Principles for nebulization

Nebulizers: Principles and Performance
Dean R Hess PhD RRT FAARC
Introduction
Pneumatic Nebulizers
Principle of Operation
Clinically Important Characteristics of Nebulizer Performance
Technical Factors Affecting Nebulizer Performance
Patient Factors Affecting Nebulizer Performance
Designs to Enhance Nebulizer Performance
Use of Reservoir Bags to Collect Aerosol During the Expiratory Phase
Breath-Enhanced Nebulizers
Breath-Actuated Nebulizers
Continuous Nebulization
Nebulizers for Specific Applications
Ultrasonic Nebulizers
Summary
[Respir Care 2000;45(6):609–622] Key words: nebulizer, pneumatic nebu-
lizer, ultrasonic nebulizer, continuous nebulization, aerosol therapy.
Introduction
Nebulizers are used to convert liquids into aerosols of a
size that can be inhaled into the lower respiratory tract.
The process of pneumatically converting a bulk liquid into
small droplets is called atomization. Pneumatic nebulizers
have baffles incorporated into their design so that most of
the droplets delivered to the patient are within the respi-
rable size range of 1–5 ␮m. Ultrasonic nebulizers use
electricity to convert a liquid into respirable droplets.
Although the first choice of aerosol generator for the
delivery of bronchodilators and steroids is the metered-
dose inhaler,1,2 nebulizers remain useful for several rea-
sons. First, some drugs for inhalation are available only in
solution form. Second, some patients cannot master the
correct use of metered-dose inhalers or dry powder inhal-
ers. Third, some patients prefer the nebulizer over other
aerosol generating devices. The physiologic benefits of
metered-dose inhalers and nebulizers are virtually equiv-
alent,3,4 and the choice of device is often based on clini-
cian or patient preference rather than clear superiority of
one approach over the other. Although cost savings have
been suggested with the use of metered-dose inhalers com-
pared to nebulizers, these benefits may be overestimated.3
The purpose of this paper is to review the performance
characteristics of nebulizers. Both pneumatic and ultra-
sonic nebulizer designs will be considered.
Pneumatic Nebulizers
Nebulizers are the oldest form of aerosol generation.
Although they have been commonly used for many years,
their basic design and performance has changed little over
the past 25 years. Nebulizers are most commonly used for
bronchodilator administration, and it is well established
that nebulized bronchodilators produce a physiologic re-
sponse. Because bronchodilators are relatively inexpen-
sive, there is little market pressure to improve nebulizer
performance. In fact, the market generally prefers an in-
expensive nebulizer rather than a high-performance neb-
Dean R Hess PhD RRT FAARC is affiliated with Massachusetts General
Hospital and Harvard Medical School, Boston, Massachusetts.
A version of this paper was presented by Dr Hess during the RESPIRA-
TORY CARE Journal Consensus Conference, “Aerosols and Delivery De-
vices,” held September 24–26, 1999 in Bermuda.
Correspondence: Dean R Hess PhD RRT FAARC, Respiratory Care,
Ellison 401, Massachusetts General Hospital, 55 Fruit Street, Boston MA
02114. E-mail: dhess@partners.org
RESPIRATORY CARE • JUNE 2000 VOL 45 NO 6 609

ulizer for bronchodilator administration. However, there
are newer drugs available for inhalation that are expensive
and for which precise dosing may be important. These
include dornase alfa, tobramycin, and pentamidine. Neb-
ulizer performance is affected by both technical and pa-
tient-related factors (Table 1).
Principle of Operation
The operation of a pneumatic nebulizer requires a pres-
surized gas supply as the driving force for liquid atomi-
zation (Fig. 1).5–10 Compressed gas is delivered through a
jet, causing a region of negative pressure. The solution to
be aerosolized is entrained into the gas stream and is sheared
into a liquid film. This film is unstable and breaks into
droplets because of surface tension forces. A baffle is
placed in the aerosol stream, producing smaller particles
and causing larger particles to return to the liquid reser-
voir. More than 99% of the particles may be returned to
the liquid reservoir.8 The aerosol is delivered into the in-
spiratory gas stream of the patient. Before delivery into the
patient’s respiratory tract, the aerosol can be further con-
ditioned by environmental factors such as the relative hu-
midity of the carrier gas.11–14
Nebulizer nozzles are of two types (Fig. 2).15 With the
internal mixing design, gas flow interacts with the solution
prior to leaving the exit port. With external mixing, gas
and the solution interact after both leave the nozzle. Mod-
ifications on these designs are used by nebulizer manufac-
turers, without clear superiority of one approach over the
other.
Determinants of droplet size produced by nebulizers
include the characteristics of the solution (density, viscos-
ity, surface tension), the velocities of the gas and solution,
and the flow rates for the gas and the solution.5,15 The most
important factors are gas velocity and the ratio of liquid to
gas flow.5 An increase in gas velocity decreases droplet
size, whereas an increase in the ratio of liquid to gas flow
increases particle size. It is interesting to note that gas
velocity affects the flow rates for both the gas and the
solution. Thus, it is impossible to separately control the
primary factors affecting droplet size from nebulizers.
An important consideration in the use of nebulizers is
the dead volume of the device. Dead volume refers to the
amount of solution that is trapped inside the nebulizer and
is thus not made available for inhalation. The dead volume
is typically in the range of 1 to 3 mL. Dead volume is
minimized by using a conical shape of the nebulizer, by
decreasing the surface area of the internal surface of the
nebulizer, and by improving the wetness of the plastic
surface of the nebulizer.5,15 To reduce medication loss due
to dead volume, clinicians and patients may tap the neb-
ulizer periodically during therapy, which has been shown
to increase nebulizer output.16 Therapy may also be con-
tinued past the point of inconsistent nebulization (sputter-
ing) in an attempt to deliver medication from the dead
volume, but this has been reported to be unproductive.17
Fig. 1. Basic components of the design of pneumatic nebulizers.
(Adapted from Reference 6.)
Table 1. Factors Affecting Penetration and Deposition of
Therapeutic Aerosols Delivered via Jet Nebulizer
Technical Factors
Manufacturer of nebulizer
Gas flow used to power nebulizer
Fill volume of nebulizer
Solution characteristics
Composition of the driving gas
Designs to enhance nebulizer output
Continuous versus breath-actuated
Patient Factors
Breathing pattern
Nose versus mouth breathing
Composition of inspired gas
Airway obstruction
Positive pressure delivery
Artificial airway and mechanical ventilation Fig.2.Internalmixingandexternalmixingnebulizerdesigns.(Adapt-
ed from Reference 5.)
NEBULIZERS: PRINCIPLES AND PERFORMANCE
610 RESPIRATORY CARE • JUNE 2000 VOL 45 NO 6

Due to evaporative water loss, the solution in the neb-
ulizer becomes increasingly concentrated during the neb-
ulization time.18–20 For this reason, gravimetric methods
underestimate nebulizer output.21,22 Due to the evaporative
effects, the nebulizer solution cools.18 Solution tempera-
ture affects nebulizer output, with output varying directly
with temperature.15,23 The droplet size produced by the
nebulizer also varies directly with temperature.18
Clinically Important Characteristics of Nebulizer
Performance
The most important characteristic of nebulizer perfor-
mance is the respirable dose provided for the patient. The
respirable dose is determined by the mass output of the
nebulizer and the size of the droplets that are produced.
The droplet size should be 2–5 ␮m for airway deposition
and 1–2 ␮m for parenchymal deposition.24 Droplet size is
usually reported as mass median aerodynamic diameter
(MMAD), which is the diameter around which the mass of
the aerosol is equally divided. Note that MMAD is used to
characterize the population of droplets produced; it does
not refer to the size of individual droplets. Because the
volume, and hence the mass, of the droplet is determined
by the cube of the radius (volume ϭ 4/3 ␲ r3
), most of the
particles will be smaller than the MMAD. The respirable
dose is sometimes reported as respirable mass, which is
the output of droplets from a nebulizer in the respirable
range of 1–5 ␮m.25,26
Other important characteristics of nebulizer performance
include nebulization time, cost, ease of use, and require-
ments for cleaning and sterilization. Nebulization time is
important for patient compliance in the outpatient setting
and clinician supervision for hospitalized patients. A short
nebulization time that delivers an effective dose is desir-
able. Many nebulizers are low-cost, mass-produced, sin-
gle-patient-use devices. This results in variability in per-
formanceamongdevices,25–28 whichmightnotbeimportant
for bronchodilator delivery, but which could be important
for delivery of other inhaled medications.
Technical Factors Affecting Nebulizer Performance
Several studies have reported performance differences
between nebulizers from different manufacturers.23,25–
27,29–36 Performance differences among nebulizers from the
same manufacturer have been reported.37–39 Hess et al25
evaluated the performance of 17 nebulizers, using a model
of spontaneous breathing. They reported a respirable mass
available to the patient that was severalfold greater from
some nebulizers than from others (Fig. 3). Performance
differences between nebulizers may have clinical implica-
tions.37,40–43 In healthy subjects, Hardy et al42 reported
aerosol deposition from some pneumatic nebulizers that
was twice that of others. In subjects with chronic stable
asthma, Johnson et al43 reported differences in bronchodi-
lation between nebulizers from different manufacturers.
Because of cost considerations, disposable single-pa-
tient-use nebulizers are typically used for many treatments.
The effects of repetitive use and cleaning were evaluated
by Standaert et al.44 In that study, nebulizers were found to
function correctly for 100 repeated uses, provided they
were properly maintained. Proper maintenance consisted
of washing with soapy water, rinsing, and air drying after
each use. Each nebulizer was also subjected to a daily
30-minute soak in 2.5% acetic acid. In the same study,44 it
Fig. 3. Comparison of the output of 17 commercially available pneumatic nebulizers. Respirable mass ϭ particles 1–5 ␮m delivered to
mouthpiece with simulated spontaneous breathing; 2.5 mg albuterol placed into nebulizer cup. (Adapted from Reference 25.)

was reported that the nebulizers started to fail after 40 uses
if they were not cleaned after each use.
Several studies have reported greater output from pneu-
matic nebulizers when the fill volume is in-
creased.23,25,33,34,45 This is probably because nebulizers
have a fixed dead volume, and thus an increase in fill
volume reduces the proportion of dead volume within the
nebulizer. Although nebulizer output increases with a
greater fill volume, there is also an increase in nebulization
time.25 The nebulization time can be reduced when a larger
fill volume is used by increasing the flow to power the
nebulizer.23,25 A nebulizer fill volume of 4–5 mL is rec-
ommended.
Output increases with an increased flow to power the
nebulizer.23,25,33 An increase in flow also decreases the
droplet size produced by nebulizers.25,39,46–48 A flow of 8
L/min is recommended. Flows lower than this result in
decreased nebulizer performance. A flow greater than this
may result in increased drug loss during the expiratory
phase, which offsets the effect of greater flow on nebulizer
output.25
It is not commonly appreciated that the drug formula-
tion can affect nebulizer performance. MacNeish et al38
reported differences in nebulizer output with two formu-
lations of albuterol. Nebulizer output was significantly
greater with the formulation containing the preservative
benzalkonium chloride, probably because of its surface
activity (Fig. 4). Large droplets were seen to adhere to the
walls of the nebulizer with the preservative-free formula-
tion, whereas foaming was seen to occur with the preser-
vative-containing formulation. Others have also reported
effects of drug formulation on nebulizer output.39,49 It is
interesting to note that metered-dose inhalers have always
been tested and approved as a drug-delivery-system com-
bination. Newer drug solutions have also been approved
for a specific nebulizer (eg, pentamidine, ribavirin, dor-
nase alpha, tobramycin).
The density of the gas powering the nebulizer affects
nebulizer performance. Hess et al50 reported the effect of
heliox (80% helium, 20% oxygen) on nebulizer function.
The inhaled mass of albuterol was significantly reduced
when the nebulizer was powered with heliox, and there
was a greater than twofold increase in nebulization time
with heliox. An increased flow with heliox produced a
respirable mass output similar to that produced when the
nebulizer was powered with air. These results are explained
by Bernoulli’s principle, which predicts that the decreased
density of heliox increases the velocity at which the gas
leaves the jet orifice and produces less negative pressure to
entrain drug solution.50
Patient Factors Affecting Nebulizer Performance
The breathing pattern of the patient affects the amount
of aerosol deposited in the lower respiratory tract. This
partially explains differences in aerosol deposition between
children and adults. To improve aerosol penetration and
deposition in the lungs, the patient should be encouraged
to use a slow and deep breathing pattern.51 Because of the
effect of breathing pattern on drug delivery from nebuliz-
ers, in vitro evaluations of nebulizer performance should
be conducted in a manner that simulates the breathing
pattern of a patient.52
Inhaled aerosols can be administered using a mouth-
piece or a face mask.53–57 Bronchodilator responses occur
with both techniques, and some have argued that the se-
lection of interface should be based on patient preference.53
However, it should be appreciated that the nasal passages
effectively filter droplets delivered from the nebulizer.
Everard et al54 reported a nearly 50% reduction in aerosol
Fig. 4. Comparison of albuterol output of a pneumatic nebulizer, using two formulations of albuterol. (Drawn from data in Reference 38.)

delivery to the lungs with nasal inhalation. Whether a
mouthpiece or a face mask is used, it is important to in-
struct the patient to inhale through the mouth. Use of a
mouthpiece may encourage oral breathing.54 It is interest-
ing to note that asthmatic patients switch their breathing
route from the nasal route to the oronasal route during
acute exacerbations and, even when not acutely broncho-
constricted, switch to oronasal breathing when wearing a
face mask.58
Airway caliber affects lung delivery of nebulized bron-
chodilators.59–61 Lipworth et al61 reported lower plasma
albuterol concentrations and attenuated bronchodilator re-
sponses in patients with severe asthma than in normal
subjects or those with mild asthma. It is ironic that the air
flow obstruction that produces the need for inhaled bron-
chodilator therapy also decreases the effectiveness of that
therapy.
Several studies have reported greater pulmonary pene-
tration of aerosols in patients with stable asthma and with
acute airway constriction during heliox breathing.62–66 Be-
cause of the lower density and greater viscosity of heliox,
gas flow becomes less turbulent, which theoretically im-
proves the transport of aerosols through constricted air-
ways to more peripheral lung regions. Henderson et al67
reported no significant advantage of heliox-driven nebu-
lizer therapy over oxygen-driven nebulizer therapy. How-
ever, they67 did not account for the effect of heliox on
nebulizer function,50 and this may have contributed to their
negative findings.
Nebulizer therapy has been used in combination with
noninvasive ventilation. Pollack et al68 randomized pa-
tients with acute asthma to receive either bronchodilator
therapy with a nebulizer and face mask or with a nebulizer,
nasal mask, and BiPAP (bi-level positive airway pressure
system made by Respironics). The BiPAP settings were:
inspiratory pressure 10 cm H2O, expiratory pressure 5 cm
H2O. The patients who received bronchodilator therapy
with BiPAP had a greater improvement in peak flow (Fig.
5). Although these results are intriguing, further positive
reports are needed before widespread acceptance of this
practice. Interestingly, this approach to nebulizer therapy
is reminiscent of intermittent positive-pressure breathing,
which was abandoned many years ago as a method for
delivery of inhaled bronchodilators to patients with asthma.
Nebulizer therapy is commonly used in mechanically
ventilated patients, and this topic has been reviewed in
detail elsewhere.69–73 A number of factors are known to
affect aerosol delivery from nebulizers during mechanical
ventilation (Table 2).12 There are disadvantages of nebu-
lizer use during mechanical ventilation, such as circuit
contamination,74 decreased ability of the patient to trigger
the ventilator75 (if the nebulizer is not powered by the
ventilator), and increases in the delivered tidal volume and
airway pressure76 (if the nebulizer is not powered by the
ventilator). The nebulizer is less efficient than the me-
tered-dose inhaler during mechanical ventilation, but the
nebulizer delivers a greater dose to the lower respiratory
tract.77
Designs to Enhance Nebulizer Performance
In recent years, several nebulizer designs have become
available to decrease the amount of aerosol lost during the
expiratory phase.78 These include reservoir bags to collect
aerosol during the expiratory phase, the use of a vented
design to increase the nebulizer output during the inspira-
tory phase (breath-enhanced nebulizers), and nebulizers
that only generate aerosol during the inspiratory phase
(breath-actuated nebulizers). Because these designs im-
prove drug delivery to the patient, they have the potential
to reduce treatment time, which should improve patient
compliance with nebulizer therapy.
Use of Reservoir Bags to Collect Aerosol
During the Expiratory Phase
For many years, it has been a common practice to use a
T-piece and corrugated tubing as a reservoir for small-
Fig. 5. Peak expiratory flow (PEF) responses with albuterol delivery
by nebulizer with bilevel positive airway pressure (BiPAP) or by
nebulizer alone. (Drawn from data in Reference 68.)
Table 2. Factors Affecting Aerosol Delivery from Nebulizers
During Mechanical Ventilation
Endotracheal tube size
Position of nebulizer placement in the circuit
Type of nebulizer and fill volume
Humidification of the inspired gas
Treatment time
Duty cycle (I:E ratio)
Ventilator brand
I:E ratio ϭ ratio of inspiratory time to expiratory time.

volume nebulizers.79 In the late 1980s and early 1990s,
there were reports of increased aerosol delivery to the
lower respiratory tract when a plastic chamber was used
with the nebulizer to capture aerosol during the expiratory
phase, and provide that to the patient during the subse-
quent inspiration.80,81 In the United States, a similar con-
cept was incorporated into the Circulaire and AeroTee
designs (Fig. 6). Both of these designs use a 750 mL bag
to store aerosol during exhalation, but differ in how they
prevent rebreathing. The Circulaire uses a one-way valve
to prevent exhaled gas from entering the reservoir bag,
whereas the AeroTee allows some exhaled gas to enter the
bag.82 These designs also decrease environmental contam-
ination with the aerosol that is generated. The Circulaire
incorporates a variable inspiratory/expiratory resister that
is set to maximize inspiration from the reservoir bag, and
to provide a positive expiratory pressure effect.
Mason et al83 reported an MMAD of 0.51 ␮m with the
Circulaire. Compared with a conventional nebulizer, they
also reported better lung deposition, less gastrointestinal
deposition, and less drug loss to the environment (Fig. 7).
However, there are several important observations about
these results. First, of 9 normal subjects, 2 actually had
decreased pulmonary deposition with the Circulaire. This
illustrates why caution must be exercised when applying
group data to individual patients. Second, the conventional
nebulizer used by Mason et al83 does not perform as well
as the nebulizer incorporated into the Circulaire. Thus, it is
unclear whether the results were the effect of the reservoir
bag or the nebulizer. The MMAD reported by Mason et
al83 for the Circulaire is not ideal. For maximal pulmonary
deposition of bronchodilators, an MMAD of 1–5 ␮m is
more desirable.
In another study by Mason et al,84 the Circulaire was
compared to a conventional nebulizer for bronchodilator
delivery in patients with chronic obstructive pulmonary
disease. In that study, the pulmonary deposition and ther-
apeutic effect were similar for the Circulaire and the con-
ventional nebulizer. Hoffman et al85 compared the Circu-
laire to a conventional nebulizer for bronchodilator delivery
in patients with acute bronchospasm presenting to an emer-
gency department. They reported a greater improvement in
bronchospasm (measured by peak flow) in the Circulaire
group. In this study,85 like those by Mason et al,83,84 the
nebulizer used with the Circulaire may have been superior
to the conventional nebulizer that was used and, thus, the
study may have compared the performance of nebulizers
rather than the effect of the reservoir bag.
Breath-Enhanced Nebulizers
The traditional nebulizer design incorporates the nebu-
lizer sidestream to the air flow of the patient. Some newer
nebulizers use a mainstream design with valves. In this
valved open-vent design, the patient breathes through the
nebulizer during inspiration, which enhances the nebu-
lizer output. During the expiratory phase, a one-way
valve directs patient flow away from the nebulizer cham-
ber (Fig. 8).
This design has been evaluated in several studies, which
have reported greater pulmonary deposition with this de-
sign than with a conventional nebulizer.86–88 A potential
advantage of the open-vent nebulizer design is an im-
provement in nebulizer output with an increase in inspira-
tory flow. Coates et al31 reported a greater output of to-
bramycin with increased inspiratory flow, using an open-
vent nebulizer, whereas changes in inspiratory flow did
not affect the output of the conventional nebulizer (Fig. 9).
As with conventional nebulizers, performance differences
between breath-enhanced nebulizers have been report-
ed.88,89
Breath-Actuated Nebulizers
Aerosol waste during the expiratory phase can be elim-
inated if the nebulizer is only active during the inspiratory
phase. Methods to manually actuate the nebulizer during
the inspiratory phase have been available for many
years.45,90 It is also of interest to note that this design is
commonly used in mechanical ventilator-actuated de-
signs.91,92 Both pneumatically and electronically controlled
breath-actuated nebulizers have recently become commer-
cially available. Their role in clinical application is yet to
be determined.
Continuous Nebulization
Since the late 1980s, there has been considerable clin-
ical and academic interest in the use of continuous aero-
solized bronchodilators for the treatment of acute asth-
ma93–106 (Table 3). These studies suggest that this therapy
is safe, at least as effective as intermittent nebulization,
and may be superior to intermittent nebulization in pa-
tients with the most severe pulmonary function.
Several configurations have been described for contin-
uous nebulization.107 These include frequent refilling of
Fig. 6. Two designs of nebulizer device that use a reservoir bag.
Circulaire (left) and AeroTee (right).

the nebulizer,93,101,104,106 use of a nebulizer and infusion
pump (Fig. 10),94,96,99,102,103,108 and use of a large-volume
nebulizer.95,97,98,106,109 Berlinski et al110 reported a consis-
tent and adequate aerosol production by a large-volume
nebulizer over a 4-hour period of operation. Reisner et
al,111 however, reported a more consistent aerosol delivery
with a small-volume nebulizer attached to an infusion pump
than with a large-volume nebulizer. A commonly used
large-volume nebulizer for this therapy is the High-output
Extended Aerosol Respiratory Therapy (HEART) nebu-
lizer. Raabe et al112 reported a detailed evaluation of the
performance of the HEART nebulizer. At a flow of 10–15
L/min, the aerosol output was 38–50 ␮L of aerosolized
drug per liter of gas flow, and the solution output was
30–56 mL/hr.
McPeck et al113 compared the HEART nebulizer to a
conventional small-volume nebulizer in a model of adult
and pediatric breathing. With the adult breathing pattern
they reported similar aerosol delivery from the HEART
nebulizer and small-volume nebulizer. For the pediatric
breathing pattern the aerosol delivery from the small-vol-
ume nebulizer was greater than from the HEART. Both
Raabe et al112 and McPeck et al113 reported an MMAD of
about 2 ␮m with the HEART nebulizer. An important
finding of McPeck et al113 was that the albuterol delivery
from the HEART nebulizer was significantly less than the
target dose from the manufacturer’s recommended setup.
Nebulizers for Specific Applications
Specially constructed small-volume nebulizers should
be used when contamination of the ambient environment
with the aerosolized drug needs to be avoided.35,114,115 The
most common example is aerosolized pentamidine.116 The
nebulizer is fitted with one-way valves and filters to pre-
vent gross contamination of the environment. Examples of
these devices include the Cadema Aero-Tech II and the
Respirgard II. These devices produce a very small particle
size, with an MMAD of about 1–2 ␮m, which is necessary
to improve alveolar deposition of the drug.
The Small-Particle Aerosol Generator is used specifi-
cally to aerosolize ribavirin (Virazole).117–119 The device
consists of a nebulizer and a drying chamber. The drying
chamber reduces the MMAD of particles to about 1.3 ␮m.
There are concerns about the potential adverse effects of
this drug on health care workers when ribavirin is used.
For this reason, a scavenging system should be used when
ribavirin is administered.120–122 This is a double-enclosure
system, with a ribavirin administration hood or mask in-
side a tent. Two high-flow vacuum scavenging systems
Fig. 7. Percent of drug delivery to the lungs, gastrointestinal (GI) tract, and room using a Circulaire nebulizer system. (Drawn from data in
Reference 83.)
Fig. 8. Schematic representation of the function of a breath-en-
hanced nebulizer. Courtesy of Pari Respiratory Equipment.

aspirate ribavirin from the system through high-efficiency
particulate air filters.
Ultrasonic Nebulizers
Ultrasonic nebulizers have been clinically available since
the 1960s.123,124 Small-volume ultrasonic nebulizers are
commercially available for delivery of inhaled bronchodi-
lators.125–131 Althoughseveralstudiesreportedgreaterbron-
chodilator response with ultrasonic nebulizers than with
other aerosol generators,127,128 this has not been confirmed
in other studies.129–131 Large-volume ultrasonic nebulizers
are used to deliver inhaled antibiotics in patients with cys-
Fig. 10. System for continuous bronchodilator administration using a conventional nebulizer and an infusion pump. (From Reference 103,
with permission.)
Fig. 9. Tobramycin output from a conventional nebulizer (Hudson) and a breath-enhanced nebulizer (Pari) with changes in inspiratory flow.
RF ϭ respirable fraction. (From Reference 31, with permission.)

Table 3. Summary of Studies Reporting Use of Continuous Nebulization
Author Study Population Drug
Research
Design
Continuous Nebulizer
Design
Major Finding
Portnoy93 Children with
severe asthma
Terbutaline;
1–12 mg/h
Case series Frequent refilling of
conventional
nebulizer
Continuously nebulized terbutaline safe and effective
for treatment of severe asthma.
Moler103 Children with
severe asthma
Terbutaline; 4
mg/h
Case series Conventional nebulizer
with infusion pump
Continuously nebulized terbutaline is an effective
therapy for severe asthma.
Calcacone95 Adults with
acute asthma
Albuterol; 10
mg over 2 h
Randomized
controlled
trial
Large volume nebulizer Continuous nebulization was as effective as
intermittent nebulization.
Chipps109 Children with
bronchospasm
Terbutaline; 4
mg/h
Case series HEART nebulizer 18 of 23 cases showed significant improvement with
continuous nebulization.
Papo96
Children with
status asthma
Albuterol; 0.3
mg/kg/h
Randomized
controlled
trial
Conventional nebulizer
with infusion pump
Continuous nebulization was safe and resulted in more
rapid improvement than intermittent nebulization.
Lin97 Adults with
acute asthma
Albuterol; 30
mg over 110
min
Randomized
controlled
trial
HEART nebulizer Continuous nebulization most beneficial in patients
with FEV1 Ͻ 50% predicted.
Rudnitsky98 Adults with
acute asthma
Albuterol; 10
mg over 70
min
Randomized
controlled
trial
HEART nebulizer Continuous nebulization may be of benefit for patients
with peak flow Ͻ 200 L/min.
Lin99
Adults with
acute asthma
Albuterol; 0.4
mg/kg/h for
4 h
Case series Conventional nebulizer
with infusion pump
High dose continuous nebulization can result in
markedly elevated serum albuterol levels and
potential cardiac stimulation.
Katz100 Infants and
children with
bronchospasm
Albuterol; 3
mg/kg/h
Case series Not reported Continuous albuterol safe and without significant
evidence of cardiotoxicity.
Olshaker101 Adults with
acute asthma
Albuterol; 7.5
mg over 1 h
Case series Frequent refilling of
conventional
nebulizer
Continuous nebulization was safe and effective.
Baker105 Adults with
acute asthma
Albuterol; 10
mg/h
Retrospective
case control
with infusion pump
Continuous and intermittent nebulization were similar
in terms of safety, morbidity, and mortality.
Reisner111 Adults with
acute asthma
Albuterol; 7.5
mg/h
Randomized
controlled
trial
with infusion pump
Continuous nebulization was as safe and effective as
Moler103 Children with
acute asthma
Terbutaline; 16
mg over 8 h
Randomized
controlled
trial
with infusion pump
Continuous nebulization produced similar plasma
terbutaline levels and cardiovascular effects as
Shrestha104 Adults with
acute asthma
Albuterol; 2.5
mg or 7.5 mg
over 2 h
Randomized
controlled
trial
Frequent refilling of
conventional
nebulizer
The standard dose continuous nebulization group had
the greatest improvement with the fewest side
effects.
Weber106 Adults with
acute asthma
Albuterol at 10
mg/h;
ipratropium at
1 mg/h
Randomized
controlled
trial
HEART nebulizer There was no significant difference in outcomes for
patients receiving continuous albuterol alone or
continuous albuterol with ipratropium.

tic fibrosis (eg, tobramycin).132–135 Ultrasonic nebulizers
have also been used during mechanical ventilation,136–139
where they have an advantage in that they do not augment
tidal volume, as occurs with pneumatic nebulizers.
Table 4 lists advantages and disadvantages of ultrasonic
nebulizers for medication delivery. Table 5 lists factors
affecting output from ultrasonic nebulizers.140 A potential
issue with the use of ultrasonic nebulizers is the possibility
of drug inactivation by the ultrasonic waves,141 although
this has not been shown to occur with commonly-used
nebulized medications.
The ultrasonic nebulizer uses a piezoelectric transducer
to produce ultrasonic waves that pass through the solution
and aerosolize it at the surface of the solution. The ultra-
sonic nebulizer creates particle sizes of about 1–6 ␮m
MMAD, depending on the manufacturer of the device.140
The volume output of the ultrasonic nebulizer is about 1–6
mL/min, depending on the manufacturer of the device.140
An ultrasonic nebulizer has 3 components: the power
unit, the transducer, and a fan. The power unit converts
electrical energy to high-frequency ultrasonic waves at a
frequency of 1.3–2.3 megahertz.140 The frequency of the
ultrasonic waves determines the size of the particles, with
an inverse relationship between frequency and particle size.
The frequency is not user adjustable. The power unit also
controls the amplitude of the ultrasonic waves. This is user
adjustable, with an increase in amplitude resulting in an
increase in output from the ultrasonic nebulizer. The trans-
ducer vibrates at the frequency of the ultrasonic waves
applied to it (piezoelectric effect). The transducer is found
in two shapes, concave (focused) and flat (unfocused).140
Concave transducers produce a higher output but require a
constant level of solution for proper operation. The con-
version of ultrasonic energy to mechanical energy by the
transducer produces heat, which is absorbed by the solu-
tion over the transducer.
In some ultrasonic nebulizers, the solution to be nebu-
lized is placed directly over the transducer. In others, the
solution to be nebulized is placed into a nebulization cham-
ber and a water couplant chamber is placed between the
transducer and the medication chamber. A fan is used to
deliver the aerosol produced by the ultrasonic nebulizer to
the patient, or the aerosol is evacuated from the nebuliza-
tion chamber by the inspiratory flow of the patient.
Summary
Nebulizers have been used clinically for many years.
Despite the increasing use of metered-dose inhalers and
dry powder inhalers, it is likely that nebulizers will con-
tinue to be used in selected patients. A number of factors
affect nebulizer performance, and these should be appre-
ciated by clinicians who use these devices. Several new
designs have recently become available that improve the
performance of the nebulizer, but their cost-effectiveness
remains to be determined.
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