Four Hours of Continuous Albuterol Nebulization

Abstract

Continuous albuterol nebulization (CAN) is a therapeutic modality available to treat status asthmaticus. Currently, CAN may be administered using a large-volume nebulizer (LVN) or a small-volume nebulizer attached to an infusion pump or refilled as needed. Few data are available regarding the reproducibility of aerosol characteristics during CAN. In this study, we determined the aerodynamic profile, drug output (DO), DO in respirable range (RD), solution output (SO), and changes in reservoir's albuterol concentration (AR) hourly during 4 hours of CAN.
A modified Puritan-Bennett 1600 jet nebulizer was tested with a large reservoir (LR; 250 mL), medium reservoir (MR; 45 mL), and small reservoir with infusion pump (SRP; 18 mL). We used 100-, 40-, and 4-mL initial fill volumes (with 10-mL/h infusion for SRP) of 1 mg/mL albuterol solution for the LR, MR, and SRP, respectively. Particle size distribution and DO consistency were determined by impaction and spectrophotometric analysis (275 nm). We also determined albuterol mass output. The SO was determined by gravimetric technique.
The PBsj produced a heterodisperse aerosol with a median mass aerodynamic diameter range of 1.8 to 2.2 microm. DO and RD paralleled SO. The LR had the highest SO, DO, and RD (8.03+/-2.36 vs 5.73+/-2.48 and 5.85+/-0.51 mg/h for MR and SRP, respectively). The AR showed no statistically significant changes.
The PBsj demonstrated consistent and adequate aerosol production during 4 hours of CAN. These bench data support the widespread use of a LVN for CAN.

Full text

DOI 10.1378/chest.114.3.847
1998;114;847-853Chest
Ariel Berlinski and J. Clifford Waldrep
Nebulization
Four Hours of Continuous Albuterol
http://chestjournal.chestpubs.org/content/114/3/847
services can be found online on the World Wide Web at:
The online version of this article, along with updated information and
ISSN:0012-3692
)
http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(
written permission of the copyright holder.
this article or PDF may be reproduced or distributed without the prior
Dundee Road, Northbrook, IL 60062. All rights reserved. No part of
Copyright1998by the American College of Chest Physicians, 3300
Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

Four
Hours
of
Continuous
Albuterol
Nebulization*
Ariel
Berlinski,
MD;
and
f.
Clifford
Waldrep,
PhD
Background
and
objectives:
Continuous
albuterol
nebulization
(CAN)
is
a
therapeutic
modality
available
to
treat
status
asthmaticus.
Currently,
CAN
may
be
administered
using
a
large-volume
nebulizer
(LVN)
or
a
small-volume
nebulizer
attached
to
an
infusion
pump
or
refilled
as
needed.
Few
data
are
available
regarding
the
reproducibility
of
aerosol
characteristics
during
CAN.
In
this
study,
we
determined
the
aerodynamic
profile,
drug
output
(DO),
DO
in
respirable
range
(RD),
solution
output
(SO),
and
changes
in
reservoir's
albuterol
concentration
(AR)
hourly
during
4
hours
of
CAN.
Design:
A
modified
Puritan-Bennett
1600
jet
nebulizer
was
tested
with
a
large
reservoir
(LR;
250
mL),
medium
reservoir
(MR;
45
mL),
and
small
reservoir
with
infusion
pump
(SRP;
18
mL).
We
used
100-,
40-,
and
4-mL
initial
fill
volumes
(with
10-mL/h
infusion
for
SRP)
of
1
mg/mL
albuterol
solution
for
the
LR,
MR,
and
SRP,
respectively.
Particle
size
distribution
and
DO
consistency
were
determined
by
impaction
and
spectrophotometric
analysis
(275
nm).
We
also
determined
albuterol
mass
output.
The
SO
was
determined
by
gravimetric
technique.
Results:
The
PBsj
produced
a
heterodisperse
aerosol
with
a
median
mass
aerodynamic
diameter
range
of
1.8
to
2.2
urn.
DO
and
RD
paralleled
SO.
The
LR
had
the
highest
SO,
DO,
and
RD
(8.03
±
2.36
vs
5.73
±
2.48
and
5.85
±
0.51
mg/h
for
MR
and
SRP,
respectively).
The
AR
showed
no
statistically
significant
changes.
Conclusions:
The
PBsj
demonstrated
consistent
and
adequate
aerosol
production
during
4
hours
of
CAN.
These
bench
data
support
the
widespread
use
of
a
LVN
for
CAN.
(CHEST
1998;
114:847-853)
Key
words:
aerosol;
albuterol;
continuous
nebulization;
drug
aerosol
therapy;
inhalation
devices;
nebulizers;
status
asthmaticus
Abbreviations:
AR=variation
in
reservoir's
albuterol
concentration
expressed
as
albuterol
ratio;
CAN
=
continuous
albuterol
nebulization;
DO
=
drug
output;
%DO=drug
output
expressed
as
percentage
of
first
hour's
drug
output;
GSD
=
geometric
standard
deviation;
IP=infusion
pump;
LR=large
reservoir;
LVN
=
large-volume
nebulizer;
MMAD
=
mass
median
aerodynamic
diameter;
MR
=
medium
reservoir;
RD
=
respirable
dose;
%RR=percentage
of
particles
in
the
0.4
to
5-|xm
size
range;
SO
=
solution
output;
SRP=small
reservoir
with
attached
infusion
pump;
SVN
=
small-volume
nebulizer
T
nhalation
of
P2-adrenergic
drugs
is
one
of
the
¦*¦
most
important
regimens
available
for
treatment
of
acute
asthma
exacerbations.
Continuous
albuterol
nebulization
(CAN)
of
several
hours'
duration
has
evolved
from
a
novel
approach
into
a
therapeutic
option
frequently
used
to
treat status
asthmaticus.
CAN
has
proven
to
be
equivalent
to
or
more
effec¬
tive
than
intermittent
albuterol
nebulization
or
IV
*From
the
Department
of
Pediatrics,
Pulmonology
Section
(Dr.
Berlinski),
and
the
Department
of
Molecular
Physiology
and
Biophysics
(Dr.
Waldrep),
Baylor
College
of
Medicine,
Houston,
TX.
Supported
by
the
Clayton
Foundation
for
Research,
Houston,
TX.
Manuscript
received
November
25,
1997;
revision
accepted
March
5,
1998.
Correspondence
to:
J.
Clifford
Waldrep,
PhD,
Department
of
Molecular
Physiology
and
Biophysics,
Baylor
College
of
Medi¬
cine,
One
Baylor
Plaza,
Houston,
TX
77030
infusion
in
treatment
of
status
asthmaticus.16
It
has
been
used
in
children12
and
in
adults,3-6
and
dem¬
onstrated
a
good
safety
profile.78
The
improvement
seen
with
CAN
seems
to
be
associated
with
direct
pulmonary
effects
rather
than
being
secondary
to
elevated
plasma
concentrations.9
Currently,
there
are
two
modalities
of
administering
CAN.
One
is
the
use
of
small-volume
nebulizers
(SVNs)
attached
to
an
expensive
infusion
pump
(IP).10'11
The
other
involves
the
use
of
more
economical
and
reusable
large-volume
nebulizers
(LVNs).3-12
Despite
the
in¬
creasing
use
of
CAN,
there
are
very
few
data
regard¬
ing
aerosol
output
characteristics.1314
While
aerosol
particle
size
is
an
important
determinant
of
aerosol
deposition
within
the
airways,15
there
are
limited
published
data
on
CAN's
aerodynamic
profile.
Under
the
appropriate
circumstances.optimal
mass
median
aerodynamic
diameter
(MMAD)
and
CHEST/
114/3
/SEPTEMBER,
1998
847
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

co
in
"c
CO
O
oa
£*
3
Q
<
1
"T"
Large
Reservoir
Small
Reservoir
Medium
Reservoir
MMAD
GSD
MMAD
GSD
MMAD
GSD
MMAD
GSD
12
3
4
Nebulization
Time
(hours)
Figure
1.
MMAD
and
GSD
during
4
h
of
CAN
using
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
three
different
reservoirs.
No
differences
in
MMAD
were
detected
across
time
in
any
of
the
reservoirs.
No
differences
in
GSD
were
detected
across
time
for
the
small
and
large
reservoirs.
$p
=
0.009
between
the
first
and
fourth
hours.
drug
output
(DO).the
use
of
the
continuous
mo¬
dality7
could
lead
to
decreased
workforce
time,
and
subsequent
reduced
health-care
costs.1
Moreover,
the
use
of
LVNs
for
CAN
would
result
in
greater
savings
while
maintaining
equivalent
patient
care.
The
use
of
CAN
by
LVN
will
allow
a
more
general¬
ized
acceptance
of
this
modality,
especially
by
low-
complexity
emergency
centers.
The
aim
of
this
study
was
to
analyze
the
aerody¬
namic
profile,
the
DO,
DO
in
the
respirable
range
of
0.4
to
5
jjLm
(respirable
dose,
or
RD),
solution
output
(SO),
and
changes
in
the
reservoir's
albuterol
con¬
centration
(AR)
of
three
delivery
systems
during
4
h
of
CAN.
Materials
and
Methods
A
modified
Puritan-Bennett
1600
jet
nebulizer16
(Nellcor
Puritan-Bennett;
Carlsbad,
CA)
attached
to
three
different
reus¬
able
reservoirs
(with
maximum
loads
of
250,
45,
and
18
mL)
was
used.
Each
reservoir
had,
respectively,
a
16-,
10-,
and
6-cm
internal
feed
tube
attached
to
the
ceramic
jet
inlet.
The
maxi¬
mum
load
was
defined
as
the
maximum
volume
that
can
be
loaded
in
the
reservoir
while
maintaining
proper
function.
The
larger
of
the
two
reservoirs
was
loaded
with
100
and
40
mL,
respectively,
of
1
mg/mL
albuterol
solution.
The
smallest
reser¬
voir
was
primed
with
4
mL
of
1
mg/mL
albuterol
solution
and
was
connected
with
a
15-mm
ID
respiratory
luer
adaptor
(Westmed;
Tucson,
AZ)
to
an
IP
(Syringe
infusion
pump,
model
2001;
Medfusion
Inc;
Duluth,
GA).
The
IP
was
operated
at
10
mL/h
to
maintain
a
constant
reservoir
volume.
The
250-,
45-,
and
18-mL
reservoirs
are
referred
to
as
the
large
reservoir
(LR),
the
medium
reservoir
(MR),
and
the
small
reservoir
with
attached
infusion
pump
(SRP),
respectively.
The
nebulizer
solution
was
prepared
by
diluting
commercially
available
albuterol
(Ventolin
inhalation
solution
0.5%;
Allen
&
Hanburys,
Glaxo
Inc;
Research
Triangle
Park,
NC)
with
sterile
normal
saline
solution.
The
nebulizer
was
initially
weighed
on
a
precision
balance
(Sartorius
Basic;
Sartorius
Corp;
Bohemia,
NY).
The
solution
was
added
and
a
200-fiL
aliquot
was
taken
and
diluted
with
9.8
mL
of
0.1-M
HCI
solution
for
spectrophotometric
analysis.
Then,
the
nebulizer
was
weighed
again
and
connected
to
a
dry
air
compressor
(Arydine
2000;
Timeter;
Lancaster,
PA)
operated
at
50
lb/in2.
A
10-L/min
air
flow
(Puritan-Bennett
flowmeter)
was
started
and
the
nebulizer
was
operated
for
55
min.
The
system
was
then
connected
with
a
corrugated
tube
to
a
multistage
cascade
impactor17
(Andersen
Instruments
Inc;
Atlanta,
GA)
operated
at
28.3
L/min.
A
Y-
shaped
adaptor
with
a
one-way
valve
was
interposed
between
the
nebulizer
and
the
tubing
to
allow
air
entrainment
(52
to
56%
relative
humidity).
A
5-min
sampling
interval
was
utilized.
The
impaction
plates
and
the
final
glass
fiber
collection
filter
were
eluted
with
8
mL
of
0.1-M
HCI
solution.
All
samples
were
848
Laboratory
and
Animal
Investigations
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

assayed
by
spectrophotometer
at
275
nm
(Cary
spectrophotom¬
eter;
Varian;
Mulgrave,
Australia).
This
process
was
repeated
hourly
for
4
h.
All
experiments
were
done
under
a
laminar
flow
hood
(Nuaire;
Plymouth,
MN).
Each
experiment
was
repeated
three
times.
The
MMAD,
geometric
standard
deviation
(GSD),
and
per¬
centage
of
particles
less
than
5
ixm
in
diameter
were
calculated
with
KaleidaGraph
3.0
(Synergy
Software;
Reading,
PA).]S
The
percentage
of
particles
in
the
0.4-
to
5-ixm
range
(%RR)
was
calculated
by
difference
between
the
percentage
of
particles
less
than
5
ixm
and
percentage
of
particles
less
than
0.4
ixm
in
diameter
determined
by
impaction
analysis.
The
SO
was
deter¬
mined
by
the
gravimetric
technique.19
The
DO
reproducibility
was
determined
by
comparing
the
successive
DO
values
from
impaction
analysis
and
expressed
as
percentage
of
the
first
hour's
DO
(%DO).
The
DO
was
determined
by
measuring
albuterol
mass
released
from
the
nebulizer
reservoir
(starting
volume
X
starting
concentration.final
volume
X
final
concen¬
tration).20
Results
were
also
expressed
as
respirable
dose
(RD
=
DO
X
%RR).21
Variation
in
the
reservoir
albuterol
con¬
centration
was
expressed
as
the
albuterol
ratio
(AR
=
final
albuterol
concentration/initial
albuterol
concentration).22-23
All
data
were
expressed
as
mean
±
SD.
Analysis
of
variance
for
repeated
measures
was
used
to
test
the
periodic
assessments
of
different
outcome
variables.
Single-factor
analysis
of
variance
was
used
to
compare
the
different
delivery
systems.
If
any
of
these
differences
were
significant,
the
Bonferroni
t
test
for
multiple-
comparison
analysis
was
applied.
Statistical
analysis
was
done
with
a
computer
package
software
(Minitab
10.2;
Minitab
Inc;
State
College,
PA).
A
p
value
of
less
than
0.05
was
considered
statistically
significant.
Results
Aerodynamic
Profile
The
intradevice
analyses
of
the
LR
and
SRP
showed
no
statistically
significant
changes
in
MMAD,
GSD,
and
%RR
throughout
the
4-h
study.
The
MR
presented
a
stable
MMAD;
however,
at
the
fourth
hour,
GSD
decreased
(2.63
±
0.08
vs
3.7
±
0.45
at
the
first
hour;
p
=
0.009)
and
%RR
increased
(72.5
±
0.9
vs
61.6
±
1.3%
at
the
first
hour;
p
=
0.008)
(Figs
1-2).
The
SRP
had
a
statisti¬
cally
significant
greater
MMAD
than
the
LR
(2.2
±
0.5
vs
1.8
±
0.2
jim;
p
=
0.016).
The
MR
presented
an
MMAD
of
2.0
±
0.4
fxm.
GSD
was
3.9
±
0.6,
3.3
±
0.5,
and
3.7
±
0.4
for
the
SRP,
MR,
and
LR,
respectively.
The
%RR
was
60.6
±
7.5,
66.6
±
4.6,
and
62.1
±
4.8%
for
the
SRP,
MR,
and
LR
respectively.
The
%RR
was
significantly
greater
for
the
MR
only
at
the
third
hour
of
CAN
(p
=
0.004
and
p
=
0.014
vs
the
SRP
and
LR,
respectively.
The
%RR
was
significantly
greater
for
the
MR
only
at
the
third
hour
of
CAN
(p
=
0.004
and
p
=
0.014
vs
the
SRP
and
LR,
respectively).
Drug
Output
The
DO
and
RD
remained
constant
throughout
the
4-h
study
(p
=
not
significant).
The
%DO
ranged
from
100
to
138.9%
for
the
MR,
from
77.6
to
103.1%
for
the
SRP,
and
from
100
to
134.8%
for
the
LR
(Fig
3).
However,
interdevice
comparison
showed
a
higher
DO
for
the
LR
(12.83
±
3.24
mg/h
for
the
LR
vs
8.44
±
3.24
mg/h
for
the
MR
and
9.66
±
1.04
mg/h
for
the
SRP;
p
=
0.002
vs
the
MR
and
p
=
0.001
vs
the
SRP).
When
RD
was
analyzed,
similar
results
were
obtained
(8.03
±
2.36
mg/h
for
the
LR
vs
5.73
±
2.48
mg/h
for
the
MR
and
5.85
±
0.51
mg/h
for
the
SRP;
p
=
0.013
vs
the
MR
and
p
=
0.0007
vs
the
SRP)
(Fig
4).
The
results
achieved
by
the
MR
and
the
SRP
were
similar
(p
=
0.3
for
DO;
p
=
0.8
for
RD).
Solution
Output
All
three
delivery
systems
showed
a
constant
SO
throughout
the
4-h
nebulization
period.
However,
the
MR
(9.9
±
0.5
mL/h)
and
SRP
(9.7
±
0.2
mL/h)
had
a
lower
SO
than
the
LR
(15.7
±
0.9
mL/h;
p
<
0.002)
(Figs
5-6).
Similar
differences
were
ob¬
served
when
normal
saline
SO
was
determined
for
all
nebulizers.
Nevertheless,
different
results
were
ob¬
tained
when
the
SO
was
assessed
for
the
LR
with
a
250-mL
initial
volume
fill
during
22
h
of
continuous
nebulization.
The
LR
showed
a
linear
increase
in
SO
with
a
decrease
in
the
remaining
reservoir
solution
volume
(Fig
5).
The
following
ranges
of
the
reser¬
voir
s
volume
fill
showed
statistically
significant
dif¬
ferences
in
SO
(p
<
0.00004):
250
to
207
mL
fill
(SO
8.4
±0.5
mL/h);
206
to
154
mL
fill
(9.4
±
0.5
e
80
0
12
3
Nebulization
Time
(hours)
Figure
2.
Percentage
of
drug
in
the
0.4-
to
5-fxm
particle
size
range
(determined
by
impaction
analysis)
during
4
h
of
CAN
using
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
three
different
reservoirs.
*No
differences
across
time.
$p
=
0.008
between
first
and
fourth
hours.
#p
=
0.004
and
p
=
0.0014
when
compared
with
the
SRP
and
LR,
respectively.
CHEST
/
114
/
3
/
SEPTEMBER,
1998
849
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

0
12
3
4
5
Nebulization
Time
(hours)
Figure
3.
SO
and
consistency
of
drug
output
(%
DO)
during
4
h
of
CAN
using
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
three
different
reservoirs.
Solid
line
=
SO
(mL/h,
determined
by
gravimetric
technique).
Dotted
line
=
%DO
(expressed
as
percentage
of
the
first
hour's
DO
determined
by
impaction
analysis).
*No
differences
across
time.
#p
0.002
when
compared
with
the
MR
and
SRP.
mL/h);
151
to
92
mL
fill
(11.1
±
1.0
mL/h);
and
89
to
22
mL
fill
(12.7
±
1.3
mL/h).
Reservoir
Concentration
(Albuterol
Ratio)
We
were
not
able
to
detect
statistically
significant
differences
in
AR
between
the
three
systems
studied
(Fig
7).
The
AR
ranged
from
1.11
to
1.27
for
the
SRP
and
from
1.07
to
1.30
for
the
LR.
In
contrast,
the
AR
for
the
MR
was
more
strongly
affected
throughout
the
CAN
period,
as
reflected
by
values
of
1.20
at
the
first
hour,
1.78
at
the
third
hour,
and
6.25
at
the
fourth
hour.
This
concentration
effect
might
reflect
the
fact
that
during
some
of
the
experiments
the
nebulizer
was
run
almost
to
dryness.
Discussion
CAN
is
one
of
the
therapeutic
modalities
available
to
treat
status
asthmaticus.
Optimal
aerosol
particle
size
and
distribution
and
reproducibility
of
DO
are
para¬
mount
for
effective
drug
delivery
in
these
situations.
Cost-effectiveness
is
also
one
of
the
driving
forces
of
current
health-care
strategies.
The
use
of
CAN
has
already
been
proven
to
improve
patient
outcome,16
to
be
safe,78
and
to
reduce
personnel
time.1
Despite
its
frequent
clinical
use,
there
are
limited
data
about
die
aerosol
characteristics
of
CAN.
Two
different
systems
have
been
reported
in
the
literature
for
the
delivery
of
CAN.310-12
Clinical
studies
have
used
different
ap¬
proaches.
Some
trials
have
used
an
SVN
either
at¬
tached
to
an
IP12
or
refilled
as
needed,6
while
others
have
used
LVNs.3,512
There
are
very
few
reports
of
nebulizer
output
of
delivery
systems
designed
for
CAN.1314
One
group
characterized
the
volume
output
of
an
LVN
(Seamless
No.
5207;
Seamless;
Ocala,
FL)
and
an
SVN
(Airlife
Misty
Nebulizer;
Raxter;
Valencia,
CA)
using
saline
solution
by
means
of
the
gravimetric
method;13
they
reconstructed
the
delivery
systems
used
in
two
previously
published
clinical
studies.23
Others
compared
the
drug
delivery
of
radiolabeled
techne-
tium/normal
saline
solution
of
the
HEART
(Vortran;
Sacramento,
CA),
Aero-Tech
II
(CIS;
Redford,
MA),
and
Hospitak
Power
Mist
(Hospitak,
Inc;
Farmingdale,
850
Laboratory
and
Animal
Investigations
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

20
a
£
15
DO
(rng/h)
RD
(mg/h)
SO
(ml/h)
20
Small
with
Pump
Figure
4.
Mean
DO,
SO,
and
RD
during
4
h
of
CAN
using
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
three
different
reservoirs.
$p
=
0.002
and
p
=
0.001
when
compared
with
the
MR
and
SRP,
respectively.
*p
<
0.002
when
compared
with
the
MR
and
SRP.
#p
=
0.013
and
p
=
0.0007
when
com¬
pared
with
the
MR
and
SRP,
respectively.
NY)
nebulizers.14
The
latter
study
used
a
mechanical
model
of
spontaneous
breathing
with
a
pediatric
and
an
adult
breathing
pattern.
In
this
study,
we
report
the
nebulizer
performance
of
a
reusable
modified
single
jet
Puritan-Bennett
1600
nebulizer
attached
to
three
different
reservoirs
(250,
45,
and
18
mL)
for
4 h
of
CAN.
An
IP
was
connected
to
the
smallest
reservoir
to
allow
continuous
nebuliza¬
tion.
The
three
systems
had
an
overall
consistent
performance
across
time.
The
LR
and
SRP
showed
stable
MMAD,
GSD,
%RR,
AR,
SO,
DO,
and
RD
throughout
the
4-h
period
of
albuterol
nebulization.
The
MR
produced
a
statistically
significant
decrease
in
GSD
and
increase
in
%RR
during
the
fourth
hour.
However,
these
changes
are
not
likely
to
be
clinically
relevant.
All
other
parameters
remained
constant
(MMAD,
percentage
of
particles
less
than
5
|xm,
SO,
DO,
and
RD).
Changes
in
AR
did
not
achieve
statistical
significance.
However,
for
the
MR,
the
AR
increased
from
1.78
to
6.25
between
the
third
and
fourth
hours.
This
is
the
result
of
die
low
residual
volume
(0.4
mL)
remaining
in
the
reservoir
after
4
h
of
CAN.
This
problem
could
be
overcome
in
the
clinical
arena
by
increasing
the
initial
volume
fill
to
45
mL
(maximum
nebulizer
load).
The
aerosol
produced
by
any
of
the
delivery
systems
had
an
MMAD
suitable
for
lower
tract
respiratory
deposition
(1.8
to
2.2
(xm).15
The
differences
seen
between
SRP
and
LR
(1.8
vs
2.2
jjliti),
although
statistically
significant,
are
not
likely
to
have
clinical
impact.
A
previous
study
reported
an
MMAD
of
2.10
jxm
for
the
HEART
nebulizer
at
the
first
and
fourth
hours
of
nebulization.
It
is
not
clear
why
the
MR
presented
a
higher
%RR
at
the
third
hour
of
CAN.
However,
we
think
that
these
differences
would
not
have
clinical
relevance.
All
delivery
systems
tested
produced
heterodisperse
aerosols
(GSD
ranging
from
2.63
to
4.63).
The
particle
size
distribution
analysis
was
carried
out
using
the
cascade
impaction
technique.
This
technology
can
underestimate
the
actual
particle
size
due
to
evaporative
losses.
Therefore,
predictions
of
particle
behavior
may
not
be
completely
accurate.
Our
SO
results
differ
from
those
in
another
study,
in
which
a
statistically
significant
variation
across
time
for
die
LVN
(except
from
60
to
120
min
of
a
4-h
contin¬
uous
nebulization)
and
SVN
(only
at
60
min)
was
noted.2
That
group
also
found
a
significant
lot
variation
for
the
LVN.2
We
did
not
design
our
study
to
look
at
this
particular
issue.
We
think
that
the
greater
SO
documented
for
the
LR
might
be
due
to
reservoir
design
characteristics.
When
the
LR
was
studied
for
saline
SO
during
22
h
of
continuous
operation,
a
significant
increase
in
SO
was
detected
with
a
decrease
in
die
reservoir's
volume
fill
(Fig
5).
This
finding
would
allow
clinicians
to
target
different
DOs
by
varying
the
nebulizer's
volume
fill.
We
speculate
that
this
finding
could
be
related
to
the
relationship
between
air
and
solution
present
in
die
nebulizer.
As
can
be
seen
in
Fig
6,
die
greater
the
ratio
between
empty
and
filled
nebulizer
volume,
the
greater
die
SO
achieved.
It
is
also
possible
diat
diis
behavior
might
represent
an
increase
in
evaporative
losses
rather
dian
true
higher
SO.
The
difference
between
the
SO
for
saline
solution
and
the
SO
for
albuterol
solution
for
the
LR
is
due
to
mediodologic
factors.
With
saline,
60
min
of
continu¬
ous
nebulization
(10
L/min)
is
used,
whereas
for
albu-
18
16
10
300
250
200
150
100
50
Initial
Reservoir's
Volume
(ml)
Figure
5.
SO
of
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
an
LR
during
22
h
of
continuous
saline
solution
nebulization:
effect
of
reservoir's
volume.
CHEST
/
114
/
3
/
SEPTEMBER,
1998
851
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

18
16
Air
Liquid
Air/liquid
ratio
=
0.5
Air/liquid
ratio
=
1
Air/liquid
ratio
=
2
0
2
4
6
8
10
12
Air/liquid
Ratio
(empty/solution
filled
nebulizer
volume
ratio)
Figure
6.
Relationship
between
the
reservoir's
air/liquid
ratio
and
SO
of
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
an
LR
during
22
h
of
continuous
saline
solution
nebulization.
terol,
the
procedure
involved
55
min
of
continuous
nebulization
(10
L/min)
and
5
min
of
connection
to
the
cascade
impactor.
The
DO
represents
the
amount
of
drug
being
aero¬
solized
during
a
time
interval.
The
RD
is
the
DO
aerosolized
in
the
0.4-
to
5-fxm
particle
size
range.
Neither
DO
or
RD
represents
drug
deposited
in
the
lungs
or
inhaled
drug.
These
two
processes
are
also
influenced
by
other
factors
not
related
to
nebulizer
performance.
Our
DO
and
RD
data
showed
a
higher
output
for
the
LR.
However,
when
these
data
were
corrected
for
SO,
performance
became
similar
(RD
was
0.55,
0.55,
and
0.61
mgfaiL
SO/h
for
the
LR,
MR,
and
SRP,
respectively).
We
found
a
good
correlation
between
DO
or
RD
and
SO.
These
results
are
in
agreement
with
some
reports1923
showing
that
DO
(albuterol22
and
technetium/normal
saline
solution18)
follows
a
pattern
similar
to
that
of
SO.
However,
our
findings
differ
from
those
of
other
groups,
who
have
previously
reported
a
plateau
in
DO
(albuterol22-25
and
cromolyn24)
despite
a
continuous
SO.
Our
DO
data
are
difficult
to
compare
with
those
obtained
by
others
because
of
methodologic
differences.14
That
group
measured
the
output
of
technetium/normal
saline
so¬
lution
from
a
HEART
nebulizer
every
30
min
for
4
h
and
from
two
SVNs
every
1
to
2
min
for
10
min
and
made
a
projection
of
the
expected
output
over
a
4-h
period.
Their
methodology
makes
the
assumption
that
DO
is
constant
for
diese
particular
devices
when
operated
continuously
for
4
h.
Also,
diat
study
em¬
ployed
a
mechanical
model
of
spontaneous
breathing,
whereas
we
used
the
"standing
cloud
technique."26
However,
if
we
correct
our
DO
data
for
a
duty
cycle
of
40%,
our
results
are
comparable
(5.1,
3.0,
and
3.9
mg/h
for
the
LR,
MR,
and
SRP,
respectively,
compared
with
3.5,
3.7,
and
5.1
mg/h
for
the
HEART,
PowerMist
and
Aero-Tech
II
nebulizers,
respectively).
Despite
these
differences,
both
studies
found
that
LVNs
produce
a
reproducible
DO
when
used
for
CAN
over
a
4-h
interval.
Previous
work
documented
a
significant
influ¬
ence
of
breathing
pattern
on
drug
deposition,
but
we
did
not
set
up
our
bench
testing
for
that
purpose.
Our
data
on
AR
confirms
the
observation
that
con¬
centration
effect
is
partially
due
to
the
reservoir's
initial
volume.
We
observed
only
a
30%
increase
in
albuterol
concentration
after
4
h
for
the
SRP
and
LR
and
after
2
h
for
the
MR.
Although
AR
increased
for
the
MR
from
1.78
to
6.25
from
the
third
to
the
fourth
hour,
we
852
Laboratory
and
Animal
Investigations
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

10
1
2
3
Nebulization
Time
(hours)
Figure
7.
Reservoir
concentration
changes
(albuterol
ratio)
during
4
h
of
CAN
using
a
modified
Puritan-Bennett
1600
jet
nebulizer
attached
to
three
different
reservoirs.
were
unable
to
demonstrate
a
statistically
significant
difference.
This
is
the
result
of
the
presence
of
a
large
standard
deviation
and
the
fact
that
the
Bonferroni
test
constitutes
a
very
conservative
approach
to
multiple-
comparison
analysis.
The
large
standard
deviation
might
be
related
to
the
fact
that
during
some
of
the
experiments
the
nebulizer
was
run
almost
to
dryness.
Our
results
are
difficult
to
compare
with
those
of
other
groups2223'25
because
SVNs
were
utilized
with
initial
volume
fills
of
1.5
to
3.5
mL
for
10
to
12
min
of
nebulization
time
in
those
studies.
In
conclusion,
this
study
showed
that
the
reusable
modified
single-jet
Puritan-Bennett
1600
LVN
at¬
tached
to
a
250-mL,
45-mL,
and
(with
an
IP)
18-mL
reservoir
has
a
consistent
and
adequate
aerosol
production
during
a
4-h
period
of
CAN.
Moreover,
LVNs
demonstrated
a
higher
DO
than
did
the
SRP.
The
use
of
LVNs
for
CAN
would
allow
a
more
cost-effective
drug
delivery
modality
and
widespread
use
in
low-complexity
emergency
centers.
These
bench
data
support
the
use
of
this
LVN
for
CAN.
References
1
Papo
M,
Frank
J,
Thompson
AE.
A
prospective,
randomized
study
of
continuous
versus
intermittent
nebulized
albuterol
for
severe
status
asthmaticus
in
children.
Crit
Care
Med
1993;
21:1479-1486
2
Reisner
C,
Kotch
A,
Dworkin
G.
Continuous
versus
frequent
intermittent
nebulization
of
albuterol
in
acute
asthma:
a
randomized,
prospective
study.
Ann
Allergy
Asthma
Immunol
1995;
75:41-47
3
Colacone
A,
Wolkove
N,
Stern
E,
et
al.
Continuous
nebuli¬
zation
of
albuterol
(salbutamol)
in
acute
asthma.
Chest
1990;
97:693-697
4
Rudnitzky
GS,
Eberlein
RS,
Schofftall
JM,
et
al.
Comparison
of
intermittent
and
continuously
nebulized
albuterol
for
treatment
of
asthma
in
an
urban
emergency
department.
Ann
Emerg
Med
1993;
22:1842-1846
5
Lin
RY,
Sater
D,
Newman
T,
et
al.
Continuous
versus
intermittent
albuterol
nebulization
in
the
treatment
of
acute
asthma.
Ann
Emerg
Med
1993;
22:1847-1853
6
Shresta
M,
Bidadi
K,
Gourlay
S,
et
al.
Continuous
vs
inter¬
mittent
albuterol,
at
high
and
low
doses,
in
the
treatment
of
severe
acute
asthma.
Chest
1996;
110:42-47
7
Kelly
HW,
McWilliams
BC,
Katz
R,
et
al.
Safety
of
frequent
high-dose
nebulized
terbutaline
in
children
with
acute
severe
asthma.
Ann
Allergy
1990;
64:229-233
8
Katz
RW,
Kelly
W,
Crowley
ML,
et
al.
Safety
of
continuous
nebulized
albuterol
for
bronchospasm
in
infants
and
children.
Pediatrics
1993;
92:666-669
9
Moler
FW,
Johnson
CE,
Laanen
CV,
et
al.
Continuous
versus
intermittent
nebulized
terbutaline:
plasma
levels
and
effects.
Am
J
Respir
Crit
Care
Med
1995;
151:602-607
10
Moler
F,
Hurwitz
M,
Custer
J.
Improvement
of
clinical
asthma
scores
and
PaC02
in
children
with
severe
asthma
treated
with
continuously
nebulized
terbutaline.
J
Allergy
Clin
Immunol
1988;
81:1101-1109
11
Voss
KR,
Willsie-Ediger
SK,
Pyszczynski
DR,
et
al.
Descrip¬
tion
of
a
delivery
method
for
continuously
aerosolized
albu¬
terol
in
status
asthmaticus.
J
Asthma
1990;
27:37-39
12
Chipps
BE,
Blackney
DA,
Black
LE
III,
et
al.
Vortran
high
output
extended
aerosol
therapy
(HEART)
for
delivery
of
continuously
nebulized
terbutaline
for
the
treatment
of
acute
bronchospasm.
Pediatr
Asthma
Allergy
Immunol
1990;
4:271-
277
13
Reisner
C,
Lee
J,
Kotch
A,
et
al.
Comparison
of
volume
output
from
two
different
continuous
nebulizer
systems.
Ann
Allergy
Asthma
Immunol
1996;
76:209-213
14
McPeck
M,
Tandon
R,
Hughes
K,
et
al.
Aerosol
delivery
during
continuous
nebulization.
Chest
1997;
111:1200-1205
15
Stahlhofen
W,
Gebhart
J,
Heyder
J.
Experimental
determina¬
tion
of
the
regional
deposition
of
aerosol
particles
in
the
human
respiratory
tract.
Am
Ind
Hyg
Assoc
J
1980;
41:385-398a
16
Waldrep
JC,
Scherer
PW,
Keyhani
K,
et
al.
Cyclosporin
A
liposome
aerosol:
particle
size
and
calculated
respiratory
deposition.
Int
J
Pharm
1993;
97:205-212
17
Hallworth
GN,
Andrews
UG.
Size
analysis
of
suspension
inhalation
by
inertial
separation
methods.
J
Pharm
Pharmacol
1977;
28:898-907
18
Nilsson
G,
Brunzell
A,
Hellberg
H.
Estimation
of
particle
size
in
medical
aerosols
with
a
cascade
impactor.
Acta
Pharmsuec
1977;
14:95-104
19
Tandon
R,
McPeck
R,
Smaldone
GC.
Measuring
nebulizer
output:
aerosol
production
vs
gravimetric
methods.
Chest
1997;
111:1361-1365
20
Newman
SP,
Pellow
PGD,
Clay
MM,
et
al.
Evaluation
of
jet
nebulizers
for
use
with
gentamicin
solution.
Thorax
1985;
40:671-676
21
O'Callaghan
C,
Barry
PW.
The
science
of
nebulized
drug
delivery.
Thorax
1997;
52(suppl
2):S31-S44
22
Wood
JA,
Wilson
RSE,
Bray
C.
Changes
in
the
salbutamol
concentration
in
the
reservoir
solution
of
a
jet
nebulizer.
Br
J
Dis
Chest
1986;
80:164-169
23
Langford
SA,
Allen
MB.
Salbutamol
output
from
two
jet
nebulizers.
Respir
Med
1993;
87:99-103
24
O'Callaghan
C,
Clarke
AR,
Milner
AD.
Why
nebulize
for
more
than
five
minutes.
Arch
Dis
Child
1989;
64:1270-1273
25
Malone
RA,
Hollie
MC,
Glynn-Barnhart
A,
et
al.
Optimal
duration
of
nebulized
albuterol
therapy.
Chest
1993;
104:
1114-1118
26
Smaldone
GC.
Drug
delivery
by
nebulization:
"reality
testing"
[editorial].
J
Aerosol
Med
1994;
7:213-216
CHEST/114/3/SEPTEMBER,
1998
853
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from

DOI 10.1378/chest.114.3.847
1998;114; 847-853Chest
Ariel Berlinski and J. Clifford Waldrep
Four Hours of Continuous Albuterol Nebulization
July 15, 2011This information is current as of
http://chestjournal.chestpubs.org/content/114/3/847
Updated Information and services can be found at:
Updated Information & Services
http://www.chestpubs.org/site/misc/reprints.xhtml
found online at:
Information about reproducing this article in parts (figures, tables) or in its entirety can be
Permissions & Licensing
http://www.chestpubs.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
Reprints
"Services" link to the right of the online article.
Receive free e-mail alerts when new articles cite this article. To sign up, select the
Citation Alerts
PowerPoint slide format. See any online figure for directions.
articles can be downloaded for teaching purposes inCHESTFigures that appear in
Images in PowerPoint format
1998 by the American College of Chest Physicians
by guest on July 15, 2011chestjournal.chestpubs.orgDownloaded from