Vol. 90, Issue 5, 1763-1769, May 2001
Saline aerosol bolus dispersion. II. The effect of conductive
airway alteration
Sylvia
Verbanck1,
Daniël
Schuermans1,
Manuel
Paiva2, and
Walter
Vincken1
1 Respiratory Division, Academic Hospital, Vrije
Universiteit Brussel, Brussels 1090; and 2 Laboratoire de
Physique Biomédicale, Université Libre de Bruxelles, 1070 Brussels, Belgium
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ABSTRACT |
In a companion study (Verbanck S, Schuermans D,
Vincken W, and Paiva M, J Appl Physiol 90:
1754-1762, 2001), we investigated whether saline aerosol
bolus tests could also be used to detect proximal, as opposed to
peripheral, airway alterations. We studied 10 never-smokers before and
after histamine challenge, obtaining, for various volumetric lung
depths (VLD), saline bolus-derived indexes computed by discarding
aerosol concentrations below either 50% of the exhaled bolus maximum
(half-width, H) or below cutoffs ranging from 5 to 25% (standard
deviation, 
5%-25%) and skew
(sk5-sk25%). Multiple-breath
N2 washout-derived indexes of conductive
(Scond) and acinar
(Sacin) ventilation inhomogeneity were also
determined. After histamine, Scond
significantly increased (P = 0.008) whereas
Sacin remained unaffected, indicating purely conductive airway alteration. Consistent with this observation, sk5% (or sk25%) was increased to the same
extent at all VLD, and 5% was increased preferentially
at low VLD. By contrast, H and 25% displayed
preferential increases at high VLD, a pattern similar to that induced
by peripheral alterations. The present work shows that proximal airway
alteration can be reliably identified by saline bolus tests only if
these include measurements at low and high VLD and if bolus dispersion
is quantified as a standard deviation with a low cutoff.
N2 washout; provocation
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INTRODUCTION |
IN MOST OF ITS CLINICAL
APPLICATIONS, the aerosol bolus dispersion technique has been
promoted for its sensitivity to small airway structural change,
essentially on the basis of the fact that the bolus test is performed
in the tidal volume range and that aerosol boluses can be
volumetrically pushed into and recovered from the peripheral lung
spaces. Although several papers (reviewed in Refs. 2 and
4) reported the behavior of aerosol boluses delivered to a range of
volumetric lung depths (VLD, typically 200-800 ml), other studies
only included the measurement of aerosol boluses that were targeted to
one given VLD of choice (11-13). In these latter
studies, high sensitivity of the aerosol bolus to lung structural
change was indeed obtained and was generally attributed to the
sensitivity of selected bolus dispersion indexes to heterogeneity of
ventilation. Yet, irrespective of whether the boluses were delivered to
VLD ~400 (11, 12) or VLD ~800 ml (13), it
was invariably suggested that this heterogeneity originated mainly in
the small airways. Although boluses targeted to such VLD do travel the
peripheral spaces, they must negotiate the extrathoracic and conductive
airways, both of which have a considerable impact on the outcome of the
aerosol bolus dispersion test (7, 15).
In fact, the identification of small or large airway structural
alteration on basis of aerosol bolus tests can only be done if the
measurements span a considerable VLD range. For purely small airway
alterations, the relative effect on shallow (VLD = 200 ml) and
deep (VLD = 800 ml) bolus dispersion is straightforward: dispersion of shallow boluses will remain essentially unchanged because
these boluses spend most of their time proximal to the acinar space,
and boluses will get gradually more dispersed as they are sent deeper
into the lungs. Thus, when bolus dispersion becomes abnormally large
with increasing VLD, this suggests small airway structural alteration,
as was shown to be the case for acinar structure alterations in a group
of asymptomatic smokers (22). In contrast to acinar
structure alterations, which can only affect the deep boluses that
travel well within the acinar space, conductive airway alterations are
bound to affect both shallow and deep boluses to some extent.
Conductive airway alterations should be reflected in a marked
dispersion increase of the shallow boluses, an effect that gets
attenuated as VLD increases (8). The primary purpose of
the present study was to verify experimentally whether this pattern can
be obtained with the saline bolus dispersion technique.
The previous saline bolus study of acinar lung alteration, which will
be further referred to as the smoker study (22), involved two groups of different subjects. In the present study, it is possible
to induce conductive airway alteration in one and the same group of
subjects by a histamine challenge procedure (21). This has
the advantage that possible interindividual bolus dispersion differences owing to extrathoracic air space geometry cannot interfere with the actual effect of the structural change we are aiming to
detect. As in the smoker study (22), we also independently assessed the location of structural change by using a conceptually different technique [N2 washout; indexes of conductive
(Scond) and acinar
(Sacin) ventilation inhomogeneity] that
distinguishes between events occurring proximal to and peripheral to
the diffusion front. Structural alterations at the level of
conductive and acinar airways are expected to be associated with an
independent increase of either Scond or
Sacin, respectively. We chose to study
never-smoker subjects who are categorized as nonresponders according to
standard lung function criteria but who are nevertheless expected to
show a marked Scond increase in the absence of
Sacin change (21).
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MATERIALS AND METHODS |
Experimental procedure.
Normal never-smoker test subjects were recruited on a voluntary basis,
and none of the subjects had ever undergone pulmonary function testing
before. Each subject performed baseline spirometry by means of
standardized lung function laboratory equipment (SensorMedics Model
2200, Bilthoven, The Netherlands), including three forced expiration
maneuvers [for forced expired volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow after exhalation of 75% FVC]. In addition, three N2 washout
tests and a sequence of ~15 saline bolus tests were performed in
exactly the same manner as described in the smoker study
(22). Subsequently, all subjects underwent a histamine
challenge procedure using the dosimeter technique (MEFAR dosimeter MB3;
vital capacity breath).
Histamine was administered in four steps (0.16-, 0.48-, 1.08-, and 2-mg
cumulative doses) during which spirometry was monitored. In the final
step, the subjects who had not decreased FEV1 by >20%
predicted were actually included in this study (n = 10). These subjects then continued with a sequence of 15 saline bolus tests and two N2 washout tests, followed by a final
spirometry. The latter spirometry was included to account for possible
time-dependent histamine effects occurring over the course of the
saline and N2 washout test sequences. The average
FEV1 decrease in each subject was computed from the
FEV1 obtained immediately after the final histamine dose
and final FEV1 measurement (i.e., after saline bolus and
N2 washout tests).
Data analysis.
Baseline and histamine N2 washout and aerosol bolus tests
were analyzed in an identical fashion to that employed in the smoker study (22). The most relevant N2
washout-derived curves and indexes are summarized in Fig.
1. Open and closed triangles correspond to the pooled normalized slope (S) curves obtained on the 10 subjects in baseline condition and after histamine challenge,
respectively. Scond and
Sacin are depicted with respect to the baseline
curve (open triangles). Fig. 1 also illustrates how the increase in the
rate of rise of S as a function of lung turnover (TO) due to
histamine challenge (closed triangles) will be reflected in an
increased Scond. Actual
Scond and Sacin values
were obtained on each subject individually, i.e., computed from the
average of three (baseline) or two (posthistamine) S vs. TO
curves obtained in each subject. The saline bolus dispersion-derived
indexes half-width (H), standard deviation (25%,
15%, or 5%), and skew
(sk25%, sk15%, or sk5%) using
cutoffs of 25, 15, and 5%, respectively, were set out against VLD and fitted with third-order polynomials to obtain interpolated values for
VLD = 200, 400, 600, and 800 ml. A set of saline bolus indexes was
obtained for each subject before and after histamine.
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Fig. 1.
Normalized slope curves (means ±SE) resulting from
pooling those obtained on all subjects before ( ) and
after ( ) histamine challenge. Normalized alveolar
slopes are expressed as a function of lung turnover (TO), and the
derivation of conductive and acinar ventilation inhomogeneity indexes
is illustrated with respect to the baseline normalized slope curve (see
text for details).
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RESULTS |
Table 1 summarizes lung function and
N2 washout indexes obtained before and after histamine in
the 10 subjects under study (30 ± 11 yr, means ± SD). All
spirometric parameters in Table 1 (FEV1,
FEV1/FVC, and forced expiratory flow after 75% FVC) were
significantly decreased after 2 mg histamine. On the part of
N2 washout, Sacin and functional
residual capacity remained unaffected by histamine, and the average
13-ml decrease in Fowler dead space (VDF) did not reach
significance (P = 0.06). Scond was significantly increased, from 0.033 to 0.068 liter
1,
consistent with Fig. 1, in which the rate of S increase with TO (beyond TO = 1.5) is seen to be doubled after
histamine. The corresponding saline bolus results are
graphically represented in Figs.
2-4, depicting H, , and skew
values for VLD = 200, 400, 600, and 800 ml before (open triangles)
and after (solid triangles) histamine. As in the smoker study
(22), and skew values are presented in various panels
according to the cutoff that was used for or skew computation (25, 15, or 5%). The present study involved the same subjects before and
after histamine, requiring pairwise comparison of H, , and skew
values for each VLD level (Wilcoxon signed-rank test). The resulting
significant (P < 0.05) differences are indicated by
asterisks on the VLD axes of Figs. 2-4.
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Fig. 2.
Average ±SE values of half-width (H) for 200, 400, 600, and 800 ml volumetric lung depth (VLD) obtained before
() and after () histamine challenge.
*VLD level showing significantly different H after histamine
(P < 0.05; Wilcoxon signed-rank test).
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Fig. 3.
Average ±SE values of standard deviation () for
200, 400, 600, and 800 ml VLD obtained before () and
after () histamine. A, B, and
C: computed using 25, 15 or 5% cutoff, respectively
(see text for details). *VLD level showing significantly different after histamine (P < 0.05; Wilcoxon signed-rank
test).
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Fig. 4.
Average ± SE values of skew (sk) for 200, 400, 600, and 800 ml VLD obtained before () and after
() histamine challenge. A, B, and
C: sk computed using 25, 15, or 5% cutoff, respectively
(see text for details). *VLD level showing significantly different sk
after histamine (P < 0.05; Wilcoxon signed-rank
test).
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H was significantly different before and after histamine for VLD = 600 and 800 ml (Fig. 2). Although became significantly different
after histamine at all VLD levels (Fig.
3), there was a very
distinct pattern of absolute differences at the different VLD
levels, depending on the cutoff that was used. For instance, 25% (Fig. 3A) showed an increase after
histamine of only 11 ml for VLD = 200 ml, which amplified to 33 ml
for VLD = 800 ml, thereby also mimicking the increasing H
difference toward the more peripheral VLD levels (Fig. 2). By contrast,
5% (Fig. 3C) showed an increase after
histamine of 62 ml for VLD = 200 ml, which attenuated to 29 ml for
VLD = 800 ml. Skew (Fig. 4) was significantly
increased after histamine to more or less the same extent at all VLD
levels for any given cutoff (25, 15, or 5%). Finally, we also computed
here, for each subject, the increase of the dispersion indexes H and
between VLD = 200 ml and VLD = 800 ml [e.g., 
H = H(800 ml) 
H(200 ml)]. The resulting H and are
summarized in Table 2 and show that H
appeared to be significantly larger after histamine, an effect that was only reproduced by 25%, consistent with the results
displayed in Fig. 3.
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Table 2.
Increase of saline bolus dispersion indexes between
VLD = 200 ml and 800 ml before and after
histamine challenge
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To illustrate the paradoxical behavior of 25% and
5% as a function of VLD as seen across Figs. 2-3,
individual bolus dispersion curves were retrieved from a subject, with
tests of comparable VLD before and after histamine in the low-VLD range (VLD = 196 and 185 ml; Fig.
5A) and in the high-VLD range
(VLD = 715 and 736 ml; Fig. 5B). Both panels of Fig. 5
show expired curves that are normalized to their respective maximum and
also indicate the 50, 25, and 5% levels that are used for H,
25%, and 5% computation, respectively.
The corresponding H, 25%, and 5% values
are also represented, showing a behavior in line with the overall
findings of Figs. 2 and 3. After histamine, H and 25%
remain virtually unchanged at low VLD (Fig. 5A), and both H
and 25% increase at high VLD (Fig. 5B). By
contrast, histamine induced a marked 5% increase at low
VLD (Fig. 5A) and a smaller 5% increase at
high VLD (Fig. 5B).
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Fig. 5.
Typical exhaled bolus traces before ( ) and after
( ) histamine for inhaled saline boluses delivered to
comparable VLDs (A: VLD = 196 and 185 ml; B:
VLD = 715 and 736 ml). All exhaled boluses are normalized to their
respective maxima, and horizontal lines are drawn at 100, 50, 25, and
5% of the exhaled bolus maximum. H, 25%, and
5% values (in ml; subscripts represent cutoffs used)
are also represented. Corresponding sk25% and
sk5% values were, respectively, 0.39 and 1.02 for VLD = 196 ml and 0.49 and 1.33 for VLD = 185 ml in A and
0.14 and 0.60 for VLD = 715 ml and 0.26 and 0.68 for VLD = 736 ml in B.
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DISCUSSION |
The present study shows that histamine challenge, which provokes
considerable parallel heterogeneity in conductive airway constriction,
i.e., doubling Scond for an FEV1
decrease of only 10%, can also be reflected in a characteristic
pattern of saline bolus dispersion behavior at different lung depths.
In particular, bolus dispersion in Fig. 3C shows a marked
increase for shallow boluses (low VLD) and an attenuation of this
increase for the deeper boluses (high VLD), i.e., a pattern consistent
with the effect of alterations in the conductive airways. However, Fig. 2 and the other panels of Fig. 3 provide a dramatic demonstration of
how a different conclusion can be reached as to whether acinar or
conductive airways are involved in the histamine challenge process,
depending on the dispersion index (or cutoff) used. This contrasts with
the smoker study (22), in which acinar airway changes were
reflected in an increased bolus dispersion at high VLD, irrespective of
the dispersion index (or cutoff) of choice. We will show that this
apparent paradox can be at least in part explained on the basis of a
markedly increased bolus skew at all VLD levels in the case of
histamine provocation (Fig. 4).
Saline bolus dispersion.
The H data in Fig. 2 and the significantly increased dependence of H on
VLD (P = 0.005; Table 2) show a very similar pattern to
that observed in the smoker study (22). This could have
suggested that histamine had also induced an acinar airway alteration,
yet Scond and Sacin
behavior in Table 1 clearly indicate histamine-induced alteration of
the conductive airways only. The reason that the dependence of H on VLD
is more or less mimicked by 25% (Fig. 3A)
and not by 5% (Fig. 3C) can be grasped from the experimental bolus curves in Fig. 5. Figure 5A shows
how, at low VLD, histamine produces a skewed bolus with a bolus tail that contains much of the dispersed aerosol bolus material that is
missed out completely at the 50% and 25% levels (H and
25%). Figure 5B illustrates that at high VLD
boluses are less skewed, and the increased dispersion after histamine
becomes apparent, irrespective of whether dispersion is quantified at
the 50%, 25%, or 5% level (H, 25%, or
5%). As a consequence, H and 25%
underestimate actual bolus dispersion and to a different degree at
different VLD, depending also on bolus skew. Hence, these dispersion
indexes are unsuitable to distinguish between structural changes in the
shallow and deep lung, and the use of with a low cutoff is imperative.
Some aerosol bolus dispersion data previously obtained in the context
of hyperresponsivity protocols, in which time is often limited for
multiple measurements, are now reconsidered with respect to our
observations. For instance, the monitoring of H for only one VLD level
(380 ml) in a dose-response protocol to methacholine (11)
could have been partly responsible for loss of sensitivity and loss of
information on whether small or large airways are involved. The same
holds for bolus studies after ozone exposure using VLD = 380 ml
(12) or in hyperresponsive women using VLD = 800 ml
(13), in which the resulting H measurements cannot be
conclusive about whether the observed changes involve small airways or
not. Yet the identification of large vs. small airway involvement in
the diseased lung constitutes the main reason for using aerosol bolus
dispersion technique in addition to traditional lung function, as
pointed out by Schultz et al. (17). Interestingly, their
study in asthmatic children showed exactly the same pattern of bolus
dispersion and skew (using a 15% cutoff) as 15% and
sk15% in the present study (Figs. 3B and
4B), and it is tempting to also interpret this as a result
of conductive airway alterations. In fact, these authors commented that
the comparison of two subgroups (younger vs. older asthmatic children)
actually revealed a different dependence on VLD, suggesting mainly
conductive airway involvement in the younger asthmatic children and an
additional peripheral alteration in the older ones. Such
pathophysiological information on the contribution of large vs. small
airways in asthma (20) certainly warrants further investigation.
In the clinical context, bolus dispersion has been most frequently
expressed in terms of H for ease of computation and robustness (2, 4). When is computed, a cutoff is considered to
avoid noise from the bolus tail in the experimental curves, and typical cutoffs used in the past range from 5 to 20% (4). In a
study on healthy subjects, Brand et al. (5) stated that
their preliminary analysis had indicated that a 15% cutoff provided
least dependency of on the exhaled peak signal-to-noise ratio.
Neither in the present study nor in the smoker study (22)
did we observe consistent differences in variability between
25%, 15%, or 5%. The
good performance of 5% may have been due to the use of
interpolation polynomials of vs. VLD, as suggested by Anderson et
al. (3), rather than the use of data pooling into VLD
bins to obtain dispersion values for any given VLD level.
Saline bolus skew.
It is generally accepted that ventilation heterogeneity can lead to
increased bolus skew. According to Rosenthal (14), bolus dispersion and skew are expected to be affected by ventilation heterogeneity, although the study considered time constants and zero
initial lung volumes, which are difficult to relate quantitatively to
lung physiology. Darquenne and Paiva (8) introduced a
typical flow sequence that was thought to exist between
gravity-dependent lung regions, and they did not find a significant
effect on exhaled bolus characteristics, probably because of the
symmetry of flow sequencing between in- and exhalation. A
three-dimensional treatment of how aerosol boluses split and recombine
at bifurcations, instead of one-dimensional (8) or
compartmental (14) approaches, could help us better
understand bolus skew, even in the normal lung. However, in the absence
of more extensive simulation and experimental studies on bolus skew in
general, we interpret the observed skew behavior as follows.
Bolus skew of the normal lung is seen to decrease as a function of VLD
(Fig. 4; open triangles) probably because the conductive air spaces
induce some initial skew but the acinar air spaces, i.e., roughly
beyond 200 ml, do not introduce an additional source of skew, whereas
continues to increase (skew computation involves normalization by
3). Histamine challenge appears to bring about an
additional source of skew that is again confined mainly to the
conductive airways (VLD = 200 ml in Fig. 4; solid triangles).
Beyond VLD = 200 ml, skew curves before and after histamine
provocation show a parallel decrease over the remaining VLD range,
probably because the histamine boluses are subject to the attenuating
effect of the acinar space, as in normal lungs. In the smoker study
(22), in which the structural alteration introduced an
additional source of heterogeneity in the acinar spaces, a small but
significant sk increase was seen, but only for high VLD.
Rosenthal et al. (15) previously drew attention to the
need for more detailed modeling of the shape of the entire exhaled bolus to better understand bolus behavior in the lungs. Skew may carry
a crucial piece of information on whether possible first-in last-out
patterns of aerosol bolus spreading over lung units during inhalation
are symmetrically reversed on bolus recombination during exhalation.
Yet experimental bolus dispersion reports rarely include skew. In
normal adult subjects, Siekmeier et al. (19) obtained skew
values that decreased from ~1.4 (VLD = 200 ml) to ~0.7
(VLD = 800 ml), whereas in Brand et al. (5) skew
values remained more or less stable around 0.2 between VLD = 200 ml and 800 ml. Other observations in normal children (17)
showed that skew decreased from 0.23 to 0 between most shallow and most
peripheral boluses, and in a study on the effect of intrinsic particle
properties on bolus characteristics in beagle dogs (18)
skew actually varied from 1.5 to 0. In addition, the latter study
showed no dependence of skew on particle size between 0.5 and 2 µm.
The baseline data in Fig. 4 show that the decrease of skew with VLD
heavily depends on the cutoff that is used for skew computation.
However, Fig. 4 also shows that the overall pattern of skew increases
as a function of VLD after histamine is very similar for all cutoffs used.
Saline bolus and N2 washout-derived indexes of
ventilation nonuniformity.
It is interesting to note the difference between aerosol and gas
behavior in the particular case in which structural alteration induces
sequential filling and emptying of units subtended by the conductive
lung zone. In the case of aerosols, asymmetry between inspiratory and
expiratory flow patterns can increase aerosol bolus dispersion and skew
(14). In the case of gases, Scond increase is brought about by a combination of specific ventilation differences and expiratory flow asynchrony between these units. Yet
specific ventilation is only determined by average inspiratory flow and
therefore is insensitive to possible inspiratory flow sequencing
between units. Therefore symmetry of flow sequencing between inhalation
and exhalation does not affect the outcome for
Scond as it does for aerosol dispersion and
skew. From this viewpoint, the increased Scond
and aerosol bolus skew after histamine are complementary in suggesting,
respectively, the occurrence of asynchronous emptying and an
asymmetrical pattern between emptying and filling. Also in an effort to
relate aerosol- and gas-related measures of convective ventilation
heterogeneity, Brown et al. (6) found an association
between bolus dispersion and 133Xe washout-derived indexes
that are independent of breath-by-breath flow asynchrony between units.
Saline vs. latex aerosol bolus tests.
In the case of lung disease, it may be of considerable advantage to use
saline instead of oil droplets or latex aerosol. We chose to assess
dispersion and skew indexes derived from the saline bolus because these
indexes have been shown to be poorly sensitive to particle size
(9, 16, 18). In the smoker study (22), we
performed exhaustive testing on a healthy subject as an example to show
overall consistency between dispersion of saline and a nonhygroscopic
aerosol. Possibly, simultaneous measurement of nonhygroscopic 0.5-, 1-, and 2-µm as well as hypotonic, hypertonic, and isotonic aerosol
boluses in the same laboratory animals (possibly with induced lung
disease) could provide some new insights into the actual fate of saline
aerosols that is still very much under debate today (10).
The measurement of indexes such as mode shift or deposition that do
depend on particle size could then possibly be included to obtain an
"effective particle size" that droplets have during most of their
residence time in the lungs. The present study at least indicates the
potential of saline aerosol to provide consistent measurements
reflective of lung structure alteration at different lung depths.
In summary, and taken together with the data from the smoker study
(22), the present results demonstrate that the saline bolus dispersion test has the potential of monitoring lung structural change at different levels of the bronchial tree, provided that the
bolus tests are performed spanning a considerable VLD range and the
resulting aerosol traces are adequately analyzed. In the particular
case in which structural alterations induce additional bolus skew,
dispersion indexes must be used that include as much of the exhaled
bolus tails as possible. Besides the important result from the smoker
study (22), namely that the saline aerosol dispersion test
can be a sensitive tool to monitor structural change in the silent zone
of the lungs in which traditional lung function tests perform poorly,
the ability of the saline bolus dispersion to distinguish lung
structural alterations occurring in the proximal lung from those
appearing in the peripheral lung could enhance quality of diagnosis as
well as the therapeutic targeting of drugs for various lung diseases.
These are most often a combination of both proximal and peripheral lung
alterations, and in the two companion papers presented here we have
tried to isolate the effect of mild acinar and conductive airway alterations.
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ACKNOWLEDGEMENTS |
This study was financed by Actie Levenslijn by the Fund for
Scientific Research-Flanders (FWO) and the Federal Office for Scientific Affairs (program PRODEX).
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FOOTNOTES |
Address for reprint requests and other correspondence: S. Verbanck, AZ-VUB, Consultatie Pneumologie, Laarbeeklaan 101, 1090 Brussels, Belgium (E-mail: sylvia.verbanck{at}az.vub.ac.be).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 17 July 2000; accepted in final form 30 November 2000.
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