Aerosol Delivery and Modern Mechanical Ventilation
In Vitro/In Vivo Evaluation
Dorisanne D. Miller, Mohammad M. Amin, Lucy B. Palmer, Akbar R. Shah, and Gerald C. Smaldone
Department of Respiratory Care, University Hospital; and Department of Medicine, Division of Pulmonary and Critical Care Medicine,
State University of New York, School of Medicine, Stony Brook, New York
no standards for drug delivery to intubated patients. Bench models
predicting drug delivery have not been validated in vivo. For modern
ventilator designs, we chose to identify, on the bench, the most
importantvariables affectingaerosol deliveryand tocorrelate invitro
predictions of aerosol delivery with in vivo end points independent
of patient response. Test aerosols of albuterol and antibiotics were
ulizer charge, mean ? SEM)ranged from 5.7 ?0.5% to 37.4? 1.6%,
with breath-actuated nebulization and humidity identified as the
most important factors determining aerosol delivery. In patients,
sputum levels of deposited antibiotics varied from 1.10 to 19.6 ?g/
ml/mg. Variation in sputum levels correlated with predictions from
the in vitro model. Aerosol delivery in ventilated patients can be
efficient and reproducible only if defined ventilator parameters are
tightly controlled. Key parameters can be determined via in vitro
bench testing defining delivery standards for clinical trials of drugs
with narrow therapeutic/toxicity ratios.
Keywords: aerosolized antibiotics; nebulizers; bronchodilators; humidi-
Modern ventilator design does not include standards that relate
to aerosol delivery. Bench models predicting nebulized drug
delivery during mechanical ventilation have not been validated
in vivo. Previous studies have measured patient- and ventilator-
related factors affecting aerosol generation and inhalation for
nebulizers on the bench (1–4). A few studies have measured
deposition of nebulized drugs in ventilated patients, but they
did not relate actual deposition to bench predictions (5–7).
Besides the variables already studied in vitro (e.g., humidity,
predictions of drug delivery. For example, the use of constant
flow in the ventilator tubing (e.g., bias flow) during all phases of
ventilation may increase aerosol losses. Indeed, adult ventilator
systems are becoming similar in design to neonatal ventilators,
which are known to be inefficient in aerosol delivery (8). Breath-
actuated nebulization, an important factor in spontaneously
breathing patients (9), is not a feature of all modern ventilators.
In vivo effects of conventional aerosols can be difficult to
relate to aerosol delivery and deposition. For example, respon-
siveness to bronchodilators may vary between patients, and in
the absence of a deposition measurement, changes in airway
resistance will not differentiate between patient-related factors
and differences in drug delivery.
The purpose of our study was to detail the most important
variables affecting aerosol delivery via nebulizer on the bench
(Received in original form October 13, 2002; accepted in final form July 25, 2003)
Correspondence and requests for reprints should be addressed to Gerald C. Smal-
done, Pulmonary and Critical Care Medicine, T17, 040 Health Science Center,
State University of New York, Stony Brook, NY 11794-8172. E-mail: gsmaldone@
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200210-1167OC on July 31, 2003
Internet address: www.atsjournals.org
Vol 168. pp 1205–1209, 2003
for modern ventilators employing the newer flow regimes with
and without breath actuation and the effects of humidity. For
the major variables defined in vitro, predictions of aerosol deliv-
ery were correlated to measured levels of antibiotic in suctioned
sputum from intubated patients. Sputum levels were chosen as
an in vivo end point to the present study because unlike bron-
chodilators they are independent of patient responsiveness.
Some of the results of these studies have been previously re-
ported in the form of an abstract (10).
In Vitro Bench Model
The bench model is diagramed in Figure 1. The test ventilator was
connected to a test lung (M.I.I. VentAid TTL; Michigan Instruments,
Inc., Grand Rapids, MI) via an endotracheal tube (inside diameter ?
8.0 mm). Aerosols were sampled just distal to the endotracheal tube
with an inhaled mass filter (Pari GmbH, Starnberg, Germany) and a
filter in the expiratory line. Aerosols were generated by nebulization
with the device located in the inspiratory line 12 inches from the Y
For the in vitro study, we decided to use albuterol (2.5 mg in 3 ml
of normal saline) labeled with technetium as the test solution, as it was
previously characterized in our laboratory. Activity of albuterol aerosol
impaction (11). This allowed for a comparison with previous studies
ery (1, 2, 12).
The breathing pattern was fixed at a tidal volume of 750 ml, a
respiratory rate of 15, a peak flow of 70 L/minute, an inspiratory time
of 0.9 seconds, and an inspiratory:expiratory ratio of 1:3.4. For the
T-Bird ventilator, bias flow was set at 10, 15, and 20 L/minute.
Ventilatory parameters were monitored with the Bicore, Pulmonary
Monitor CP 100 (VIASYS Healthcare, Critical Care, Conshohocken,
PA). For experiments using humidification, a Hudson RCI Concha III
humidifier (Hudson Respiratory Care Incorporated, Temecula, CA)
without added humidity.
Aerosol particle distribution was sampled via a cascade impactor
(GS 1 IMPAQ; California Measurements, Inc., Sierra Madre, CA)
with the device located distal to the endotracheal tube. Aerosols were
sampled over a 4-minute period. Radioactivity on the cascade stages
was measured by a collimated ratemeter (Ludlum Measurements Inc.,
Sweetwater, TX) and the distribution plotted on log probability paper.
Activity at the median defined the mass median aerodynamic diameter
Aerosol production was quantified by measuring radioactivity on
the filters via a well counter (CRC-10; Capintec, Inc., Montvale, NJ),
and all activity (filters plus nebulizer) was summed in a “mass balance”
designed to trace aerosol losses.
The experimental configurations are outlined on Figure 2. There
were multiple configurations/combinations that were designed to test
major variables. These included the ventilator type, nebulizer brand,
form of nebulizer activation (continuous versus breath actuation), and
presence of humidification and magnitude of bias flow. Some devices
could not perform all functions; for example, the Evita ventilator does
not have adjustable bias flow, and the T-Bird ventilator does not have
nebulizer breath actuation.
Ventilators were chosen based on properties that may affect aerosol
1206 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1682003
Figure 1. Diagram of experimental appara-
ratory line 12 inches before the Y piece and
either triggered by breath actuation or pow-
ered continuously by a separate pressure
source. Aerosol was captured just distal to
the endotracheal (ET) tube (inhaled mass fil-
ter). For particle sizing experiments, a cas-
cade impactor was placed between the ET
tube and the inhaled mass filter. The Bicore
monitor confirmed the breathing pattern
• PB 7200 (Puritan Bennett, Pleasanton, CA): breath-actuated neb-
ulization, no bias flow, previously tested in our laboratory
• Evita 4 (Drager Inc., Critical Care Systems, Telford, PA): newer,
actuation, mandatory bias flow
The nebulizers that were tested included the AeroTechII Aerosol De-
livery System (CIS-US, Bedford, MA), which was previously tested in
our laboratory, and the Portex Small Volume Medication Nebulizer
Kit (SIMS Portex, Inc., Fort Myers, FL), which is a nebulizer that was
used for routine aerosol therapy in our hospital. Nebulizers, run to
dryness, were driven directly by the ventilator (breath actuation) or
continuously via compressed air or wall oxygen at a flow of 8 L/minute
The variables evaluated for each configuration were as follows:
• Humidified versus nonhumidified ventilator circuit (heated wire
circuits were not used)
• Breath-actuated nebulization versus continuous nebulization
• Bias flow set at flow rates of 10, 15, and 20 L/minute
• Nebulizer brand
Parameters measured for each of the variables evaluated were as follows:
• Inhaled mass(%), theamount ofdrug onthe filteras apercentage
of the nebulizer charge
• Mass balance (percentage of recovery), the sum of both filters
plus remnant activity in the nebulizer
Figure 2. Outline of bench protocol.
Data obtained from the configurations listed in Figure 2 were com-
bined by the test parameter when reported in the results. For example,
“breath-actuated humidification” included data from all devices that
satisfied that specific criteria.
In Vivo Model
Based on our bench data, the effects of major parameters predicting
aerosol delivery were tested in vivo by measuring sputum levels of aero-
solized antibiotics sampled fromintubated patients. Patientswere partici-
pating in a parallel protocol designed to measure the effectiveness of
aerosolized antibiotics. The routine consent for the institutional review
board–approved antibiotic protocol was modified to allow variation in
the mode and conditions of nebulization, that is, breath actuated or
continuous as well as humidified or nonhumidified. Institutional review
board approval was obtained for these modifications. For these parame-
ters, paired data for each patient were obtained for sputum suctioned
from theproximal airways 1 hourafter aerosol therapywith an antibiotic.
The protocol incorporated a standardized suction routine (13) and avoid-
ance ofinstilled saline.Patients weretreated withGentamicin, Amikacin,
or Vancomycin via the AeroTech II nebulizer (the clinical “dose” or
nebulizer charge was 80 mg for Gentamicin, 400 mg for Amikacin, and
120 mg for Vancomycin). Sputum was sampled after ventilator parame-
ters were set for 24 hours (humidification was maintained throughout
exceptas notedlater here).Theantibiotic treatmentregimen consistedof
is important to note that for the “nonhumidified” treatment regimen, the
humidifier was turned off and bypassed only during the actual nebulizer
Miller, Amin, Palmer, et al.: Aerosols and Mechanical Ventilation1207
TABLE 1. INHALED MASS PERCENTAGE*(MEAN ? SEM) EFFECTS OF BREATH-ACTUATED
NEBULIZATION AND HUMIDIFICATION
Inhaled Mass %
Nebulization ModeNonhumidifiedn Humidifiedn NH/H p Value
37.4 ? 1.6
10.4 ? 0.8
17.9 ? 2.4
8 9.6 ? 1.0
5.7 ? 0.5
7.7 ? 0.7
Definition of abbreviation: NH/H ? ratio of nonhumidified to humidified values.
* Value of inhaled mass reported as a percentage of nebulizer charge.
†Ventilator type used for breath-actuated nebulization was PB 7200 and Drager Evita 4.
‡Ventilator type used for continuous nebulization was T-Bird.
treatment (approximately 1 hour). After the 24-hour test period, sputum
was obtained for the 1-hour period between 1 and 2 hours after an
aerosol treatment. The sample was weighed, and the volume was stan-
dardized with normal saline to 4.0 ml and centrifuged at 40,000 rpm for
60 minutes at 4?C. The supernatant phase was diluted 1:100 for Gentami-
cin and Vancomycin and 1:1,000 for Amikacin to allow analysis within
the reference range of the assay (Roche Integra; Roche Diagnostics,
Somerville, NJ). Results are reported in micrograms per milliliter sputum
per milligram of drug placed in the nebulizer.
Results are reported as mean ? SE. The Mann-Whitney and unpaired
t tests were used in the statistical analysis of the in vitro data. In vivo
data were analyzed as pairs using the Wilcoxin signed rank test and
paired t tests (Stat View 4.5; Abacus, Inc., Berkley, CA). When the n
was small, the nonparametric p values were reported.
In Vitro Bench Study
Table 1 lists the values of inhaled mass affected by breath-
actuated nebulization and humidity. Data are presented as the
percentage of nebulizer charge. On average, for all ventilators
tested, turning off and bypassing the humidifier significantly in-
creased aerosol delivery. The ratio of inhaled mass for nonhu-
midified gas to humidified gas was 2.09:1 (p ? 0.0001), indicating
a doubling of delivery when the humidifier was turned off and
bypassed. When controlled for the presence of breath-actuated
nebulization, there was an even greater effect of humidity with
the ratio increasing to 3.84:1 (p ? 0.0001). Continuous nebuliza-
tion was the least efficient delivery method under all circum-
The effect of bias flow on inhaled mass percentage is shown
in Table 2. Although values of inhaled mass ranged from 3.08 ?
0.8 to 10.0 ? 0.7%, much of the effect was explained by the
TABLE 2. EFFECT OF BIAS FLOW ON INHALED MASS
PERCENTAGE (MEAN ? SEM)
Inhaled Mass %
Bias Flow (L/min)NonhumidifiednHumidified n
10.0 ? 0.7
8.3 ? 1.0
8.6 ? 0.7
7 5.3 ? 0.4
5.3 ? 0.5
3.8 ? 0.8
All experiments were preformed with the T-Bird ventilator.
TABLE 3. INHALED MASS PERCENTAGE (MEAN ? SEM) FOR
DIFFERENT NEBULIZERS, EFFECT OF HUMIDIFICATION
Inhaled Mass %
Ventilator ModeAeroTech II nPortexnp Value
20.8 ? 3.0
10.7 ? 1.3
12.3 ? 3.6
6.1 ? 0.5
TABLE 4. CASCADE IMPACTION DATA (MASS MEDIAN
AERODYNAMIC DIAMETER, MEAN ? SEM) FOR
Ventilator ModeAeroTech IInPortexnp Value
1.2 ? 0.1
2.3 ? 0.3
1.9 ? 0.2
2.2 ? 0.2
Definition of abbreviation: MMAD ? mass median aerodynamic diameter.
influence of humidity. When the circuit humidifier was turned off
and bypassed, the effects of bias flow were small.
Aerosol delivery was not a strong function of the brand of
nebulizer. As shown in Table 3, differences in inhaled mass were
found between devices, but because of variability in the data,
results were statistically significant for experiments only when
the system was humidified.
The aerodynamic behavior of the particles is summarized in
Table 4. Differences in MMAD between nebulizers were small
and statistically significant only for the nonhumidified condition.
The addition of humidity to the circuit increased the size of the
particles presented to the patient (cascade impactor placed at
distal tip of endotracheal tube) presumably by hygroscopic
growth. Although MMAD increased from 1.5 ? 0.1 to 2.3 ? 0.2
?m (p ? 0.0006, all data humidified vs. nonhumidified, n ? 45),
total aerosol delivery decreased with humidification (Table 2),
suggesting greater particle impaction in the ventilator tubing.
Tubing losses with added humidity were also suggested by
the recovery data. When the humidifier was turned off and by-
88.2 ? 0.9% (n ? 29). With humidification, recovery dropped
to 73.9 ? 1.8% (n ? 36).
Insummary, undertypicalclinical conditionsof aerosoldeliv-
ery, for example,continuous nebulization in ahumidified circuit,
only 5.7 ? 0.5% of the nebulizer charge was delivered. On the
other hand, an optimized system (breath-actuated nebulization,
nonhumidified) delivered 37.4 ? 1.6% to the filter (Table 1).
In Vivo Clinical Study
Six patients were studied. Diagnoses, ventilators, settings, endo-
tracheal and tracheostomy tube sizes, and peak airway pressures
are listed in Table 5. Paired sputum samples for each are also
shown with the mean data for each patient. Depending on the
drug, individual levelsranged from 86 ? 10?g/ml for gentamicin
to 5,790 ? 2,140 ?g/ml for amikacin (68-fold variation). Two
major factors accounted for this variability: The first was the
variation in nebulizer charge (the clinical “dose” of 80 mg for
Gentamicin, 400 mg for Amikacin, and 120 mg for Vancomycin);
the second was the differences in aerosol delivery. Normalizing
the levelsfor thenebulizer charge assessedthe latterfactor. When
listed as ?g/ml/mg nebulizer charge, the range decreased (0.66 to
1208 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 168 2003
19.6), a 20-fold variation. These data are analyzed for ventilator-
related parameters in Table 6. Average levels varied from 0.83 ?
0.11 to 12.57 ? 1.80 ?g/ml/mg. In general, nonhumidified aerosol
delivery was more effective in raising sputum levels than the
conventional humidified condition, with levels averaging 3.63
times higher in sputum from nonhumidified circuits (p ? 0.0002).
When the mode of nebulization was considered, levels after
ous nebulization. The 20-fold range in sputum levels appeared
to be accounted for by the combined effects of breath-actuated
nebulization and reduced humidification.
When compared with the bench data, there were similarities
as well as systematic differences between the predicted aerosol
delivery (Table 1) and in vivo sputum levels (Table 6). The
inthe invivo levelsof antibiotics(predicted ratiosof nonhumidi-
zation 3.84 and 1.81; ratio of nonhumidified to humidified values
observed 3.89 and 2.20, respectively). However, breath-actuated
nebulization compared with continuous nebulization was more
effective in raising sputum levels in vivo than predicted on the
bench. In the bench study, depending on humidification, inhaled
mass was 1.7 to 3.6 times higher for breath actuation compared
with continuous nebulization (Table 1). In vivo levels of sputum
antibiotics were four to seven times higher (Table 6), indicating
that other in vivo factors were important (see Discussion).
The present study illustrates the major factors affecting aerosol
bench model predicted that breath-actuated nebulization and
In patients, after inhalation of antibiotics, sputum values ranged
over an order of magnitude, but much of this variability was
explained when the data were normalized for breath actuation
and humidification. Sputum levels of deposited antibiotics pro-
vided a direct index of drug delivery (as opposed to an indirect
index such as a change in airway resistance). When reported as
cin level of 12.6 ?g per ml of sputum per mg of drug multiplied
by 80 mg ? 1,008 ?g per ml of sputum) if the humidifier was
turned off and bypassed. These results are consistent with pre-
viously reported values (5). However, if a clinical response were
TABLE 5. DETAILS OF IN VIVO STUDY
Ventilator Sputum Levels (?g/ml) Sputum Levels (?g/ml/mg) PIP
Pairs Case No. Diagnosis TypeModeSetting AntibioticHumidified NonhumidifiedHumidifiedNonhumidified Before After
T-Bird*AC 12 500 40%8.0†
Amikacin6263 ? 46 553 ? 1080.66 ? 0.121.38 ? 0.27 2628
10 600 50%
6 700 35%
86 ? 10
1,777 ? 519
200 ? 34
5,790 ? 2,140 4.44 ? 1.30
1.08 ? 0.122.51 ? 0.43
14.48 ? 5.35
14 700 50%
15 450 40%
18 450 30%
133 ? 21
1,576 ? 280
734 ? 99
4,947 ? 941
1.66 ? 0.27
3.94 ? 0.70
9.18 ? 1.24
12.37 ? 2.35
Definition of abbreviations: AC ? assist control; COPD ? chronic obstructive pulmonary disease; I.D. ? inside diameter (mm); IMV ? intermittent mandatory ventilation;
PC ? pressure control; PIP ? peak inspiratory pressure.
* Bias flow ? 10 L/min.
Settings: rate/tidal volume/% O2.
Aerosolized antibiotics were delivered via continuous (T-Bird) or breath-actuated nebulization (Bear and Puritan Bennett ventilators); sputum levels are reported as
mean ? SEM.
TABLE 6. SPUTUM LEVELS OF DEPOSITED ANTIBIOTICS
(MEAN ? SEM)
Sputum levels (?g/ml/mg)
Nebulizer Activationn NonhumidifiedHumidified NH/H p Value
12.6 ? 1.8
1.8 ? 0.3
8.1 ? 1.5
3.2 ? 0.5
0.8 ? 0.1
2.2 ? 0.4
Definition of abbreviation: NH/H ? ratio nonhumidified to humidified.
dependent on drug level, the simple addition of humidification
would reduce the average gentamicin level to 258 ?g per ml of
The recovery data coupled with the changes seen in MMAD
suggest hygroscopic growth of particles and losses via tubing
impaction in the presence of humidification of inspired gases.
The humidifier supersaturates the ventilator gas and promotes
rainout as the humid air cools. Aerosol particles can serve as
nuclei and losses are enhanced.
Early studies from our group suggested that nebulizer type
may be important (12, 14), but later bench studies showed that
running the nebulizer to the point of sputtering (loosely termed
“dryness” in the literature) reduced device-related variability
(2). The present protocol ran the devices to dryness (run time
of approximately 60 minutes). When the data were corrected
for breath actuation and humidification, the AeroTechII was
more efficient than the Portex device (Table 3).
The bench model predicted that breath-actuated nebulization
and humidification would have the greatest effects in vivo. Bench
predictions for humidity effects appeared to be the most accurate.
However, the bench model seemed to underestimate the effects
of breath-actuated nebulization. As presented in the Results, the
in vivo levels of antibiotic between breath actuated and continuous
nebulization were approximately twice as high as predicted. We
believe that these observations can be explained by the differences
in the concepts of inhaled mass versus actual aerosol deposition.
In a bench model, it is possible to measure variables that affect
the quantity of aerosol presented to the patient and “inhaled,” that
is, the “inhaled mass.” Once the particles are inhaled, a certain
fraction of the inhaled particles are deposited (the “deposition
fraction”), and sites of deposition are determined by the breathing
pattern, airway geometry, and the MMAD. Although we did not
Miller, Amin, Palmer, et al.: Aerosols and Mechanical Ventilation1209 Download full-text
TABLE 7. MASS MEDIAN AERODYNAMIC DIAMETER (MEAN ?
SEM) FOR AEROTECH II NEBULIZER AS A FUNCTION OF
ACTUATION MODE AND HUMIDIFICATION
Moden Nonhumidifiedp Valuen Humidified p Value
Breath actuated9 1.5 ? 0.17 3.0 ? 0.2
Continuous7 0.9 ? 0.16 1.6 ? 0.5
Definition of abbreviation: MMAD ? mass median aerodynamic diameter.
measure actual deposition in our patients, we did control many of
the parameters that affect the deposition of inhaled particles. For
example, all of our in vivo experimental conditions were paired,
except for changes in nebulizer actuation and humidification. In
nebulizer was used. A comparison of the data between Tables 1
and 6 suggests that for breath-actuated nebulization, either the
deposition fraction was increased or particle deposition was more
central than during treatment with continuous nebulization. A pa-
rameter linked to increases in both deposition fraction and central
deposition is the MMAD. To isolate this factor, we returned to
our bench studies.Table 7 summarizes experiments with the Aero-
actuation and humidification. MMADs were always significantly
greater during delivery via breath-actuated nebulization. With all
in deposition and/or greater deposition in central airways. We can-
not distinguish between the two possibilities, as suctioned sputum
levels are related primarily to centrally deposited particles (15).
Further studies are necessary to determine the extent that these
processes account for the observed differences in sputum levels.
Our findings have important implications for clinical trials.
Future studies will be needed to define the safety and efficacy of
circuit). For drugs such as antibiotics, control of dose requires
strict control of the aerosol delivery protocol. Failure to specify
the ventilator type, the presence or absence of humidity, and/or
breath actuation will prevent control of drug dosing and may
affect the assessment of clinical effects.
delivered in this study exceed those given in clinical trials (16),
and thus, potent safe drugs should still be effective in most
patients even under conditions that promote inefficient aerosol
delivery (e.g., continuous nebulization and added humidifica-
tion); however, the potential remains that with efficient delivery
toxic levels can be achieved and with inefficient delivery some
patients (e.g., those with severe asthma) may be undertreated.
In clinical situations different from those studied with our
model, there may be important differences in drug delivery.
Aerosol delivery is notoriously difficult during neonatal ventila-
tion primarily because of high bias flow (8). In adults, the use
of other modes of ventilation may have an impact on delivery.
If important to the investigator, bench studies under clinically
relevant conditions will help in understanding and controlling
potential confounding factors.
In conclusion, bench models can determine factors important
ized drugs require strict control of the ventilator and conditions
of nebulization if the dose to the patient is important in assessing
has no declared conflict of interest. L.B.P. is a co-inventor of patents held by SUNY
in the use of antibiotics in intubated patients. None of the data or support for
this study are related to those patents or to the money received from Nektar.
A.R.S. has no conflict of interest. G.C.S. is a co-inventor of patents held by SUNY
in the use of antibiotics in intubated patients. None of the data or support for
this study are related to those patents or to the money received from Nektar.
Acknowledgment: The authors thank Drager Inc., Critical Care Systems, Telford,
PA, for the loan of the Evita 4 ventilator.
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