![Effect of albuterol on maximum inspiratory airway resistance (R max ). R max significantly decreased (compared to baseline [p 0.01]) within 10 min of albuterol administration. A: R max change (from baseline) after 4 metered-dose inhaler (MDI) puffs of albuterol. B: R max change (from baseline) after 2.5 mg albuterol via small-volume nebulizer (SVN). Significant R max reduction was sustained for 120 min and returned to baseline at 240 min. The response pattern was similar with MDI and nebulizer delivery in a group of stable, mechanically ventilated patients with chronic obstructive pulmonary disease. The error bars represent the standard error of the mean. (From Reference 61).](https://www.researchgate.net/profile/Alexander-Duarte-2/publication/8541790/figure/fig3/AS:601622199676937@1520449318188/Effect-of-albuterol-on-maximum-inspiratory-airway-resistance-R-max-R-max_Q320.jpg)
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Inhaled Bronchodilator Administration
During Mechanical Ventilation
Alexander G Duarte MD
Introduction
Lower-Respiratory-Tract Deposition
Nebulizer Performance
Metered-Dose Inhaler Performance
Factors That Influence Lower-Respiratory-Tract Deposition
Endotracheal Tube and Ventilator Circuit
Heating and Humidification
Density of the Inhaled Gas
Position of the Aerosol Generator in the Ventilator Circuit
Ventilation Parameters
Clinical Aspects
Patient Selection
Bronchodilator Selection
Administration Technique
Assessing Response
Bronchodilator Dosing
Toxicity
Metered-Dose Inhaler Versus Nebulizer
Bronchodilators Via Noninvasive Ventilation
Summary
Inhaled bronchodilators are routinely administered to mechanically ventilated patients to relieve dys-
pnea and reverse bronchoconstriction. A lower percentage of the nominal dose reaches the lower
respiratory tract in a mechanically ventilated patient than in a nonintubated subject, but attention to
device selection, administration technique, dosing, and patient-ventilator interface can increase lower-
respiratory-tract deposition in a mechanically ventilated patient. Assessing the airway response to
bronchodilator by measuring airway resistance and intrinsic positive end-expiratory pressure helps
guide dosing and timing of drug delivery. Selecting the optimal aerosol-generating device for a mechan-
ically ventilated patient requires consideration of the ease, reliability, efficacy, safety, and cost of ad-
ministration. With careful attention to administration technique, bronchodilator via metered-dose in-
haler or nebulizer can be safe and effective with mechanically ventilated patients. Key words: aerosol,
bronchodilator, mechanical ventilation,

agonist, chronic obstructive pulmonary disease, COPD, asthma,
inhalation therapy, noninvasive ventilation. [Respir Care 2004;49(6):623–634. © 2004 Daedalus Enterprises]
Alexander G Duarte MD is affiliated with the Division of Pulmonary and
Critical Care Medicine, University of Texas Medical Branch, Galveston,
Texas.
Alexander G Duarte MD presented a version of this report at the 49th
International Respiratory Congress, held December 8–11, 2003, in Las
Vegas, Nevada.
Correspondence: Alexander G Duarte MD, Division of Pulmonary and
Critical Care Medicine, University of Texas Medical Branch, Galveston
TX 77555-0561. E-mail: aduarte@utmb.edu.
RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6 623
Introduction
Compared to ambulatory, nonintubated subjects, de-
livery of inhaled bronchodilators to mechanically ven-
tilated patients differs with respect to the delivered dose,
administration technique, and patient-device interface.
Bronchodilator administration via inhalation provides
therapeutic efficacy similar to systemic administration
but with a smaller drug dose
1
and less systemic absorp-
tion and thus less adverse systemic effect.
2
In the crit-
ical care setting bronchodilators are principally admin-
istered via metered-dose inhaler (MDI) or nebulizer.
These devices generate aerosol with mass median aero-
dynamic diameter (MMADs) of 1–5
m, which is the
MMAD range that allows aerosol to reach the lower
respiratory tract.
3
MDIs are chiefly used to deliver bron-
chodilator and corticosteroid aerosols and are consid-
ered more efficient than jet nebulizers. Successful aero-
sol therapy in ventilator-dependent patients requires a
precise understanding of the principles that govern aero-
sol delivery during mechanical ventilation.
Lower-Respiratory-Tract Deposition
Compared to a nonintubated subject, a mechanically
ventilated patient receives less of a given dose of aerosol
in the lower respiratory tract. An initial report examining
lower-respiratory-tract delivery of aerosolized radiotracer
to intubated, mechanically ventilated patients found that
2.9% of the nominal dose was deposited in the airways,
compared with 11.9% in nonintubated subjects.
4
The dep-
osition pattern revealed substantial uptake of radiotracer
within the endotracheal tube (ETT), which suggests that
the ETT and ventilator circuit are barriers to lower-respi-
ratory-tract deposition. Interestingly, more recent studies
have demonstrated that the ETT and ventilator circuit are
not as formidable barriers as once believed and that atten-
tion to ventilatory variables may significantly influence
deposition.
5
Other investigators have reported lower-res-
piratory-tract deposition to range from 0 to 42% withnebu-
lizers
6–9
and from 0.3 to 97.5% with MDIs (Fig. 1).
10–13
Some of that variability is probably from different aerosol
delivery methods and lack of a standard model with which
to reliably assess lower-respiratory-tract delivery. With a
standardizedmethod and model, thelower-respiratory-tract
delivery is similar with nebulizers and MDIs (about
15%).
12,13
Nebulizer Performance
The most commonly used nebulizers are the jet/pneu-
matic type, which use compressed gas to create aerosol
particles of a size that can reach and deposit in the lower
respiratory tract. Ultrasonic nebulizers transform elec-
trical energy into high-frequency vibrations that aero-
solize the liquid. Nebulizer performance varies with the
gas flow, diluent volume, and operating pressure, and
the various nebulizer models differ in performance.
7,9,14
During mechanical ventilation, lower-respiratory-tract
deposition is most likely with an MMAD of 1–3
m;
aerosol particles larger than that tend to impact and
attach to the ventilator circuit and ETT. Within the lim-
its of a nebulizer’s design, the higher the gas pressure
and/or flow to the nebulizer, the smaller the MMAD.
14
During mechanical ventilation nebulizers can be oper-
ated continuously or intermittently (ie, only during in-
spiration).Continuousaerosolgenerationrequiresapres-
surized gas source, whereas intermittent operation
requires a separate line to conduct inspiratory airflow
from the ventilator to the nebulizer. Intermittent nebu-
lization decreases aerosol loss during exhalation and is
thus more efficient than continuous aerosol generation.
15
Importantly, the driving pressure provided by most ven-
tilators to the nebulizer (⬍ 15 psi) is much lower than
that provided by compressed air or oxygen sources com-
monly available in the hospital (50 psi), so the effi-
ciency of some ventilator-powered nebulizers is less
than continuous-operation nebulizers powered by a high-
er-pressure gas but at a similar flow.
16
For mechanical
ventilation ultrasonic nebulizers have the advantage that
they do not increase the tidal volume (V
T
), whereas jet
nebulizers can increase V
T
.
Fig. 1. Deposition values reported in bench models of mechanical
ventilation. Note the broad range of values reported (the range is
represented by the upper and lower limits of the bars). Depending
on the administration technique, between 0 and 97.5% of the
nominal dose was deposited in the lower respiratory tract.
6 –13
Aero-
sol delivery was greatest when a metered-dose inhaler (MDI) was
actuated into a catheter that directly deposited the aerosol at the
distal end of the endotracheal tube. (From Reference 1, with per-
mission).
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
624 RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6
Metered-Dose Inhaler Performance
Delivering MDI aerosol to a mechanically ventilated
patient requires the use of an actuator device that allows
the MDI to be discharged into the ventilator circuit. The
dose from the MDI is released from the canister through
a metering valve and a stem that fits into an actuator
boot designed and tested by the manufacturer to work
with that specific formulation. The liquid spray leaves
the MDI at about 15 m/s, declining by 50% within 0.1 s
as the aerosol cloud develops and moves away from the
actuator orifice.
17
Actuating the MDI into a chamber-
style spacer reduces the velocity of the aerosol jet,
18
thereby allowing time for the propellant to evaporate
and for particle size to stabilize and helping to minimize
aerosol lost to impaction in the ventilator circuit.
The dose of medication delivered by an MDI is much
smaller than that from a nebulizer. The quantity of al-
buterol delivered by an MDI actuation is only 100
g,
and a careful administration technique is necessary to
ensure adequate drug delivery to the lower respiratory
tract of a mechanically ventilated patient. Several types
of adapters are commercially available to attach an MDI
canister to the ventilator circuit or the ETT. The former
include chamber adapters, such as cylindrical spacers
and reservoir devices, and nonchamber devices. In vitro
and in vivo studies have demonstrated that, with MDIs,
chamber devices give 4–6-fold better aerosol delivery
than elbow adapters (directly attached to the
ETT)
10,12,19,20
or inline devices that lack a chamber.
20
Lack of therapeutic effect has been reported with an
MDI and elbow adapter attached to the ETT, even with
very high doses of albuterol (up to 100 actuations to-
taling 10.0 mg).
21
Factors That Influence
Lower-Respiratory-Tract Deposition
Aerosol delivery to mechanically ventilated patients is a
complex process involving the interaction of several fac-
tors. Various elements influence the efficiency of lower-
respiratory-tract deposition (Table 1) and attention to these
factors affects the efficiency of lower-respiratory-tract de-
livery.
Endotracheal Tube and Ventilator Circuit
The efficiency of lower airway delivery is reduced by
the impaction of aerosol particles inside the ETT and
ventilator circuit. With a pediatric ETT (inner diameter
of 3–6 mm) it appears that the narrower the ETT di-
ameter, the greater the particle impaction and thus the
lower percentage of the dose delivered to the lower
respiratory tract.
22,23
Yet the efficiency with which vari-
ous nebulizers deliver aerosol beyond the ETT did not
differ in a study of adult-size ETTs (inner diameter 7–9
mm).
7
Earlier reports overestimated the aerosol-delivery
impediment created by the artificial airway, probably be-
cause the aerosol generator was placed close to the ETT.
Placing the aerosol generating device away from the pa-
tient increases pulmonary deposition, though drug losses
in the ventilator circuit are higher than those in the ETT.
Importantly, the model of aerosol generator and the me-
chanical ventilation parameters influence aerosol deposi-
tion within the ETT more than does the ETT’s diameter.
5
Heating and Humidification
Conditioning the inspired gas involves heating and hu-
midification, which diminishes pulmonary deposition of
aerosols, with MDIs and nebulizers, by approximately
40%,
7,9,12,24,25
most likely because of increased particle
impaction in the ventilator circuit. Fink et al studied the
effect of heating and humidification on MDI albuterol dep-
osition in the ventilator circuit, ETT, and filters in a tra-
cheobronchial model (Fig. 2).
24
They found greater albu-
terol deposition in the ventilator circuit and ETT with
heated, humidified gas and, consequently, less drug deliv-
ery to the lung model. Accordingly, some investigators
have proposed bypassing the humidifier during aerosol
administration.
26,27
The absence of humidification is un-
likely to pose a problem during the brief interval required
to administer an MDI aerosol. However, some nebulizers
require up to 35 min to complete aerosolization,
12
and
inhaling dry gas for that long could harm the airway mu-
cosa. In addition, disconnecting the ventilator circuit to
bypass the humidifier increases the risk of ventilator-as-
sociated pneumonia. Thus it is recommended that MDI or
nebulizer delivery of bronchodilators be performed with
humidification.
Density of the Inhaled Gas
During mechanical ventilation, high inspiratory flow
produces turbulent airflow, which is associated with
greater drug particle-impaction losses. Use of a less-dense
Table 1. Factors That Influence Lower-Respiratory-Tract-Deposition
During Mechanical Ventilation
Physical and chemical properties of the medication
Characteristics of the aerosol-generating device
Position of the aerosol-generating device in the circuit
Ventilator settings
Characteristics of the ventilator circuit and endotracheal tube
Humidity of the inspired air
Airway anatomy and secretions
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6 625
gas, such as helium-oxygen mixture (heliox), reduces airflow
turbulence and thereby promotes greater drug delivery to the
lung.
28–30
In ambulatory subjects with airway obstruction,
heliox provides better aerosol lung-retention than air.
29
Dur-
ing mechanical ventilation heliox increases MDI albuterol
airway deposition.
28,31
However, the nebulizer should not be
powered by heliox, because heliox is less effective at nebu-
lizing the liquid. A practical method to achieve maximum
pulmonary aerosol deposition with a nebulizer during me-
chanical ventilation is to operate the nebulizer with oxygen at
a flow of 6–8 L/min and to entrain the aerosol into a venti-
lator circuit that contains heliox. With that method aerosol
delivery to the lower airways of a tracheobronchial model
was 50% higher than with oxygen in the ventilator circuit.
31
However, during mechanical ventilation heliox may interfere
with the performance of the ventilator, so prior to using he-
liox the clinician should test and adjust the ventilator to avoid
a potentially disastrous patient outcome.
32
Position of the Aerosol Generator in the Ventilator
Circuit
Aerosol delivery is improved by placing the nebulizer
30 cm from the ETT rather than between the Y-piece and
the ETT, because the ventilator tubing acts as a spacer for
the aerosol to accumulate between breaths.
7,9,15
Further-
more, a modest increase in aerosol delivery is achieved by
adding a spacer device in the ventilator circuit between the
nebulizer and the ETT.
33
Ventilation Parameters
The ventilation parameters, including ventilation
mode, V
T
, flow, and respiratory rate, influence the char-
acteristics of the breath used to deliver aerosol to a
mechanically ventilated patient. For optimal aerosol de-
livery MDI actuation must be precisely at the onset of
inspiration. In one study, synchronizing MDI actuation
(into a cylindrical spacer) with inspiration resulted in
approximately 30% greater aerosol delivery than when
actuation occurred during expiration.
12
With an elbow
adapter MDI actuation not synchronized with the onset
of inspiration achieved negligible pulmonary aerosol
delivery.
12
Adequate aerosol delivery can be achieved during
assistedventilation modes, provided the patient’s breath-
ing pattern is in synchrony with the ventilator. Up to
23% greater albuterol deposition was observed during
Fig. 2. Albuterol deposition from a metered-dose inhaler, expressed as percent of the nominal dose in the spacer chamber, ventilator circuit,
endotracheal tube (ETT), and on filters at the bronchi under dry (top panel) and humidified (bottom panel) conditions. Under dry conditions
55.2% of the albuterol was deposited in the spacer, 10.2% in the ventilator circuit, 4.2% in the ETT, and 30.4% in the bronchi. Under
humidified conditions 39.5% of the albuterol was deposited in the spacer, 31.4% in the ventilator circuit, 12.9% in the ETT, and 16.2% in
the bronchi. CFC ⫽ chlorofluorocarbon. RH ⫽ relative humidity. (From Reference 24, with permission).
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
626 RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6
simulated spontaneous breaths (with continuous posi-
tive airway pressure) than during volume-cycled breaths
of equivalent V
T
.
13
To achieve adequate lower-respira-
tory-tract delivery the V
T
must be larger than the vol-
ume of the ventilator tubing and ETT. Thus, with adult
patients a V
T
of ⱖ 500 mL is associated with adequate
aerosol delivery.
13,34
Increasing the duty cycle (ie, the
ratio of inspiratory time to total breathing cycle time)
improves lower-respiratory-tract aerosol delivery.
7,13
That relationship applies with nebulizers because a
longer inspiratory time allows a larger proportion of the
nebulizer-generated aerosol to be inhaled with each
breath.
35
Because nebulizers generate aerosol over sev-
eral minutes, longer inspiratory times have a cumulative
effect in augmenting aerosol delivery. In contrast, MDIs
produce aerosol over a finite portion of a single inspi-
ration, and the mechanism by which longer inspiratory
time increases aerosol delivery is unclear. Finally, sev-
eral investigators have reported that the efficiency of
bronchodilator delivery is not influenced by the inspira-
tory flow pattern
13,36
or the addition of an end-inspira-
tory pause.
37
Clinical Aspects
Patient Selection
A frequently posed question concerns the indications
for inhaled bronchodilator therapy. There is a paucity of
published information regarding which mechanically
ventilated patients should receive inhaled bronchodila-
tor therapy. Bronchodilators reverse bronchoconstric-
tion and decrease airway resistance and consequently
relieve dyspnea, so they are indicated for acute asthma
or chronic obstructive pulmonary disease (COPD) ex-
acerbation. Bronchodilators should be administered to
mechanically ventilated patients who have obstructive
airway disease and signs of dynamic hyperinflation, sus-
tained elevation in peak airway pressure, or wheezing
episodes. Patients with COPD or asthma who are not
having difficulty with mechanical ventilation may re-
ceive bronchodilators and should be evaluated for the
latter signs.
Followingbronchodilatordeliverytheclinicianshould
observe the patient for improvement, and if there is no
objective or clinical improvement, then discontinuing
bronchodilators may be appropriate. It is less clear
whether mechanically ventilated patients who have a
history of smoking or clinically suspected COPD and
who are tolerating mechanical ventilation should re-
ceive regularly scheduled bronchodilators. Patients with
acute respiratory distress syndrome have elevated air-
way resistance, and several reports have found that neb-
ulized albuterol decreased airway resistance.
38,39
How-
ever, increased airway resistance is not a central feature
of acute respiratory distress syndrome, so further stud-
ies are needed before recommending routine broncho-
dilator delivery for those patients. Alternatively, a trial
of scheduled bronchodilator delivery for 24–48 hours
may be considered, but in the absence of improvement
in airway measurements, discontinuation of this therapy
would be justified. Finally, it is difficult to predict which
mechanically ventilated patients will respond to bron-
chodilators, because neither elevated airway resistance
nor expiratory airflow limitation have predictive value.
40
Bronchodilator Selection
Bronchodilator response has been found following
administration of inhaled

-adrenergic
21,38,41–49
and an-
ti-cholinergic agents.
47,50–52
Inhaled isoproterenol,
46,53
isoetharine,
54
metaproterenol,
45
fenoterol
41,47
and albu-
terol
1,42–44,55,56
have been reported to produce signifi-
cant bronchodilation when administered to mechanically
ventilated patients. There have been no comparison stud-
ies of the relative efficacy of

agonists in mechanically
ventilated patients, and there is little evidence to sup-
port the use of one agent over another.
With mechanically ventilated patients the effect of
combining

agonist and anticholinergic has not been
extensively evaluated. One report found the combina-
tion of fenoterol and ipratropium bromide more effec-
tive than ipratropium alone in mechanically ventilated
COPD patients.
47
Administration Technique
Careful attention to the aerosol administration tech-
nique during mechanical ventilation is essential for ef-
fective therapy. Table 2 shows a technique for admin-
istering nebulizer aerosol
26
and Table 3 shows a
technique for administering MDI aerosol
1
to mechani-
cally ventilated patients. With mechanically ventilated
patients the aerosol administration method often requires
a compromise between the optimal operating character-
istics of the aerosol generator and the patient’s respira-
tory mechanics. For example, increasing the duty cycle
increases pulmonary deposition but may also increase
dynamic hyperinflation in patients with airflow limita-
tion from asthma or COPD. The maximum aerosol de-
livery with a nebulizer during mechanical ventilation
(15%) was achieved with a specialty nebulizer (Aero-
Tech II) that produces an MMAD ⬍ 2
m (and that
requires 35 min for drug administration) with a dry
ventilator circuit and a duty cycle of 0.5.
7
Using a com-
monly available nebulizer with an MMAD of 3.5
m
halves the time for drug administration but also reduces
pulmonary deposition to about half of that achieved
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6 627
under optimal conditions (ie, approximately 7.5%). Hu-
midification reduces drug delivery by an additional 40%
(deposition down to 4%), and a duty cycle of 0.25–0.33
(which is more commonly employed) is expected to
reduce deposition to 2% of the nominal dose (ie, only
50
g of albuterol delivered to the lung). That amount
is similar to the 60
g of albuterol expected from 4 MDI
(with chamber) puffs in a humidified circuit (15% dep-
osition). Although the amount of drug placed in the
nebulizer is several times greater than that delivered
from an MDI, the devices probably deliver comparable
amounts of drug to the lower respiratory tract of a me-
chanically-ventilated patient. Recent studies have estab-
lished that using a spacer with an MDI improves the
efficacy of bronchodilator therapy in mechanically ven-
tilated patients. The best results are obtained when the
MDI actuation is synchronized with the onset of inspi-
ration.
12,43
With careful attention to the administration
technique, a bronchodilator response can be expected in
most mechanically ventilated asthma or COPD patients.
Assessing Response
The main goal of aerosol therapy is to maximize drug
deposition in the lower respiratory tract and minimize ad-
verse drug effects. However, increasing drug deposition in
the lower respiratory tract does not necessarily increase
therapeutic effect. The response to bronchodilator admin-
istration depends on several variables, including patient
airway geometry, degree of airway responsiveness, sever-
ity of disease, quantity of airway secretions, counter-reg-
ulatory effects of airway inflammation, and interactions
with other drugs in the patient. Evaluating bronchodilator
response requires physical examination, including atten-
tion to breathing pattern and auscultation; however; the
physical examination findings may not accurately reflect
changes in airway caliber. Therefore, measurements of
airwaypressure, airwayresistance,andflowlimitationhave
been proposed to more accurately assess bronchodilator
response.
Most investigators have assessed bronchodilators’ clin-
ical efficacy by their effect on inspiratory airway resis-
tance. Airway resistance in mechanically ventilated pa-
tients is commonly measured by performing rapid airway
occlusions at constant-flow inflation.
57,58
This technique
involves performing a breath-hold at end-inspiration by
occluding the expiratory port. Graphic displays of the air-
way pressure profile reveal that airway occlusion imme-
diately decreases airway pressure (P
peak
) to a lower initial
pressure (P
init
), from which a gradual decline occurs over
3–5 s to a plateau pressure (P
plat
) (Fig. 3). Similarly, air-
way occlusion at end-expiration increases airway pressure
to a constant value, which is the intrinsic positive end-
expiratory pressure (see Fig. 3).
43,59
In a passively venti-
lated patient and using a square-wave inspiratory flow
pattern, the respiratory mechanics are calculated as fol-
lows:
R
rsmax
⫽ (P
peak
– P
plat
)/airflow
R
rsmin
⫽ (P
peak
– P
init
)/airflow
R
rs
⫽ R
rsmax
– R
rsmin
in which R
rsmax
is the entire resistance of the respiratory
system, R
rsmin
is the “ohmic” resistance (the resistance
of the conducting airways, as opposed to the resistance
of the entire thorax), and R
rs
is the additional effective
resistance from time-constant inhomogeneities within
the lung (pendelluft) and the viscoelastic behavior of
the pulmonary tissues. In most mechanically ventilated
COPD patients airway resistance and PEEPi decrease
following bronchodilator administration.
21,37,42,43,49
Al-
though there are no established threshold values, an
R
rsmax
decrease of ⬎ 10% may indicate significant bron-
chodilator response in mechanically ventilated patients.
Bronchodilator Dosing
Based on the finding that aerosol deposition is mark-
edly lower in mechanically ventilated patients than in
nonintubated patients, higher bronchodilator doses were
recommended for mechanically ventilated patients.
60
Table 2. Using a Nebulizer During Mechanical Ventilation
1. Clear secretions from the endotracheal tube
2. Be sure the tidal volume is ⬎ 500 mL
3. If possible, decrease the inspiratory flow to ⱕ 60 L/min
4. Place the drug solution in the nebulizer. Total volume in the
nebulizer should be 4–6mL
5. Place the nebulizer in the inspiratory limb, 30 cm from the Y-piece
6. Be sure the gas flow to the nebulizer is ⱖ 6 L/min
7. If possible, nebulize the solution only during inspiration
8. Tap the nebulizer intermittently during operation
9. When nebulization ends, disconnect the nebulizer from the
ventilator circuit
Table 3. Using a Metered-Dose Inhaler During Mechanical
Ventilation
1. Clear secretions from the endotracheal tube
2. Be sure the tidal volume is ⬎ 500 mL
3. If possible, decrease the inspiratory flow to ⱕ 60 L/min
4. Be sure the actuator-spacer device is in the inspiratory limb
5. Shake the MDI and place it into the actuator-spacer device
6. Actuate the MDI at the onset of inspiration
7. Wait 20–30 s before administering the next MDI actuation
MDI ⫽ metered-dose inhaler
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
628 RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6
However, the precise dosing regimen was not specified,
leading some investigators to propose that bronchodi-
lator dosing should be titrated to a physiologic effect.
21
Studies of bronchodilator dose response in mechani-
cally ventilated patients demonstrated significant re-
sponse with 2.5 mg of albuterol via nebulizer
21,61
(Fig.
4) or 4 MDI puffs (400
g) (Fig. 5).
42,61
Minimal ther-
apeutic advantage was gained by administering higher
doses, whereas the potential for adverse effects in-
creased.
21,42
In patients with severe airway obstruction
or if the administration technique is not optimal, higher
doses may be required.
The duration of bronchodilator effect was studied with
a group of stable, mechanically ventilated COPD pa-
tients. The response pattern was similar when optimiz-
ing the ventilator settings and the effect of 2.5 mg of
nebulized albuterol was similar to that of 4 puffs from
an MDI with spacer (Fig. 4).
61
However, further studies
are needed to assess the duration of the bronchodilator
effect and establish a rational dosing schedule in me-
chanically ventilated patients. In summary, with a care-
fully executed administration technique, most stable me-
chanically ventilated COPD patients achieve near-
maximal bronchodilation from 4 MDI puffs or 2.5 mg
of nebulized albuterol.
Toxicity
Higher doses of

agonists are associated with higher
risk of serious arrhythmia and hypokalemia, but no serious
adverse effects have been reported after bronchodilator
Fig. 3. Airflow and airway pressure (P
aw
) tracings from a mechan-
ically ventilated patient with chronic obstructive pulmonary dis-
ease (COPD). The figure shows the effect of rapid airway occlusion
at end-expiration (upper 2 panels) and at end-inspiration (lower 2
panels). End-expiratory occlusion increases airway pressure, and
its plateau value determines the intrinsic positive end-expiratory
pressure (PEEP
i
). End-inspiratory occlusion rapidly decreases peak
pressure (P
peak
) to a lower initial pressure (P
init
), followed by a
gradual decline to a plateau (P
plat
). (From Reference 43, with per-
mission).
Fig. 4. Effect of albuterol on maximum inspiratory airway resis-
tance of the respiratory system (R
rsmax
). R
rsmax
significantly de-
creased within 5 min of 4 puffs of albuterol. Administration of 8
puffs and 16 puffs (cumulative doses of 12 and 28 puffs, respec-
tively) of albuterol also significantly reduced R
rsmax
below baseline
(p ⬍ 0.001). The decrease in airway resistance with cumulative
doses of 12 and 28 puffs was not significantly greater than with 4
puffs (p ⬎ 0.05). The error bars represent the standard error of the
mean. (From Reference 42, with permission).
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6 629
administration to mechanically ventilated patients. Dhand
et al reported a significant increase in heart rate following
a cumulative dose of 28 MDI puffs of albuterol (Fig. 6).
42
Episodes of supraventricular tachycardia and ventricular
ectopy occurred following administration of 3–6 times the
normal nebulized dose of albuterol,
21
but no arrhythmias
wereobserved following administration of4–10 MDI puffs
of albuterol.
42,43,61
Concern regarding the toxicity of chlorofluorocarbon
propellants in MDIs is negligible, because chlorofluoro-
carbons have a very short half-life (⬍ 40 s) in the blood.
62
However, when very high doses are administered from an
MDI or when a catheter is attached to the MDI nozzle to
deliver aerosol directly to the main bronchus, beyond the
ETT tip,
11,63
the chlorofluorocarbon could be cardiotox-
ic.
64
Also, the catheter aerosol-delivery system can pro-
duce localized ulceration in the respiratory tract,
65
an ef-
fect attributed to oleic acid, which is a surfactant in some
MDI formulations.
Metered-Dose Inhaler Versus Nebulizer
The efficacy of an aerosol-generating device can be
evaluated via in vitro measurements, scintigraphy, phar-
macokinetics, clinical outcomes, and cost analysis. Each
assessment method is required in the development and
use of an aerosol device, and a composite evaluation of
the assessment methods is required for the clinician.
Traditionally, MDIs have been prescribed for out-pa-
tient treatment, whereas nebulizers have been more fre-
quently used in in-hospital visits. This has led to the
erroneous belief that nebulizers are preferred for bron-
chodilator delivery in critically ill patients. In fact, sev-
eral investigators have demonstrated MDI and nebulizer
to be equally effective with spontaneously breathing
Fig. 6. Effect on heart rate of increasing albuterol dose. Heart rate
did not change after 4 puffs or a cumulative dose of 12 puffs
(p ⬎ 0.05). After a cumulative dose of 28 puffs heart rate increased
significantly (p ⬍ 0.01) and was significantly higher than baseline
at 80 min (p ⬍ 0.05). The error bars represent standard error of the
mean. (From Reference 42, with permission).
Fig. 5. Effect of albuterol on maximum inspiratory airway resis-
tance (R
max
). R
max
significantly decreased (compared to baseline
[p ⬍ 0.01]) within 10 min of albuterol administration. A: R
max
change
(from baseline) after 4 metered-dose inhaler (MDI) puffs of albu-
terol. B: R
max
change (from baseline) after 2.5 mg albuterol via
small-volume nebulizer (SVN). Significant R
max
reduction was sus-
tained for 120 min and returned to baseline at 240 min. The re-
sponse pattern was similar with MDI and nebulizer delivery in a
group of stable, mechanically ventilated patients with chronic ob-
structive pulmonary disease. The error bars represent the stan-
dard error of the mean. (From Reference 61).
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
630 RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6
patients suffering obstructive lung disease.
60
Likewise,
MDIs and nebulizers have been reported to deliver a
bioequivalent mass of aerosol beyond the ETT in a
model of mechanical ventilation.
12
In mechanically ven-
tilated patients lower-respiratory-tract deposition of in-
haled bronchodilator via nebulizer is in the range of 1.2
to 3%, whereas with MDI it is approximately 5.6%, as
compared to 12–14% in nonintubated, spontaneously-
breathing subjects.
4,8,66,67
Still, MDI and nebulizer bron-
chodilator produce similar therapeutic effects in me-
chanically ventilated patients.
61
For mechanically ventilated patients, MDIs are pre-
ferred for routine bronchodilator therapy because of sev-
eral problems associated with nebulizers. The rate of
nebulizer aerosol production is highly variable, not only
among different brands of nebulizer but among different
batches of the same nebulizer model.
68
In addition, the
aerosol particle size is highly variable among different
nebulizers,
7,14,68
and nebulizer efficiency varies with in-
spiratory flow, pressure of the driving gas, and fill vol-
ume. Also, the efficiency of some nebulizers is drasti-
cally decreased when they are operated with gas flow
from the ventilator, because that pressure is much lower
than from an air compressor unit. Furthermore, a change
in ventilator settings leading to a decrease in inspiratory
time may lead to diminished functional time of a neb-
ulizer. Therefore, before using a nebulizer with a me-
chanically ventilated patient, it is imperative to charac-
terize the aerosol-delivery efficiency with the intended
ventilator and clinical conditions.
Nebulizers have been associated with bacterial contam-
ination, so they must be scrupulously cleaned and disin-
fected to minimize the risk that they will aerosolize bac-
teria
69
and thus increase the risk of nosocomial
pneumonia.
70
During continuous nebulizer operation the
gas flow driving the nebulizer produces additional airflow
in the ventilator circuit, which requires adjusting the V
T
and inspiratory flow. The additional gas flow from the
nebulizer can create a situation in which the patient is
unable to trigger the ventilator during pressure support
ventilation, which can cause hypoventilation.
71
In contrast,
MDIs are easy to administer, require less personnel time,
provide a reliable dose, and do not pose a risk of bacterial
contamination. Using a bench model of mechanical ven-
tilation, Hess et al demonstrated more reliable bronchodi-
lator delivery with an MDI-with-spacer than with a neb-
ulizer.
35
When the MDI is used with an inline spacer, the
ventilator circuit need not be disconnected, thereby reduc-
ing the risk of ventilator-associated pneumonia. In sum-
mary, MDIs offer several advantages over nebulizers for
routine bronchodilator therapy to mechanically ventilated
patients.
Bronchodilator therapy accounts for a substantial per-
centageofthecostofcareofmechanicallyventilatedCOPD
patients.
72
It would be useful to conduct a cost-effective-
ness analysis of MDI versus nebulizer delivery of bron-
chodilators and compare their outcomes and costs. How-
ever, equipment, medication, and labor costs differ among
hospitals, making it difficult to conclusively determine
whether MDI or nebulizer is more cost-effective.
73
Con-
version from nebulizer to MDI delivery has been reported
to lower costs and save time.
74
Bowton et al found that
substituting MDIs for nebulizers in a 700-bed hospital
decreased potential patient costs of aerosol therapy by
$300,000 a year.
75
Bronchodilators Via Noninvasive Ventilation
MDIs and nebulizers has been used to deliver bron-
chodilator during noninvasive ventilation.
76,77
One study
randomized patients with acute bronchospasm to re-
ceive either nebulized albuterol alone or nebulized al-
buterol delivered through a portable bi-level ventilator
circuit and nasal mask. The patients who received al-
buterol via the ventilator had greater improvement in
peak flow.
78
Recently, Chatmongkolchart et al used a
bench model to examine nebulized albuterol delivery
under varying inspiratory and expiratory pressure set-
tings and found marked variability in albuterol delivery.
The greatest delivery occurred when the nebulizer was
placed between the leak port and the patient connection
while applying 20 cm H
2
O inspiratory pressure and 5
cm H
2
O expiratory pressure.
79
Nava et al reported a
bronchodilator response after 4 puffs of albuterol from
an MDI with spacer to 18 stable COPD patients under-
going noninvasive ventilation via face mask.
80
Bron-
chodilator delivery with noninvasive ventilation is fea-
sible, and attention to the technique and placement of
the aerosol-generating device are important. Further air-
way deposition and clinical outcome studies will be
necessary before applying noninvasive-ventilation aero-
sol delivery with patients in acute respiratory failure.
Summary
Inhaled bronchodilators are commonly administered to
mechanically ventilated patients and are a considerable
component of the cost of care. Careful attention to the
factors that influence lower-respiratory-tract deposition in
mechanically ventilated patients is required to optimize
drug delivery and, thus, patient response. When adminis-
tration is carefully executed, bronchodilator administration
via MDI or nebulizer is safe and effective for mechani-
cally ventilated patients.
REFERENCES
1. Dhand R, Tobin MJ. Inhaled bronchodilator therapy in mechanically
ventilated patients. Am J Respir Crit Care Med 1997;156(1):3–10.
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6 631
2. Duarte AG, Dhand R, Reid R, Fink JB, Fahey PJ, Tobin MJ, Jenne
JW. Serum albuterol levels in mechanically ventilated patients and
healthy subjects after metered-dose inhaler administration. Am J
Respir Crit Care Med 1996;154(6 Pt 1):1658–1663.
3. Brain JD, Valberg PA. Deposition of aerosol in the respiratory tract.
Am Rev Respir Dis 1979;120(6):1325–1373.
4. MacIntyre NR, Silver RM, Miller CW, Schuler F, Coleman RE.
Aerosol delivery in intubated, mechanically ventilated patients. Crit
Care Med 1985;13(2):81–84.
5. Dhand R. Special problems in aerosol delivery: artificial airways.
Respir Care 2000;45(6):636–645.
6. Fuller HD, Dolovich MB, Chambers C, Newhouse MT. Aerosol
delivery during mechanical ventilation; a predictive in vitro lung
model. J Aerosol Med 1992;5:251–259.
7. O’Riordan TG, Greco MJ, Perry RJ, Smaldone GC. Nebulizer func-
tion during mechanical ventilation. Am Rev Respir Dis 1992;145(5):
1117–1122.
8. Thomas SHL, O’Doherty MJ, Page CJ, Treacher DF, Nunan TO.
Delivery of ultrasonic nebulized aerosols to a lung model during
mechanical ventilation. Am Rev Respir Dis 1993;148(4 Pt 1):
872–877.
9. O’Doherty MJ, Thomas SHL, Page CJ, Treacher DF, Nunan TO.
Delivery of a nebulized aerosol to a lung model during mechanical
ventilation: effect of ventilator settings and nebulizer type, position,
and volume of fill. Am Rev Respir Dis 1992;146(2):383–388.
10. Rau JL, Harwood RJ, Groff JL. Evaluation of a reservoir device for
metered-dose bronchodilator delivery to intubated adults: an in vitro
study. Chest 1992;102(3):924–930.
11. Taylor RH, Lerman J, Chambers C, Dolovich M. Dosing efficiency
and particle-size characteristics of pressurized metered-dose inhaler
aerosols in narrow catheters. Chest 1993;103(3):920–924.
12. Diot P, Morra L, Smaldone GC. Albuterol delivery in a model of
mechanical ventilation: comparison of metered-dose inhaler and neb-
ulizer efficiency. Am J Respir Crit Care Med 1995;152(4 Pt 1):
1391–1394.
13. Fink JB, Dhand R, Duarte AG, Jenne JW, Tobin MJ. Aerosol
delivery from a metered-dose inhaler during mechanical ventila-
tion: an in vitro model. Am J Respir Crit Care Med 1996;154(4 Pt
1):382–387.
14. Hess D, Fisher D, Williams P, Pooler S, Kacmarek RM. Medication
nebulizer performance: effects of diluent volume, nebulizer flow,
and nebulizer brand. Chest 1996;110(2):498–505.
15. Hughes JM, Saez J. Effects of nebulizer mode and position in a
mechanical ventilator circuit on dose efficiency. Respir Care 1987;
32(12):1131–1135.
16. McPeck M, O’Riordan TG, Smaldone GC. Choice of mechanical
ventilator: influence on nebulizer performance. Respir Care 1993;
38(8):887–895.
17. Dhand R, Malik SK, Balakrishnan M, Verma SR. High speed pho-
tographic analysis of aerosols produced by metered dose inhalers.
J Pharm Pharmacol 1988;40(6):429–430.
18. Dolovich M. Physical principles underlying aerosol therapy. J Aero-
sol Med 1989;2:171–186.
19. Marik P, Hogan K, Krikorian J. A comparison of bronchodilator
therapy delivered by nebulization and metered-dose inhaler in me-
chanically ventilated patients. Chest 1999;115(6):1653–1657.
20. 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: a study comparing four
different actuator devices. Chest 1994;105(1):214–218.
21. Manthous CA, Hall JB, Schmidt GA, Wood LDH. Metered-dose
inhaler versus nebulized albuterol in mechanically ventilated pa-
tients. Am Rev Respir Dis 1993;148(6 Pt 1):1567–1570.
22. Ahrens RC, Ries RA, Popendorf W, Wiese JA. The delivery of
therapeutic aerosols through endotracheal tubes. Pediatr Pulmonol
1986;2(1):19–26.
23. Crogan SJ, Bishop MJ. Delivery efficiency of metered dose aero-
sols given via endotracheal tubes. Anesthesiology 1989;70(6):
1008–1010.
24. Fink JB, Dhand R, Grychowski J, Fahey PJ, Tobin MJ. Reconciling
in vitro and in vivo measurements of aerosol delivery from a me-
tered-dose inhaler during mechanical ventilation and defining effi-
ciency-enhancing factors. Am J Respir Crit Care Med 1999;159(1):
63–68.
25. Lange CF, Finlay WH. Overcoming the adverse effect of humidity in
aerosol delivery via pressurized metered-dose inhalers during me-
chanical ventilation. Am J Respir Crit Care Med 2000;161(5):1614–
1618.
26. Gross NJ, Jenne JW, Hess D. Bronchodilator therapy. In: Tobin, MJ,
editor. Principles and practice of mechanical ventilation. New York:
McGraw Hill; 1994:1077–1123.
27. O’Doherty MJ, Thomas SHL. Nebuliser therapy in the intensive care
unit. Thorax 1997;52 Suppl 2:S56–S59.
28. Habib DM, Garner SS, Brandenburg S. Effect of helium-oxygen on
delivery of albuterol in a pediatric, volume-cycled, ventilated lung
model. Pharmacotherapy 1999;19(2):143–149.
29. Svartengren M, Anderson M, Philipson K, Camner P. Human lung
deposition of particles suspended in air or in helium/oxygen mixture.
Exp Lung Res 1989;15(4):575–585.
30. Anderson M, Svartengren M, Bylin G, Philipson K, Camner P. Dep-
osition in asthmatics of particles inhaled in air or in helium-oxygen.
Am Rev Respir Dis 1993;147(3):524–528.
31. Goode ML, Fink JB, Dhand R, Tobin MJ. Improvement in aerosol
delivery with helium-oxygen mixtures during mechanical ventila-
tion. Am J Respir Crit Care Med 2001;163(1):109–114.
32. Tassaux D, Jolliet P, Thouret J-M, Roeseler J, Dorne R, Chevrolet
JC. Calibration of seven ICU ventilators for mechanical ventilation
with helium-oxygen mixtures. Am J Respir Crit Care Med 1999;
160(1):22–32.
33. Harvey CJ, O’Doherty MJ, Page CJ, Thomas SHL, Nunan TO,
Treacher DF. Effect of a spacer on pulmonary aerosol deposition
from a jet nebuliser during mechanical ventilation. Thorax 1995;
50(1):50–53.
34. O’Riordan TG, Palmer LB, Smaldone GC. Aerosol deposition in
mechanically ventilated patients: optimizing nebulizerdelivery. Am J
Respir Crit Care Med 1994;149(1):214–219.
35. Hess DR, Dillman C, Kacmarek RM. In vitro evaluation of aerosol
bronchodilator delivery during mechanical ventilation: pressure-con-
trol vs. volume control ventilation. Intensive Care Med 2003;29(7):
1145–1150.
36. Mouloudi E, Prinianakis G, Kondili E, Georgopoulos D. Effect of
inspiratory flow rate on

2
-agonist induced bronchodilation in me-
chanically ventilated COPD patients Intensive Care Med 2001;27(1):
42–46.
37. Mouloudi E, Katsanoulas K, Anastasaki M, Askitopoulou E, Geor-
gopoulos D. Bronchodilator delivery by metered-dose inhaler in me-
chanically ventilated COPD patients: influence of end-inspiratory
pause. Eur Respir J 1998;121(1):165–169.
38. Wright PE, Carmichael LC, Bernard GR. Effect of bronchodilators
onlungmechanicsintheacuterespiratorydistress syndrome (ARDS).
Chest 1994;106(5):1517–1523.
39. Morina P, Herrera M, Venegas J, Mora D, Rodriguez M, Pino E.
Effects of nebulized salbutamol on respiratory mechanics in adult
respiratory distress syndrome. Intensive Care Med 1997;23(1):
58–64.
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
632 RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6
40. Reinoso MA, Gracey DR, Hubmayr RD. Interruptor mechanics of
patients admitted to a chronic ventilator dependency unit. Am Rev
Respir Dis 1993;148(1):127–131.
41. Bernasconi M, Brandolese R, Poggi R, Manzin E, Rossi A. Dose-
response effects and time course of effects of inhaled fenoterol on
respiratory mechanics and arterial oxygen tension in mechanically
ventilated patients with chronic airflow obstruction. Intensive Care
Med 1990;16(2):108–114.
42. Dhand R, Duarte AG, Jubran A, Jenne JW, Fink JB, Fahey PJ, Tobin
MJ. Dose-response to bronchodilator delivered by metered-dose in-
haler in ventilator-supported patients. Am J Respir Crit Care Med
1996;154(2 Pt 1):388–393.
43. Dhand R, Jubran A, Tobin MJ. Bronchodilator delivery by metered-
dose inhaler in ventilator-supported patients. Am J Respir Crit Care
Med 1995;151(6):1827–1833.
44. Fernandez A, Lazaro A, Garcia A, Aragon C, Cerda E. Bronchodi-
lators in patients with chronic obstructive pulmonary disease on
mechanical ventilation: utilization of metered-dose inhalers. Am Rev
Respir Dis 1990;141(1):164–168.
45. Gay PC, Rodarte JR, Tayyab M, Hubmayr RD. Evaluation of bron-
chodilator responsiveness in mechanically ventilated patients. Am
Rev Respir Dis 1987;136(4):880–885.
46. GoldMI.Treatmentofbronchospasmduringanesthesia.AnesthAnalg
1975;54(6):783–786.
47. Guerin C, Chevre A, Dessirier P, Poncet T, Becquemin M-H, Dequin
PF, et al. Inhaled fenoterol-ipratropium bromide in mechanically
ventilated patients with chronic obstructive pulmonary disease Am J
Respir Crit Care Med 1999;159(4 Pt 1):1036–1942.
48. Mancebo J, Amaro P, Lorino H, Lemaire F, Harf A, Brochard L.
Effects of albuterol inhalation on the work of breathing during wean-
ing from mechanical ventilation. Am Rev Respir Dis 1991;144(1):
95–100.
49. Waugh JB, Jones DF, Aranson R, Honig EG. Bronchodilator re-
sponse with use of OptiVent versus Aerosol Cloud Enhancer me-
tered-dose inhaler spacers in patients receiving ventilatory assis-
tance. Heart Lung 1998;27(6):418–423.
50. Fernandez A, Munoz J, de la Calle B, Alia I, Ezpeleta A, de la Cal
MA, Reyes A. Comparison of one versus two bronchodilators in
ventilated COPD patients. Intensive Care Med 1994;20(3):199–
202.
51. Wegener T, Wretman S, Sandhagen B, Nystrom SO. Effect of ipra-
tropium bromide aerosol on respiratory function in patients under
ventilator treatment. Acta Anaesthesiol Scand 1987;31(7):652–654.
52. Yang SC, Yang SP, Lee TS. Nebulized ipratropium bromide in
ventilator-assisted patients with chronic bronchitis. Chest 1994;
105(5):1511–1515.
53. Fresoli RP, Smith RM Jr, Young JA, Gotshall SC. Use of aerosol
isoproterenol in an anesthesia circuit. Anesth Analg 1968;47(2):
127–132.
54. Sprague DH. Treatment of intraoperative bronchospasm with nebu-
lized isoetharine. Anesthesiology 1977;46(3):222–224.
55. Manthous CA, Chatila W, Schmidt GA, Hall JB. Treatment of bron-
chospasm by metered-dose inhaler albuterol in mechanically venti-
lated patients. Chest 1995;107(1):210–213.
56. Gay PC, Patel HG, Nelson SB, Gilles B, Hubmayr RD. Metered dose
inhalers for bronchodilator delivery in intubated, mechanically ven-
tilated patients. Chest 1991;99(1):66–71.
57. Bates JHT, Rossi A, Milic-Emili J. Analysis of the behavior of the
respiratory system with constant inspiratory flow. J Appl Physiol
1985;58(6):1840–1848.
58. Bates JHT, Milic-Emili J. The flow interruption technique for mea-
suring respiratory resistance. J Crit Care 1991;6:227–238.
59. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in me-
chanically ventilated patients withairflow obstruction: the auto-PEEP
effect. Am Rev Respir Dis 1982;126(1):166–170.
60. Aerosol consensus statement. Consensus Conference on Aerosol De-
livery. Chest 1991;100(4):1106–1109.
61. Duarte AG, Momii K, Bidani A. Bronchodilator therapy with me-
tered-dose inhaler and spacer versus nebulizer in mechanically ven-
tilated patients: comparison of magnitude and duration of response.
Respir Care 2000;45(7):817–823.
62. Dollery CT, Williams FM, Draffan GH, Wise G, Sahyoun H, Pater-
son JW, Walker SR. Arterial blood levels of fluorocarbons in asth-
matic patients following use of pressurized aerosols. Clin Pharmacol
Ther 1974;15(1):59–66.
63. Niven RW, Kacmarek RM, Brain JD, Peterfreund RA. Small bore
nozzle extensions to improve the delivery efficiency of drugs from
metered dose inhalers: laboratory evaluation. Am Rev Respir Dis
1993;147(6 Pt 1):1590–1594.
64. Silverglade A. Cardiac toxicity of aerosol propellants. JAMA 1972;
222(7):827–828.
65. Spahr-Schopfer IA, Lerman J, Cutz E, Newhouse MT, Dolovich M.
Proximate delivery of a large experimental dose from salbutamol
MDI induces epithelial airway lesions in intubated rabbits. Am J
Respir Crit Care Med 1994;150(3):790–794.
66. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl
J Med 1986;315(14):870–874.
67. Fuller HD, Dolovich MB, Posmituck G, Pack WW, Newhouse MT.
Pressurized aerosol versus jet aerosol delivery to mechanically ven-
tilated patients: comparison of dose to the lungs. Am Rev Respir Dis
1990;141(2):440–444.
68. Alvine GF, Rodgers P, Fitzsimmons KM, Ahrens RC. Disposable
jet nebulizers: how reliable are they? Chest 1992;101(2):316–
319.
69. Craven DE, Lichtenberg DA, Goularte TA, Make BJ, McCabe
WR. Contaminated medication nebulizers in mechanical ventila-
tor circuits: a source of bacterial aerosols. Am J Med 1984;77(5):
834–838.
70. Hamill RJ, Houston ED, Georghiu PR, Wright CE, Koza MA,
Cadle RM, et al. An outbreak of Burkholderia (formerly Pseudo-
monas) cepacia respiratory tract colonization and infection asso-
ciated with nebulized albuterol therapy. Ann Intern Med 1995;
122(10):762–766.
71. Beaty CD, Ritz RH, Benson MS. Continuous inline nebulizers
complicate pressure support ventilation. Chest 1989;96(6):1360–
1363.
72. Ely EW, Baker AM, Evans GW, Haponik EF. The distribution of
costs of care in mechanically ventilated patients with chronic ob-
structive pulmonary disease. Crit Care Med 2000;28(2):408–413.
73. Camargo CA Jr, Kenney PA. Assessing costs of aerosol therapy.
Respir Care 2000;45(6):756–763.
74. Summer W, Elston R, Tharpe L, Nelson S, Haponik EF. Aerosol
bronchodilator delivery methods: relative impact on pulmonary func-
tion and cost of respiratory care. Arch Intern Med 1989;149(3):618–
623.
75. Bowton DL, Goldsmith WM, Haponik EF. Substitution of metered-
dose inhalers for hand-held nebulizers: success and cost savings in a
large, acute-care hospital. Chest 1992;101(2):305–308.
76. Ceriana P, Navalesi P, Rampulla C, Prinianakis G, Nava S. Use of
bronchodilators during non-invasive mechanical ventilation.Monaldi
Arch Chest Dis 2003;59(2):123–127.
77. Parkes SN, Bersten AD. Aerosol kinetics and bronchodilator effi-
cacy during continuous positive airway pressure delivered by face
mask. Thorax 1997;52(2):171–175.
78. Pollack CV Jr, Fleisch KB, Dowsey K. Treatment of acute broncho-
spasm with

-adrenergic agonist aerosols delivered by a nasal bi-
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6 633
level positive airway pressure circuit. Ann Emerg Med 1995;26(5):
552–557.
79. Chatmongkolchart S, Schettino GP, Dillman C, Kacmarek RM, Hess
DR. In vitro evaluation of aerosol bronchodilator delivery during non-
invasive positive pressure ventilation: effect of ventilator settings and
nebulizer position. Crit Care Med 2002;30(11):2515–2519.
80. Nava S, Karakurt S, Rampulla C, Braschi A, Fanfulla F. Salbu-
tamol delivery during non-invasive mechanical ventilation in pa-
tients with chronic obstructive pulmonary disease: a randomized,
controlled study. Intensive Care Med 2001;27(10):1627–1635.
INHALED BRONCHODILATOR ADMINISTRATION DURING MECHANICAL VENTILATION
634 RESPIRATORY CARE • JUNE 2004 VOL 49 NO 6
