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1 Respiratory Division, Academic Hospital, Vrije Universiteit Brussel, 1090 Brussels; and 2 Laboratoire de Physique Biomédicale, Université Libre de Bruxelles, 1070 Brussels, Belgium
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ABSTRACT |
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We explored the possibility of using a saline aerosol for bolus dispersion measurements to detect peripheral airway alterations in smokers. Indexes of ventilation inhomogeneity in conductive (Scond) and acinar (Sacin) lung zones, as derived from the multiple-breath N2 washout (Verbanck S, Schuermans D, Van Muylem A, Noppen M, Paiva M, and Vincken W, J Appl Physiol 83: 1807-1816, 1997), were also measured. The saline bolus test consisted of inhaling 60-ml saline aerosol boluses to different volumetric lung depths (VLD) in the 1.1 liter volume above functional residual capacity. In the never-smoker group (n = 12), saline boluses showed bolus dispersion values consistent with normal values reported in the literature for 0.5- to 1-µm aerosols. In the smoker group (n = 12; 28 ± 9 pack years, mean ± SD), significant increases were seen on dispersion and skew of the most peripherally inhaled saline boluses (VLD = 800 ml; P < 0.05) as well as on Sacin (P = 0.007) with respect to never-smokers. Shallow inhaled boluses (VLD = 200 ml) and Scond did not reveal any significant differences between smokers and never-smokers. This study shows the consistent response of two conceptually independent tests, in which both saline aerosol and gas-derived indexes point to a heterogeneous distribution of smoking-induced structural alterations in the lung periphery.
N2 washout; smokers
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INTRODUCTION |
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IN RECENT YEARS, AEROSOLS have been introduced as a promising new diagnostic tool allowing noninvasive monitoring of lung structural changes in lung disease (3). When a small aerosol volume (bolus) is inhaled to a given volumetric lung depth (VLD), the dispersion of the recovered bolus depends, among other things, on the structure it has encountered on the way in and out of the lungs. The aerosol bolus dispersion technique is particularly attractive because it can potentially reflect lung structural changes at different levels of the lung, depending on whether the aerosol bolus was inhaled to peripheral (high VLD) or shallow lung depths (low VLD). The drawbacks of the existing bolus dispersion technique are that it generally requires the inhalation of oil droplets or latex aerosol and that, even in the case of these monodisperse nonhygroscopic aerosols, the experimental bolus dispersion data in normal subjects are as yet not fully understood. This is partly because of the lack of quantitative information on 1) the effect of the orolaryngeal pathway (18), which is thought to also introduce a gender-related contribution to bolus dispersion in humans (6), 2) the potential differential contribution from left and right lungs (2, 25), and 3) the actual effect of asynchronous emptying and filling of lung units (8, 17).
Despite these drawbacks, the bolus dispersion test seems to pick up even subtle lung structural changes (1, 5, 15, 22), and we therefore further explored the possibilities of the technique in the case of mild lung alteration. We have used an aerosol bolus dispersion test similar to the one previously employed by others (1, 5, 22) but substituted nebulized saline for latex microsphere (1) or oil droplet (5, 22) aerosols. The rationale for using saline was that, in the VLD range (200-800 ml) and particle range (0.5-1 µm) of interest for detection of lung structural change (1, 5, 22), bolus dispersion appears to be only poorly sensitive to aerosol particle size (9, 19, 21) and bears no causal relationship to deposition (1, 18, 22). As a consequence, dispersion of the exhaled bolus is still expected to be similar to that obtained with monodisperse nonhygroscopic aerosols in a similar size range. Even if the absolute bolus dispersion value obtained with saline aerosol varied somewhat from that obtained with, e.g., 1-µm latex aerosol, its ability to detect lung structural alteration may persist as long as dispersion is evaluated by consistently using the same aerosol. The use of saline for bolus dispersion measurements could make this test more attractive for application in patients.
Because the potential of the aerosol bolus dispersion technique lies in the ability to detect structural change at different lung depths, we complemented the proposed saline bolus dispersion technique with a test of ventilation distribution that can also distinguish between alterations at the level of proximal and peripheral air spaces, i.e., a multiple-breath N2 washout test. Indeed, the normalized phase III slope analysis of the N2 washout (28) yields two independent measures of conductive and acinar ventilation heterogeneity (Scond and Sacin, respectively). We have previously used this technique in a number of clinical settings, such as during bronchoprovocation in hyperresponsive subjects (29), in stable chronic obstructive pulmonary disease (COPD) patients (28), and in asthmatic patients before and after bronchodilatation (27). In these populations, the observed increases in Scond and Sacin were substantial with respect to normal, and it could therefore be expected that these indexes would also pick up more subtle lung alterations and, more importantly, locate them in the conductive or acinar zone of the airway tree.
We applied the saline bolus dispersion and the N2 washout techniques in two groups of subjects who were expected to show distinct structural alterations at different lung depths. A first group consisted of asymptomatic smokers, in which we expected a priori a combination of conductive and acinar airway alteration on the basis of previous N2 washout results in COPD patients (28). A second group involved nonsmoking normal subjects before and after 2-mg histamine provocation, for which we have previously shown only a conductive airway response (29). The smoker study will be presented here, and the provocation study will be outlined and discussed in the companion paper (26).
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MATERIALS AND METHODS |
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All subjects participating in this study were recruited on a voluntary basis among hospital and laboratory personnel and had never undergone pulmonary function testing before. None of the subjects took any medication. Smokers (S) with at least 10 pack years (py) and never-smokers (NS) were recruited until the following criteria were fulfilled: 1) at least 10 subjects per group, 2) similar age, 3) similar proportion of female and male subjects, and 4) similar functional residual capacity (FRC). This yielded 12 subjects in the S group (5 women/7 men; 39 ± 6 yr; all values given as means ± SD) with a smoking history of 28 ± 9 py and 12 subjects in the NS group (4 women/8 men; 36 ± 6 yr). Smokers were asked to refrain from smoking in the 4-h period preceding the test procedure. Within the time span of ~1 h, each subject performed a set of lung function tests, three N2 washout tests, and a series of ~15 aerosol dispersion tests.
Lung function parameters were obtained by means of standardized lung
function laboratory equipment (SensorMedics Model 2200, Bilthoven, The
Netherlands). They included 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], and a single-breath carbon monoxide diffusing capacity test
[for diffusing capacity (DLCO) and for
DLCO divided by alveolar volume
(KCO)]. For the multiple-breath N2
washout and aerosol bolus tests, the subjects were aided by a
computer-controlled breathing assembly, in which data acquisition,
pneumatic valve control, and visual feedback to the subjects are
handled by Labview software (National Instruments, Austin, TX). The
schematic representation in Fig. 1
essentially shows the setup in its configuration for the aerosol bolus
tests, and only part of it is used for the N2 washout
tests. Previous work reports the detailed functioning of the equipment
to adequately perform the aerosol bolus experiments (23)
and N2 washout experiments (29). Both
procedures can be briefly summarized as follows.
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Saline bolus and N2 washout tests: experimental setup and procedure. For the saline bolus procedure, all valves depicted in Fig. 1 were operational, but the inspiratory bag was blocked. The black box in front of the subject's mouth represents a laser photometer (PARI, Starnberg, Germany) to measure the aerosol, and the pneumotachograph in the wall of the bag-in-box was used to monitor all respiratory volume changes. Photometer and volume data acquisition frequency were 100 Hz. The aerosol reservoir, i.e., the 60-ml tubing between valves 2 and 3, was placed at a right angle with respect to the mouthpiece and photometer to achieve a blunt aerosol profile of the bolus on its passage through the photometer (23). The aerosol to be fed into the 60-ml reservoir tube between valves 3 and 2 was obtained by nebulization of normal saline (0.9% NaCl) using an Acorn II (Marquest Medical Products, Englewood, CO) with a driving pressure of 1.5 bar. When measuring the wet aerosol sampled from the 60-ml reservoir by means of a particle counter/sizer (PCS2000, PALAS, Karlsruhe, Germany), we obtained an aerosol number concentration of ~106 droplets/cm3 with 52% of the aerosol volume in the respirable range (1-5 µm) comparable to the 45% reported by others for this particular nebulizer (14). Of more relevance to the present experiments, however, 87% of the total number of droplets were seen to be sized under 1 µm.
The saline bolus test started with some tidal clean air breaths, i.e., inhalation from the box [via valves 5, 4, nonreturn (NR), and 1] and exhalation into the expiratory bag (via valves 1 and NR). Simultaneously, saline was nebulized into an open circuit through the 60-ml aerosol tube between valves 3 and 2. The actual bolus test then started at FRC with clean air inhalation from the box (via valves 5, 4, NR, and 1) until a predefined volume above FRC was reached, and valves 1, 2, and 3 were reversed so that the aerosol bolus volume between valves 2 and 3 could be inhaled, followed by clean air beyond valve 3 from the box via valve 5. Inhalation continued until volume reached the target inspiration volume of 1.1 liter above FRC. At end-inspiration, further inspiration was prevented by switching valves 1 and 4 to the inspiratory bag pathway, which was blocked in the aerosol setup configuration. The subject then exhaled via valves 1 and NR into the exhalation bag to residual volume. The VLD to which each bolus was delivered corresponded to the actual air volume after the aerosol bolus until end-inspiration. One bolus test sequence consisted of having each subject perform a series of ~15 bolus tests with VLD targeted between 200 and 800 ml. In this test sequence, the subject was not given a visual feedback but was coached by the operator. A few dry runs enabled the subject to practice a typical aerosol test, with particular attention to a steady inspiratory flow rate and a prompt reaction at end-inspiration while avoiding exaggerated expiratory flow in the initial phase of expiration. Bolus tests were considered acceptable when inspiratory and expiratory flow rates were between 250 and 350 ml/s and end-inspiratory breath hold was <1 s. One subject from the NS group performed additional bolus tests using either saline or 1.07 ± 0.01µm latex particles (Duke Scientific, Palo Alto, CA) as the inspired bolus aerosol. The 1-µm latex aerosols were prepared from a 10% solid aqueous suspension and diluted in pure water (aqua ad iniectabilia, Braun, Melsungen, Germany) for nebulization (Acorn II, Marquest Medical Products). Finally, the nebulizer output was dried in a silica gel tunnel before being delivered to the aerosol reservoir between valves 2 and 3. In this NS subject, ~45 saline and latex bolus dispersion tests were accumulated in the VLD range 200-800 ml. For the N2 washout procedure, valves 2 and 3 were removed, and the disconnected sides of valves 5 and 1 were blocked. The black box in front of the subject's mouth now represents the N2 analyzer (P. K. Morgan, Kent, UK), and volume was again obtained from the pneumotachograph in the wall of the bag-in-box. N2 concentration and volume were now acquired at 25 Hz. The washout procedure started with tidal air breathing, with inhalation from the box via valves 5, 4, NR, and 1, and exhalation via valves 1 and NR into the expiratory bag. During a given exhalation to FRC, valve 4 was switched to substitute the air from the box by the pure O2 in the inspiratory bag for all subsequent inhalations. The subjects were given a visual feedback of inspiratory volume to target 1-liter inspirations, whereas expiration back to FRC occurred spontaneously. The N2 washout test continued until the number of 1-liter O2 breaths yielded at least six lung turnovers, where one lung turnover (TO) is defined as tidal volume divided by FRC (for a subject with an FRC = 3.5 liters, the N2 washout test will consist of at least 21 breaths). At the end of the washout test, the subject is instructed to exhale to residual volume.Saline bolus analysis.
Photometer signals were normalized to inspiratory peak concentration
and plotted against cumulative inspired and expired volume as in Fig.
2, representing typical dispersion traces
for saline and 1-µm latex boluses inhaled to similar VLD (i.e., the
volume difference between inspiratory peak and end of inspiration).
With an inspiration of 1,100 ml and peak inspiration ~650 ml, the
boluses in Fig. 2 corresponded approximately to VLD = 450 ml.
Aerosol bolus dispersion traces such as these were analyzed in terms of half-width (H), standard deviation (
) and skew (sk), using the standard formulas as specified in Brand et al. (4).
Briefly, H is given by the square root of the difference
Hex2
Hin2,
where Hin and Hex are inhaled and exhaled bolus
half-width, determined as the volumetric width at half-inspiratory or
half-expiratory peak height (see the Hex indications in
Fig. 2). In analogy to H,
is given by the square root of the
difference
ex2
in2, i.e., of the second moment of exhaled
and inhaled boluses. sk was computed as the third moment of the exhaled
bolus divided by
3. The moment analyses for
and sk
computation are usually done by using a cutoff concentration for the
integrations involved (1, 4). Brand et al.
(4) recommended that integration of the inhaled and
exhaled boluses should only involve aerosol concentrations >15% of
the exhaled bolus peak concentration. We computed
and sk, using 5, 15 and 25% cutoffs that will be specified in the subscript (e.g.,
25%,
15%, or
5%, respectively). All dispersion indexes were set out against VLD, fitted
with a third-order polynomial, and interpolated to obtain values for
VLD = 200, 400, 600, and 800 ml as was done in Anderson et al.
(1).
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N2 washout analysis.
The N2 washout tests were first used to determine the
subject's FRC and the Fowler dead space of the first breath
(VDF). The actual N2 washout analysis and
theory at the basis of the indexes of Scond and
Sacin have been extensively described elsewhere
(24, 29). We only reiterate here the computation method,
which started by plotting N2 concentration as a function of
volume in each expiration, determining its N2 phase III
slope, and normalizing each consecutive N2 phase III slope
by the corresponding mean expired N2 concentration. If
normalized slope is then plotted as a function of TO, this results in
curves such as those shown in Fig. 3,
that is, progressively increasing normalized slopes as a function of
TO. The open and closed triangles in Fig. 3 correspond to the pooled,
normalized slope curves of the NS and S in this study. Figure 3 also
illustrates how indexes Scond and
Sacin are derived; note, however, that actual Scond and Sacin
computations were done on the average of three normalized slope curves
obtained in each subject. Scond is actually defined as the normalized slope difference per unit TO in the part of
the N2 washout in which only conductive airways are known to contribute to an increase normalized slope, i.e., between TO = 1.5 and TO = 6. This conductive airway contribution to the
increasing normalized slopes should extrapolate to a zero slope for
TO = 0. This is not the case (see also Fig. 3), and in fact the
normalized slope of the first exhalation mainly originates in the more
peripheral acinar airways. Therefore, Sacin is
determined by subtracting from the slope of the first breath the part
that is attributed to the conductive airways, i.e.,
Scond multiplied by the TO value of the first
breath.
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RESULTS |
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Table 1 summarizes lung function and
N2 washout indexes obtained in the NS and S groups. The S
group had significantly lower values on 75% FVC end-expiratory flow
and on DLCO (but not on KCO) with respect to the NS group. By
contrast, the slightly lower FEV1 and FEV1/FVC
values in the S group did not reach significance. There was a
significantly larger Sacin in the S vs. NS
groups, whereas the slightly larger average
Scond value in the S group was not significantly
different from that obtained in the NS group. Fowler dead space was
also similar between both groups. Finally, Table 1 shows comparable FRC
values in both groups, discarding the possibility that FRC differences
could have been at the origin of the presence or absence of differences
in N2 washout or bolus dispersion indexes among groups.
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Figure 4 represents
extensive sets of 1-µm latex and saline bolus dispersion data
obtained from a NS subject. In the VLD range considered, saline and
1-µm latex showed similar trend lines on all depicted bolus
dispersion indexes as a function of VLD. This was true for bolus
dispersion in terms of H (Fig. 4A) or
25% or
5% (Fig. 4B) and also sk25% or
sk5% (Fig. 4C) despite the larger variability
of the latter index;
15% and sk15% are not
depicted in Fig. 4, B and C, for clarity.
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By interpolation of the third-order polynomial trend lines, such as
those obtained from the saline data in Fig. 4, a set of H,
, and sk
values was obtained for VLD = 200, 400, 600, and 800 ml for each
subject under study. Comparison of H,
, and sk values from NS and S
groups could then be done for each VLD level (1). The
resulting average H (Fig. 5) and average
25%,
15%, and
5% (Fig.
6) or sk25%,
sk15%, or sk5% (Fig.
7) per VLD level
obtained from the NS and S groups are represented by the open and
closed symbols, respectively. H was significantly different between NS
and S groups only for the most peripherally inhaled boluses (VLD = 800 ml; Fig. 5). Although
(Fig. 6) mimicked H behavior, actual
significance of the
difference between NS and S groups depended on
the cutoff that was used, with the 5% cutoff obtaining a significant
difference for VLD = 800 ml. The sk was also significantly greater
in smokers in the higher VLD range, with a significant difference for
VLD = 600 ml and 800 ml or only for VLD = 800 ml, depending
also on the cutoff that was used for sk computation.
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On the basis of previous observations by others (1, 5, 22)
in which smokers were essentially characterized by a steeper increase
of dispersion between shallow and deep VLD levels, we also computed 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, in which smokers showed a
significantly larger dispersion increment between 200 and 800 ml for
H as well as for 
(for cutoffs 5 and 15%).
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DISCUSSION |
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The smokers under study present the particular feature
that with respect to age- and sex-matched nonsmokers, they show
abnormal acinar ventilation distribution (significantly greater
Sacin) in the absence of conductive ventilation
distribution abnormality (no significant Scond
change). The possibility that the absence of
Scond change in the present study could have
been due to a lack of Scond sensitivity is
contradicted by the fact that twofold Scond
increases are seen during histamine provocation for a FEV1 decrease of only 11% (29), a result that was reproduced
in the companion study (26). The severity of the acinar
ventilation impairment observed in the S group with an average 28-py
smoking history (Sacin = 0.11 ± 0.04 liter
1) is largely inferior to that previously reported
in patients with overt COPD and a 16-py longer smoking history
(Sacin = 0.43 ± 0.18 liter
1) (28). In fact, previous studies in
COPD and asthmatic patients (27, 28) had always shown a
combination of impaired ventilation distribution at the level of both
conductive and acinar airways (abnormal Sacin
and Scond values). The observation that the
structural alterations in our smokers are confined to the acinar lung
zone (only Sacin increased) makes the S group
even more attractive for the study of aerosol bolus dispersion at
different lung depths.
With respect to aerosol behavior in smokers, our points of comparison
are the early work by McCawley and Lippmann (15) and more
recent studies by Siekmeier et al. (22), Anderson et al. (1), and Brand et al. (5). These bolus
dispersion studies made use of 0.5µm triphenyl phosphate
(15), 1-µm latex particles (1), or 0.8-µm
oil droplets (5, 22) with a variety of maneuvers (e.g.,
starting bolus inhalation from residual volume or FRC) and different
analyses of bolus dispersion (using
with different cutoffs and/or
H). Despite these methodological differences, all three studies
indicated an increased bolus dispersion in smokers vs. nonsmokers for
the more peripherally inhaled boluses. In the present study, the same
conclusion is reached by using a saline aerosol. Indeed, the saline
bolus shows a pattern of increased H (Fig. 5) and increased
(Fig.
6) in the S compared with the NS group as VLD increases. In fact, the
rate of H increase with VLD (Table 2) was significantly larger in the S
group [
H = 502 (S) vs. 377 ml (NS); P = 0.03], and
showed statistically significant differences between NS
and S only if 
15% (P = 0.03) and 
5% (P = 0.01) were used (although
the mean differences in 
25%, 
15%,
or 
5% between NS and S groups were all of the order
of 30 ml; Table 2). Given these subtle differences between the various
measures of bolus dispersion in the S group, they all indicated
structural change in the lung periphery consistent with the abnormal
Sacin values obtained in this group (Table 1).
The results in our S group and the results in Brand et al.
(5) diverge somewhat from those obtained by Siekmeier et
al. (22) and Anderson et al. (1) in that
separation between smokers and nonsmokers in the latter two studies
occurred for boluses inhaled as shallow as VLD = 400 ml in terms
of H or even VLD = 200 ml in terms of
. Neither Brand et al.
(5) nor the present study (Figs. 5-6) revealed any
significant differences in bolus dispersion (H or
) between NS and S
groups at shallow lung depth (VLD = 200 ml). We suspect that the
increased dispersion at shallow lung depths of the smokers in the
studies of Anderson et al. and Siekmeier et al. may be due to
additional presence of conductive airway alterations. Their smoker
populations had average smoking histories of 41 (1) and 44 (22) py, respectively, in contrast to the ~20 py
estimated from the report of Brand et al. and 28 py in our S group.
Table 1 indicates that our S group showed a tendency to increase
Scond, but this increase failed to reach significance. Anderson et al. also found an increased
N2 phase III slope in their smoker group, but because it
derived from a vital capacity single-breath washout maneuver it is
difficult to distinguish conductive from acinar lung zone
contributions, probably because of the influence of airway closure on
phase III slope (10).
Finally, Fig. 7 shows that sk of the peripheral boluses (VLD = 800 and/or 600 ml, depending on cutoff) was increased in S vs. NS groups. This is again consistent with a smoke-induced acinar lung structure alteration, but it also strongly suggests that the structural alterations were probably heterogeneously distributed in the lung periphery. Such structural heterogeneity could indeed lead to nonreversible first-in last-out bolus distribution patterns, which would increase sk (17). The smokers in the Siekmeier et al. (22) study also showed a consistent increase in sk. However, this occurred at all VLD levels between 200 and 800 ml, again consistent with the presence of conductive airway alterations in Siekmeier et al's smoker group (22). Unfortunately, the other bolus dispersion studies in smokers (1, 5, 15) did not report sk.
Saline bolus- and N2 washout-derived indexes of ventilation nonuniformity. It is interesting to explore the underlying theory of N2 washout and bolus dispersion analysis to understand how gas and aerosol transport mechanisms operating in the same lung structure can be held responsible for the increased Sacin and increased bolus dispersion in the deep lung (high VLD). On the basis of N2 washout theory (11, 24) and experiments (29, 28), Sacin originates from convection-diffusion interaction at the acinar level, where gas convective and gas diffusive transport are of the same order of magnitude, and Sacin may be considered independent of gas-mixing events occurring proximal to the acinar lung level. Also, Sacin heavily depends on the asymmetry of the acinar lung structure, and a perturbation in the volumetric or cross-sectional asymmetry of parallel intra-acinar units can modify Sacin. In Fig. 3, this is reflected by an upward shift of the entire normalized slope curve of the S group with respect to the NS group. Recent simulation work has shown that Sacin is sensitive not only to structural asymmetry at any given intra-acinar branch point but even more so to heterogeneity in asymmetry among parallel intra-acinar branch points (11).
The parallel heterogeneity of lung structure (and alteration thereof in mild lung disease) was also the effect that was thought to allow efficacious detection of lung structural change by means of aerosol bolus dispersion (1, 15). In the context of studies in smokers, McCawley and Lippmann (15) and Anderson et al. (1) pointed to the crucial role of heterogeneity in structural alterations that would introduce different time constants when aerosol boluses distribute over and recombine from peripheral lung units. In mild lung disease such as shown here, in which FEV1 is not significantly affected (Table 1), bolus dispersion was indeed expected to increase at any given lung depth owing to an increased heterogeneity in airway structure rather than to a gross overall structure alteration. The combined information from increased Sacin and increased dispersion of VLD = 800 ml boluses strongly suggests that parallel heterogeneities in the peripheral lung structure constituted the link between the performance of saline bolus and N2 washout-derived indexes of ventilation nonuniformity in the smokers under study.Aerosol dispersion tests with saline. Previous aerosol bolus dispersion studies in smokers made use of 0.5µm triphenyl phosphate (15), 1-µm latex particles (1) or 0.8-µm oil droplets (5, 22). We used a nebulized saline aerosol that is generally referred to as unstable. However, in a recent editorial, Finlay and Smaldone (12) suggested that this assumption of aerosol instability is essentially based on studies using dried salt particles and may be exaggerated. These authors argued that, in the case of a wet aerosol cloud as used here, a two-way coupled hygroscopic effect, which is expected to stabilize hygroscopic aerosols against size changes, needs to be considered. In addition, isotonic (as opposed to hypotonic or hypertonic) aerosols are supposedly least subject to change in the airway tree (13, 16). Persons et al. (16) suggested the possibility of a relatively rapid growth in the mouth and trachea after the shrinkage of the saline aerosol in the breathing assembly through evaporation. Finally, Schmehl et al. (20) even used saline aerosols for single-breath deposition measurements by introducing a growth correction factor that was considered constant beyond the dead space. Although such a correction is not readily applicable to a bolus experiment, the study of Schmehl et al. points to the fact that saline aerosols can represent effects that are directly related to those observed with a nonhygroscopic aerosol.
For the saline bolus in Fig. 2, the area under the expiratory bolus curve exceeds that under the inspiratory bolus curve, in contrast to what is observed for the 1-µm latex bolus. This illustrates that in our saline bolus experiments some degree of hygroscopic growth occurred between saline bolus in- and exhalation. Considering, however, that photometer signal amplitude varies approximately with the square of particle diameter, this effect does not appear to be dramatic. On the other hand, not all particles contained in the inspiratory bolus contribute to the exhaled bolus signal and, in fact, the inspiratory bolus has very little impact on the exhaled H values (23). For all these reasons, saline bolus dispersion was expected to reflect comparable behavior to that usually observed with particles in the 0.5-1µm range. Besides the general agreement in an exhaustive test sequence using either saline or 1-µm latex on a subject from the NS group (Fig. 4), the H values obtained for different VLD levels in our NS group (Fig. 5) were actually consistent with the ranges of values encountered in the literature using nonhygroscopic aerosols. Combing data from various previous reports (4, 5, 7, 18) using nonhygroscopic aerosols in the 0.5-1µm size range, we found that H values for healthy subjects ranged 180-300 ml for VLD = 200 ml and 400-600 ml for VLD = 800 ml. In summary, we presented N2 washout and saline bolus dispersion results that are consistent with a pattern of smoking-induced structural alteration in the lung periphery. Both gas- and aerosol-related tests were obtained by having the subjects breathe in the same volume ranges (between FRC and 1 liter above FRC), thereby avoiding airway closure effects. The analyses of N2 washout and saline aerosol bolus tests rely on totally different theoretical concepts of how gas or aerosol ventilation heterogeneities are identified at different lung levels. In the particular case of acinar structure changes, the present paper indicated the potential of saline dispersion as a strictly noninvasive probe for early detection of lung structural alterations.| |
ACKNOWLEDGEMENTS |
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We are grateful to Dr. J. D. Blanchard for comments on our preliminary saline bolus results in smokers, which made us reassess the way we look at bolus data in general.
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FOOTNOTES |
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This study was financed by Actie Levenslijn by the Fund for Scientific Research-Flanders (FWO) and the Federal Office for Scientific Affairs (program PRODEX).
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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