol delivery device. They are also
instructed to exhale to functional residual capacity
(FRC) before initiating inspiration. However, 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 drug. It has
been shown that breath holding is important in
maximising the drug delivery. Breath holding increases
the penetration as well as the number of particles
deposited in the lungs. However, the duration for which
the breath should be held has been debated. A study by
Newman and colleagues10 showed that a four-second
hold is extremely helpful in improving the delivery of
the drug whereas a longer duration may not help. The
mechanism of increased penetration of aerosol particles
is not fully understood. To elucidate the role of breath
hold, Darquenne and collegues 11 compared the
penetration of aerosol bolus inhalations of 1-µm-
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 breath-hold time in microgravity,
whereas on the ground, deposition increased with
increasing breath-hold time. This provided an indirect
evidence of role of gravitational sedimentation as the
main mechanism of deposition and dispersion of
2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 211

aerosol during breath holds. Finally, while using an included a 50µL metering device, a 10mL amber vial,
MDI, it is important to coordinate inspiration with the and a plastic mouthpiece with molded nozzle to
actuation of the inhaler. An uncoordinated actuation administer salts of isoproterenol and epinephrine. The
may lead to loss of most of the drug. 12 This is not a next year, a surfactant and micronised powder were
major factor while using aerosol generated by other added to the propellant, creating the first commercially
equipments, such as nebulisers. available formulation.2 Today the modern MDI (Figure
Among the airway factors, status of the airways and 1) comprises of a pressurised metal canister containing
the lung pathology do not affect the total amount of a mixture of propellants, surfactants, preservatives, and
drug delivered to the airways but may play a major role the drug.
in deciding the fraction of dose reaching the desired site.
For example, increased airway resistance seen in
patients with obstructive airway disease leads to the
aerosol particles being deposited in predominantly
proximal locations. 13,14 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 subjects.15 This may be responsible for poor
response to inhaled drugs in smokers as compared to
non-smokers with similar severity of the disease.
Chalmers and co-workers 15 reported that in mild
asthamatics 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. However,
importantly these problems have been shown to be
overcome by using certain techniques that improve
delivery of aerosol particles to the peripheral locations
within the airways. The rate at which patient inspire,
the timing of inhalation, and the period of breath-
holding can be suitably modified to increase the fraction
of aerosol entering the lungs at the desired locations.
There is an inverse relationship between the patient
Figure 1. Metered dose inhaler.
inspiratory flow rates and the extent of peripheral
deposition. 16,17 Schiller-Scotland et al18 compared the
Metered dose inhalers are the most commonly used
deposition of aerosol particles in the size range between
devices for generation of aerosol. They consist of a
1µ and 3µ in patients with obstructive lung disease and
micronised form of the drug in a propellant under
in normal people. It was shown that a breath holding
pressure with surfactants to prevent clumping of drug
interval of six seconds after inhalation reduced the
crystals. Lubricants for the valve mechanism and other
difference in the deposition of aerosol particles between
solvents are the other constituents. When the device is
the two groups and thereby compensated for
actuated, the propellant gets exposed to atmospheric
differences in airway resistance and lung mechanics.
pressure, which leads to aerosolisation of the drug. As it
Therefore, the optimum inhalation technique for aerosol
travels through the air, the aerosol warms up leading to
therapy is slow inspiration followed by breath holding
evapouration of the propellant that reduces the particle
for at least six seconds.
size to the desirable range. The fraction of drug to the
airways ranges from 5 percent to 15 percent.19
AEROSOL DEVICES Propellants used for aerosol generation in MDIs have
The devices available for generation of aerosols can be generated some controversy. The conventional
broadly divided into three categories: metered dose propellants used in these devices has been chloro-
inhaler (MDI), dry powder inhaler (DPI), and nebuliser. fluorocarbon (CFC). In the year 1987, all substances that
Two types of nebulisers, namely, jet nebuliser and could deplete the ozone layer in earth’s atmosphere
ultrasonic nebuliser are available for use as aerosol were banned. Chlorofluorocarbon is also known to
generators. cause this effect and hence came under the imposed
ban. Although products used for medical purposes were
Metered Dose Inhaler (MDI) exempted from the ban, newer propellants have been
The history of the MDI dates back to 1955. The first MDI developed. Already MDI using newer propellant like
212 Aerosol Therapy
hydrofluoroalkane (HFA) have become available.
Substitution of HFA for CFC has resulted in critical
changes in the pharmacokinetic profile of drugs, such as
beclomethasone used for aerosol therapy. 20 Among
other differences, the CFC based MDIs contain the drug
in suspension form whereas the HFA ones have it in a
solution form. Moreover, no surfactant is used in the
HFA devices. However, alcohol is added for dispersal.
The particle size produced by HFA based MDIs is finer
and softer and is generated at slower speeds.
Consequently, the oropharyngeal deposition is lesser
with HFA based MDIs and delivery to lower airways is
double compered to that of CFC based MDIs. It is no
surprise that the major conclusion to come out of a
study comparing the two different propellant based
MDIs was that only 50% of the usual dose used in CFC
MDIs was required to produce the equivalent clinical
effect.20
Metered dose inhalers have been popular because of
ease of usage, small and compact size and the relative
cost-effectiveness. On the other hand, the commonest
error in the usage of an MDI is the lack of coordination
between the actuation of the device and the initiation of
inspiration. Many other problems can also 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.
1. Even with the best technique, only 10% to 20% of
the total drug makes it to the large airways and
only 5% of the drug reaches the small airways.21
2. Various additives and cold propellant in MDIs
may cause airway irritation, that may lead to
cough or occasionally, bronchospasm. Since the
drug contained is usually a bronchodilator, this
effect may not be revealed clinically and may
manifest as a poor response to the treatment.
3. 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 actuation.
4. It is important to keep in mind that the MDI may
continue to deliver the aerosol even after the drug
is finished. This aerosol consists only of the
propellant at this time. This tends to occur usually
in patients who do not shake the canister well as a
routine. Since most manufacturers do not provide
dose counters, patients must keep a track of the
number of actuations. Such problems can be taken
care of by noting the manufacturer ’s recom-
mended number of actuations and marking the
estimated completion date.
5. Each actuation of the aerosol device leads to
cooling of its contents temporaly. A 30- to 60-
second pause between actuations is recommended
so as to allow the device to re-warm as the
G.C. Khilnani and A. Banga
predictability of the aerosol produced is poor when
the contents are cool.
Steps for Ideal Use of an MDI
1. Shake the canister.
2. Hold the canister upright.
3. Gently exhale to functional residual capacity (do
not exhale to residual volume).
4. Place the mouthpiece in mouth, between teeth,
and close lips or keep the same 5 cm in front with
mouth open.
5. With initiation of inhalation, actuate the canister
6. Slowly inhale up to the maximum capacity (total
lung capacity).
7. Hold breath for 10 seconds or as long as possible.
8. Wait for at least 60 seconds before the next puff.
In breath-activated MDIs which have been available
in the West, coordination between breathing and
actuation is not required.22 These devices consist of a
mechanical flow trigger that gets activated when
inhalation flow reaches ≥ 30 L/min. However, a
drawback is that the elderly patient may be unable to
use this device.23
Valved Holding Chambers/Spacers
To overcome the major problem related to coordination,
a valved holding chamber may be used as an adjunct to
the MDI (Figure 2). It is also useful for old patients and
those who are unable to hold breath. This adjunct has
many advantages including improved coordination
with the inspiratory flow of the patient. When an MDI
is used with spacer devices, reduction occurs in the
overall particle size of the inhaled aerosol, as larger
particles tend to stick to the chamber walls/valves. This
also leads to a reduction in particle velocity leading to
decreased upper airway deposition. It should be
explained to the patient that the aerosol must be inhaled
immediately after the MDI is discharged into the
chamber and only a single actuation should be
discharged into the chamber for each inhalation.
Following this, the patient should be instructed to
breath in and out for a few breaths before actuating
another discharge of MDI. The reduced oropharyngeal
Figure 2. Metered dose inhaler with spacer.
deposition associated with the use of a spacer chamber
is an advantage when using corticosteroid MDIs as the
local adverse effects are then much less likely to occur.
In spite of all these advantages, it has been shown
2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 213

that no extra benefit in terms of delivery is achieved by available for clinical use. The devices may be single
using a spacer device by the patients who follow the dose device such as a Rotahaler® where each dose needs
correct technique with MDI alone.24 Holding chambers to be loaded by the patient or the pre-loaded multi-dose
are also not totally free of problems. Electrostatic charge device such as Diskus® where the patient does not need
develops on the inside of the chamber due to regular to load the drug every time. More recently another
washing and drying and affects delivery of larger multi-dose DPI device called Novolizer® was launched
particles. Patients should be instructed to dry the which can be re-filled by replacement of cartridges.
chamber using a non-static cloth or to let it air dry. Moreover, the Novolizer® has several other benefits over
Another drawback of using the holding chamber is that other DPI devices including a patient feedback
the new HFA based MDI have not been evaluated with mechanism, a trigger flow valve and low to medium
the presently available chambers. Because of the intrinsic resistance that ensures that the patient have
differences in the physical characteristics of the particles high flow rates while using this device in comparison to
generated by HFA based MDI, drug delivered to the others.29 It has been shown that particle size generated
patient may be different. by Novolizer ® is largely independent of the flow
generated by the patient 30 and tends to have higher
Dry Powder Inhalers (DPI) drug deposition at higher flow rates.31 However, direct
head-to-head clinical comparisons among various DPI
Dry powder inhalers (DPI) consist of pharmacologically devices are lacking and preference for a particular may
active powder as an aggregate of fine micronised be dictated by physicians and the patient’s preferences
particles in an inhalation chamber (Figure 3). These considering the costs, design, ease of use, etc.
aggregates are converted into an aerosol by inspiratory
airflow through the inhaler generated by the patient.
This basic fact excludes the problem of coordination
between the delivery of the drug and the initiation of
inspiration. But the very same fact also makes it
unsuitable for patients who are unable to generate high
inspiratory flow rates. Lack of requirement of propellant
is an advantage of DPIs over MDIs. The fraction of the
drug delivered to the site of action by a DPI varies from
9% to 30% and varies among different commercially
available products.24,25 The DPIs tend to fail in patients
who cannot generate moderate to high inspiratory flow
rates since unlike the MDI, they are driven by the
patient’s own effort. In a DPI, the aerosol needs to be
generated from the powder formulation by patient’s
own effort. For achieving this, a high turbulence is
needed to break the large agglomerates of the drug into
smaller, finer and inhalable particles. Turbulence is
generated by creating resistance to air flow in the DPI
device and the effort required to generate adequate flow
rates is dependent on the extent of resistance. Whereas
the flow rates required to be generated vary among
various available DPIs, a flow rate of 60-90 L/min is
generally required. 26 This makes the use of DPI
unsuitable for elderly as well as younger pediatric Figure 3. Commonly used dry powder inhaler.
patients and those with severe bronchospasm. Some of
the newer innovations in the field of DPI devices have Studies comparing the fraction of the drug delivered
attempted to circumvent this drawback. The device by MDI devices with turbohaler have found the latter to
used for the recently launched inhaled insulin, Exubera®, be superior in this regard.32 However, an extensive
uses compressed air to aerosolise the insulin powder review of comparisons of clinical outcomes in patients
and converts it into a standing cloud in a holding using MDI versus DPI did not find any difference.33
chamber. Other environmental factors may also
influence the extent of the drug delivered with DPI Steps for Ideal Use of DPI
devices. High humidity and rapid changes in
temperature may affect de-aggregation of the drug 1. Check that the device is clean and the mouthpiece
particles and reduce the fraction of the drug being free of obstruction.
delivered.27,28 2. Load a dose into the device as directed (if single-
There is a wide range of DPI devices that are dose device).
214
3. Hold the inhaler level with the mouthpiece and
facing down.
4. Tilt your head back slightly, and beathe out slowly
and completely without straining or breathing into
the device (moisture from breath can clog the
inhaler valve).
5. Place teeth over the mouthpiece and seal lips
around it making sure not to block the device
outlet with tongue.
6. Breathe in quickly and deeply (over two to three
seconds) through the mouth to activate the flow of
medication.
7. Remove the device from the mouth. Hold breath
for 10 seconds (or as long as is comfortable), and
then breathe out slowly against pursed lips. This
step is very important. It allows the medication to
get deeply into the lungs.
Nebulisers
Two types of nebulisers are available for use as aerosol
generators: jet nebuliser and ultrasonic nebuliser. These
work on different principles but have many features in
common. These are non-propellant based, do not
require patient coordination and can be used to deliver
high doses of a particular drug over a short time, such
as during acute exacerbations of obstructive airway
diseases in emergency settings. 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.
A jet nebuliser works on the Bernoulli’s 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 chamber. Smaller particles pass through
the outlet to the patient whereas larger particles are
retained behind in the jet chamber to be re-aerosolised.
The 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 medication.34 The commonly used neublisers,
however, deliver the aerosol continuously.
An 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 a high frequency vibration. These
intense vibrations pass through the drug to be
aerosolised and result in formation of droplets. The
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 nebuliser.35,36 Because of
Aerosol Therapy G.C. Khilnani and A. Banga
this fact drug deposition in the upper airways may be
higher than that with a jet nebuliser.
The major disadvantage of the nebuliser is the cost
factor. Equipment is relatively 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 setting37,38 the efficacy
of MDI and nebuliser was comparable for home use as
well as for hospitalised patients. Also, the cost of using
an MDI is much lower than the nebuliser. Hence,
wherever feasible, an MDI should be used, with holding
chamber if necessary. However, there are definite
clinical situations where use of nebulisers is warranted,
such as acute exacerbations managed in emergency and
intensive care settings.
Steps for Ideal Use of Nebulisers
1. Hands should be washed prior to preparing each
nebuliser treatment.
2. If using a multi-dose bottle of medicine, the
dropper to put the correct amount of medication
into the chamber along with saline solution should
be used.
3. The mouthpiece should be connected to the T-
shaped part adapter of the chamber.
4. Connect the nebuliser tubing to the port on the
compressor.
5. Hold the nebuliser in an upright position to
prevent spilling.
6. Turn the compressor on and check the nebuliser
for misting.
7. As the mist starts, patients should inhale slowly
and deeply through the mouth, taking over three
to five seconds for each breath.
8. Hold the breath for up to 10 seconds before
exhaling (if possible).
9. Continue until the medicine is finished in the
chamber. This may take 5 to 10 minutes.
CHOICE OF AEROSOL GENERATION
DEVICE
A comparison of the three major aerosol generators is
presented in table 2. 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 may be used if a high drug dose or large
volume is to be given. A nebuliser may also be
indicated if the drug is only available as a solution or
MDI/DPI are not effective. Patient preference should be
2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 215

considered when selecting an aerosol delivery device. CLINICAL USES OF AEROSOL THERAPY
Many patients might prefer a nebuliser to an MDI or a
DPI because of better response, but most of the times it Majority of drugs available for use as aerosolised
is a consequence of a higher dose being used during medications are used for obstructive airway diseases.
nebulisation. In such cases, increasing the total daily Table 3 lists these drugs with their dosages and the type
dose provided by an MDI or DPI might be useful and of aerosol generator available with each drug. In
may help to convince the patient to continue using the addition, a few antibiotics and mucolytic agents are also
inhalers. available for aerosol therapy. Use of inhaled tobramycin
In an evidence-based review by a panel of the is now well established in patients with cystic fibrosis.
American College of Chest Physicians, 33 it was Many studies have shown improvement in lung
determined that for most patients with asthma, function by use of aerosolised tobramycin in patients
nebulisers, DPIs and MDIs were equally effective in with cystic fibrosis. 42,43 This improvement in lung
delivering short-acting β 2-agonists, if the device was function is attributed to clearing of colonised
used appropriately by the patient. Moreover, Pseudomonas aureugenosa, which causes recurrent
salbutamol given via an MDI has also been shown to be episodes of pneumonia in these patients. Other
at least as effective as the nebulised form for the therapy antibiotics that have been used in aerosolised mode are
of acute moderate to severe asthma episodes in pentamidine for Pneumocystis carinii pneumonia
children.39-41 prophylaxis, colistin in cystic fibrosis,44 amphotericin B
Table 2. Characteristics of the aerosol generators
MDI DPI Nebuliser
Technique of generation of aerosol Propellant based Patient driven flow Bernoulli’s principle/piezoelectric
crystal
Particle size 1-10 µ 1-10 µ Variable
Drug deposition 5-10% 9-30% 2-10%
Oro-pharyngeal deposition Significant Variable Insignificant
Patient coordination Required Not applicable Not required
Breath hold Required Not required Not required
Patient generation of flow Not required Required Not required
Amount of drug Small doses on!y Small doses only Large doses possible
Contamination No No Possible
Use for chronic therapy Yes Yes Rarely
Use for emergency management No No Yes
Use for intubated patients Preferred No Second choice
Cost Cheap Cheap Expensive
MDI = metered dose inhaler, DPI = dry powder inhaler

Table 3. Inhaled drugs used for obstructive airway diseases

Drug Type of Aerosol Generator Dose
Salbutamol MDI 100-200 µg, 4-6 times/day
Salbutamol Sulphate DPI 200-400 µg, qid
Salbutamol Sulphate Solution for nebuliser 2.5-5 mg
Terbutaline Sulphate MDI 250-500 µg, qid
Terbutaline Sulphate Solution for nebuliser 10-20 mg
Salmeterol Xinafoate MDI 50 µg, bid
Salmeterol Xinafoate DPI 50 µg, bid
Formoterol Fumarate MDI 12-24 µg, bid
Formoterol Fumarate DPI 12-24 µg, bid
Ipratropium Bromide MDI 20-40 µg, qid
Ipratropium Bromide DPI 20-40 µgm, qid
Ipratropium Bromide Solution for nebuliser 100-500 µg
Tiotropium DPI 18 µg/day
Sodium Cromoglycate MDI 5 mg, qid
Sodium Cromoglycate DPI 20 mg, qid
Sodium Cromoglycate Solution for nebuliser 20 mg, qid
Beclomethasone Dipropionate MDI 100-400 µg, 2-4 times/day
Beclomethasone Dipropionate DPI 200-400 µg, 2-4 times/day
Budesonide MDI 100-400 µg, bid
Budesonide DPI 200-400 µg, bid
Fluticasone propionate MDI 100-1000 µg, bid
Fluticasone propionate DPI 100-1000 µg, bid
MDI = metered dose inhaler, DPI=dry powder inhaler
216 Aerosol Therapy
for bronchopulmonary fungal infections in lung
transplant recipients 45 and amikacin for E. coli
pneumonia.46 Mucolytics that have been investigated
are N-acetyl cysteine, 47 recombinant human
deoxyribonuclease48 and Nacystelyn49 in cystic fibrosis,
and mercapto-ethane sulfonate (Mesna) in patients with
COPD.50
All the above discussed drugs act through local
action in the airways. Recently, a few drugs have been
developed or are in the process of development, that are
supposed to be delivered through the airways for
systemic action. Major steps have been taken in the
direction of developing aerosolised insulin that could be
used for diabetic patients in place of daily injections.51, 52
This formulation has been approved in the US and is
likely to become available in India in 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.
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
travel before reaching the lower airways. Aerosol
particles have a strong tendency to stick to the walls of
the airways and this results in a significant reduction in
the fraction of the total drug reaching the lower airways.
To avoid this, it has been suggested that the
endotracheal tube (ETT) could be bypassed by using a
long catheter that attaches to the nozzle of the MDI and
release the drug distally in the airways.53 Other factors
that result in poor delivery of the aerosol particles to the
distal airways are heating and humidification54,55 of the
inhaled gas, which results in almost 40% reduction in
the fraction of the 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 higher fraction of drug sticking to the artificial
airway. This can be circumvented to some extent by
using a less dense gas, such as oxygen and helium. Use
of this mixture for ventilation has been shown to
improve aerosol delivery.56 Among the generators, MDI
have been found to be more effective than nebulisers.57
The technique of connecting the generator to ETT is also
an important factor that affects the drug delivery. It has
been shown that attaching a spacer between the
G.C. Khilnani and A. Banga
generator and the ETT58 as well as coordinating the
actuation with the inspiration 59 results in a greater
delivery of aerosol particles. Several studies have shown
that the fraction of delivered dose is almost four times
when using a combination of an MDI and a chamber
device as compared to that achieved by attaching it
directly to the ETT.
AEROSOL THERAPY IN PEDIATRIC
PATIENTS
Aerosol therapy can be effectively given in children of
all the ages. As in an adult, aerosol therapy is preferred
to systemic administration of bronchodilators and anti-
inflammatory drugs. All the methods including
nebulisation, MDI, MDI with spacer and DPI are used
depending upon the age of the child. For very young
children below four years, a spacer is used with face
mask (baby maks). Metered dose inhalers use with
spacer has been found to be comparable to nebulisers in
delivering salbutamol in acute exacerbation of asthma
in children. 63 It is very important to select an
appropriate device for aerosol therapy that should be
given to patients, although there are rough guidelines
for choosing the same.64 These are: (a) children below
four years of age, MDI with spacer with face mask;
(b)children above four years, MDI with spacer, (c) for
children above six years DPI can also be used, and (d)
for children above 12 years of age, MDI can be used
directly.
SAFETY OF AEROSOL THERAPY
Although drugs delivered as aerosols have been largely
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 β2-
agonists administered through the nebuliser have been
reported in rare cases to lead to arrhythmias. Inhaled
corticosteroids may have local and systemic adverse
effects. Among the local adverse effects oral candidiasis,
dysphonia and cough are well known.65 Incidence of
oral candidiasis may vary from 0%-77% depending on
the definition used.66 The data on comparative risk of
developing candidiasis with different corticosteroids is
conflicting.67-70 However, there seems to be a trend
towards higher incidence of candidiasis with fluticasone
propionate, especially at higher doses, in comparison to
budesonide and ciclesonide.71 Moreover, fluticasone
propionate may also result in esophageal candidiasis,
again in a dose dependent manner.72,73 Incidence of
dysphonia is to the tune of 5%-50% and is the result of
vocal stress and is again dose dependent. 74 Cough
occurs in as many as one-third of patients on inhaled
corticosteroids with no difference between different
2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences
formulations. 75 The usual interventions aimed at
preventing these local adverse effects consist of oral
rinse after inhalations, reduction in frequency of inhaled
corticosteroids and use of spacer device or holding
chamber. Nonetheless, there have been some
contradictory results with spacer devices where
incidence of cough and dysphonia were noted to be
higher with their use. 66 Among the systemic adverse
effects, large doses of inhaled corticosteroids may lead
to suppression of hypothalamus-pituitary-adrenal axis
and must be used cautiously in growing children.76 A
meta-analysis did not find an increase in the risk of loss
of bone density and fractures.77 However, the risk of
glaucoma78 and cataracts79 tends to increase in patients
taking long-term inhaled corticosteroids. Risk of cross-
infection with the use of nebuliser in hospital patients is
also well known and various methods for
decontamination of nebulisers have been described.80
CONCLUSIONS
Aerosol therapy has been around for more than 50 years
and forms the cornerstone of management of
obstructive airway diseases. Recent times have
witnessed many advances in this field. Improved
aerosol generators with different drug formulations are
now available. However, the fraction of total drug
eventually delivered to the site of action still remains
small. Metered dose inhalers with or without a valved
spacer have emerged as the preferred devices 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
improve management strategies for various diseases.
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220 The Indian Journal of Chest Diseases & Allied Sciences 2008; Vol. 50

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