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1 Department of Medicine,
University of California, San Diego, La Jolla, California 92093-0931;
2 Department of Pneumology
Akademisch Ziekenhuis, ABSTRACT Lauzon, Anne-Marie, G. Kim Prisk, Ann R. Elliott, Sylvia
Verbanck, Manuel Paiva, and John B. West. Paradoxical helium and
sulfur hexafluoride single-breath washouts in short-term vs. sustained
microgravity. J. Appl. Physiol. 82(3):
859-865, 1997.
phase III slope; inhomogeneity; convection; diffusion
INTRODUCTION HELIUM (He) and sulfur hexafluoride
(SF6) have different molecular
masses (4 and 146, respectively) and gaseous diffusion coefficients
(~6:1) and are therefore spread differently in the lung periphery
(7). Incorporation of tracer concentrations of He and
SF6 in the test-gas mixture in the
performance of single-breath-washout (SBW) tests allows investigation
of diffusion-dependent ventilatory inhomogeneity in the lung periphery.
In particular, the difference between the phase III slopes of He and
SF6 has been used as an index of
peripheral gas mixing in normal and diseased lungs (15, 19).
In normal human subjects, the phase III slope of
SF6 is steeper than that of He,
and therefore the SF6-to-He slope
difference is positive (4). A combination of two mechanisms is thought to account for this phenomenon. First, diffusion tends to equilibrate gas concentration differences in the lung periphery, where distances are small. Due to its higher diffusivity, He concentration
inhomogeneities are more easily abolished than those of
SF6, therefore reducing its slope
with respect to SF6. The second
factor contributing to the larger slope of
SF6 is
diffusion-convection-dependent ventilatory inhomogeneity (DCDI), which
is introduced at branch points subtended by unequal volumes or unequal
cross-sectional areas (14). DCDI occurs in the zone of the lungs in
which convection and diffusion are of comparable magnitude, which in
humans is at, or peripheral to, the acinar entrance, at the level of
the diffusion fronts (14). Because of its lower diffusivity, the
diffusion front of SF6 is situated
more distally than that of He, and therefore the two gases are
representative of ventilatory inhomogeneity occurring at different
levels of the lung periphery. In humans, the DCDI mechanism generates a
greater alveolar slope for SF6 than for He because asymmetry of the lungs is greater in the peripheral part of the acinus (20).
This acinar-level ventilatory inhomogeneity has always been thought to
be gravity (G) independent. Thus it was expected that in SBW
measurements performed in microgravity (µG) the slopes of He and
SF6 would be reduced by a similar
amount, due to the elimination of their common gravitationally induced
convection-dependent inhomogeneity (gravitational CDI). However, during
a recent spaceflight study [Spacelab Life Sciences (SLS)-2
], we showed that in µG the difference between the
SF6 and He slopes was abolished
(17). Furthermore, when the subjects held their breath for 10 s at
total lung capacity (TLC), the SF6
slope became flatter than that of He. This suggested either alterations
in acinar conformation, perhaps due to changes in blood volume
distribution, or alterations in cardiogenic mixing as a result of the
removal of G.
As part of a study performed to elucidate the mechanisms by which the
SF6-to-He slope difference varied
between 1 G and µG, we repeated the SBW tests during short (~27-s)
periods of µG provided by parabolic flight profiles aboard a National
Aeronautics and Space Administration (NASA) KC-135 µG research
aircraft. Contrary to the results obtained during the spaceflight
study, the SF6-to-He slope
difference increased during short periods of µG.
METHODS
During single-breath washouts in normal gravity (1 G), the phase III slope of sulfur hexafluoride
(SF6) is steeper than that of
helium (He). Two mechanisms can account for this:
1) the higher diffusivity of He
enhances its homogeneous distribution; and
2) the lower diffusivity of
SF6 results in a more peripheral
location of the diffusion front, where airway asymmetry is larger.
These mechanisms were thought to be gravity independent. However, we
showed during the Spacelab Life Sciences-2 spaceflight that in
sustained microgravity (µG) the
SF6-to-He slope difference is
abolished. We repeated the protocol during short periods (27 s) of µG
(parabolic flights). The subjects performed a vital-capacity
inspiration and expiration of a gas containing 5% He-1.25%
SF6-balance
O2. As in sustained µG, the
phase III slopes of He and SF6
decreased. However, during short-term µG, the
SF6-to-He slope difference
increased from 0.17 ± 0.03%/l in 1 G to 0.29 ± 0.06%/l in
µG, respectively. This is contrary to sustained µG, in which the
SF6-to-He slope difference decreased from 0.25 ± 0.03%/l in 1 G to 
0.01 ± 0.06%/l
in µG. The increase in phase III slope difference in short-term µG
was caused by a larger decrease of He phase III slope compared with that in sustained µG. This suggests that changes in peripheral gas
mixing seen in sustained µG are mainly due to alterations in the
diffusive-convective inhomogeneity of He that require >27 s of µG
to occur. Changes in pulmonary blood volume distribution or cardiogenic
mixing may explain the differences between the results found in
short-term and sustained µG.
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Data analysis. The data were analyzed by using the techniques applied to the SLS-2 spaceflight data (17). Briefly, slopes of gas concentration vs. volume were normalized by considering the pretest concentration as 100% and the inspired concentration as 0%. This results in positive phase III slopes for all gases. Phase III slopes of gas concentrations vs. volume were estimated by an iterative procedure with the use of linear regression. The beginning of phase III was marked by choice of a point beyond the end of phase II. A point marking the end of phase III was then tentatively chosen, and linear regression was performed between these two points. The results of the regression were displayed on the actual data. If the best fit line from the linear regression showed a new end (the point at which the data remained above the regression line), the new point was chosen as the end of phase III. The end point of phase III was repeatedly chosen in this manner until no more change in its position resulted (see Ref. 8 for a more detailed explanation of this analysis technique). In the analysis of the spaceflight data, the tests in which the inspired and expired VC differed by >5% were rejected. In the present study, the test maneuver was more difficult to accomplish because it occurred at the time of changes in G levels. For that reason, we extended the exclusion criteria to 7% difference between inspiratory and expiratory VC. Guy et al. (9) have demonstrated during previous experiments aboard the KC-135 aircraft that barometric pressure changes of 0.8 mmHg/s for 8 s induced an error in VC measurements of ~50 ml. In the present experiment, the expiratory time was, at most, 15 s, and therefore the error resulting from the changes in barometric pressure would be ~100 ml. Such an error in VC will result in a <3% error in phase III slope in all gases in our smallest subjects (smallest subject's VC = 3,500 ml, error in VC = 100 ml/3,500 ml = 2.9%). The magnitude of this error is exceeded by the variability of the measurements, and so no attempt was made to correct for the changing barometric pressure in the aircraft. Statistical methods. The same statistical procedure was followed as that used in the spaceflight study (17). Subjects acted as their own controls. Statistical analysis was performed by using Systat version 5.0 (Systat, Evanston, IL). Data were grouped according to subject and position (1 G/µG), and a two-way analysis of variance was performed. Post hoc testing by using Bonferroni adjustment was performed to determine significance levels in cases in which there were significant F-ratios. Significance was accepted at the P < 0.05 level, and the results were expressed as means ± SE.
RESULTS
The phase III slopes of He and SF6
decreased during the µG phases of the parabolic flights compared with
the measurements at 1 G. The average slope of He and
SF6 for all subjects in 1 G and
µG is shown in Fig. 2. In 1 G, the phase
III slope of He was 0.88 ± 0.06%/l and that of
SF6 was 1.07 ± 0.08%/l. In
µG, the phase III slope of He decreased by 66%
(P < 0.01), whereas that of
SF6 decreased by 37%
(P < 0.01). In Fig.
3, the results of the parabolic flights
(short-term µG) are compared with those from the spaceflight study
(sustained µG) (17). During spaceflight, the phase III slope of He
decreased by 28%, whereas the phase III slope of
SF6 decreased by 46%. Thus the
pattern of decrease of the phase III slope of He was different during
short-term µG from that during sustained µG. As shown in Fig.
4, the
SF6-to-He slope difference fell
from 0.25 ± 0.03 to 0.01 ± 0.06%/l during sustained
µG, whereas during short-term µG in the parabolic flights the
SF6-to-He phase III slope
difference rose from 0.19 ± 0.03%/l in 1 G to 0.37 ± 0.05%/l
in µG (P < 0.01). It can be seen
from Figs. 2, 3, 4 that the major difference between the short-term and sustained µG results was the decrease in He slope from 1 G to
µG. Whereas the decrease in SF6
slope was similar in short-term compared with sustained µG (37 vs.
46%), the decrease in He was considerably larger in short-term
compared with sustained µG (66 vs. 28%).
) and SF6 (
) from
spaceflight mission, subjects standing in 1 G and during sustained µG, and from short-term µG study, subjects sitting in 1 G and during short-term µG.
* SF6 slope significantly
different from that of He, P < 0.05.
Individual data from the short-term µG-exposure study are shown in
Fig. 5. All subjects exhibited an increase
in SF6-to-He phase III slope
difference in µG, in strong contrast to the results from the
sustained µG study, in which all subjects showed a decrease (17). Of
particular interest is subject 8, who
participated in the measurements of both the spaceflight mission and
the parabolic flights. The filled circles in Fig. 5 show the
SF6-to-He phase III slope
difference for subject 8 during the
short-term µG study, and the filled squares show data from the same
subject during the sustained µG study. This subject's
SF6-to-He phase III slope difference was virtually identical in the baseline measurements performed before spaceflight and in the baseline measurements performed
in this study. His SF6-to-He phase
III slope difference was essentially reversed in sustained µG,
decreasing from 0.17 ± 0.06%/l in 1 G to 0.11 ± 0.10%/l in µG. In contrast, during the short periods of µG on the
aircraft, this subject's
SF6-to-He phase III slope
difference (Fig. 5, filled circles) increased from 0.21 ± 0.01%/l
in 1 G to 0.30 ± 0.10%/l in µG (not significant).
,
Phase III slope difference in 1 G and µG for subject
8 during parabolic flight study; 
, same subject's
data during sustained µG study; 
, means for 1 G
(left) and µG
(right). * Significantly
different from 1 G (subjects in sitting position),
P < 0.05.
DISCUSSION
The major finding of this study is that, although the slopes of both He and SF6 decreased during short-term µG, the abolition of the SF6-to-He slope difference observed during sustained µG was not reproduced. Indeed, in short-term µG the SF6-to-He phase III slope difference actually increased. This increase in the phase III slope difference was introduced by a considerably larger decrease in the He phase III slope in short-term compared with sustained µG.
SF6-to-He phase III slope difference. Whereas the phase III slope of N2 has traditionally been used to quantify whole lung ventilation inhomogeneity (6), the difference between the He and SF6 phase III slopes can be used as an index of peripheral gas mixing in normal and diseased lungs (15, 19). Subtraction of the He slope from the SF6 slope allows the elimination of the convective component common to both gases, retaining only the peripheral gas-mixing component. Because G was thought to induce only changes in the convective distribution of gas in the lung, we expected the SF6-to-He phase III slope difference to be essentially independent of G. However, during the sustained µG study (17), we observed an abolition of the SF6-to-He slope difference and attributed this to either generalized changes in acinar geometry or changes in cardiogenic mixing in the lung. In either case, the exact mechanism of these changes was unclear. Furthermore, we were unable to determine whether the changes we observed were due to a relatively greater flattening of the phase III slope for SF6 or to a lack of flattening of the He slope with respect to SF6. If the effect were on SF6, the implication would be that the alterations introduced by exposure to µG would be more peripherally located as opposed to an effect on He, which would imply more central alterations. In the present study, the pattern of reduction of the He slope with respect to SF6 observed in short-term µG was completely different from what was previously seen in sustained µG (17). In both conditions, the SF6 slope was decreased by similar amounts (37% in short-term µG, 46% in sustained µG) (Fig. 3), but the reduction in the He slope was much greater in short- term than in sustained µG (66% in short-term µG, 28% in sustained µG). This markedly different behavior in short-term vs. sustained µG is clearly not an effect of a different subject population. In sustained µG, all four subjects studied showed a decrease in SF6-to-He slope difference in µG compared with 1 G. In the present study, all eight subjects showed an increase in SF6-to-He slope difference in µG compared with 1 G (Fig. 5). This is further emphasized by the results of subject 8, who participated in both studies. In 1 G, this subject's SF6-to-He slope difference was comparable to that seen in the 1-G control data collected for the sustained µG study. The small difference (which is not statistically significant) is probably due to the different inspiratory and expiratory flow rates used in the two studies and to the fact that control data for this study were collected for subjects sitting in a posture that mimicked the position in the aircraft, as opposed to the standing position used for the control measurements of the spaceflight study. However, subject 8, who exhibited a marked decrease in SF6-to-He slope difference in sustained µG, showed an increase in this measurement when the studies were performed in short-term µG. Previous single-breath test studies in µG. Parabolic flights have been shown before to be a reasonable model of sustained weightlessness for SBW tests of lung function. Michels and West (12) demonstrated that most parameters representing topographical inequality of ventilation (cardiogenic oscillation amplitude, phase IV height, closing volume) were greatly decreased in the performance of N2 SBW tests during the µG phases of parabolic flights. They did not, however, show a decrease in N2 phase III slope when the whole test maneuver was performed in µG, but that was attributed to the higher flow rates used in µG compared with those used in 1 G, allowing the whole test to be done during the short µG period. Inspiratory flow rate influences the position of the front of the inspired (and resident) gas and thus affects the phase III slope (5). When the test inspiration was performed in µG at the same flow rate as that used in 1 G and the expiration took place during the 1.8-Gz period, it showed a decrease in N2 phase III slope. The results that Michels and West (12) obtained during parabolic flights were, therefore, accurate predictions of the subsequent results obtained in sustained µG during the SLS-1 mission (8). Along with decreases in cardiogenic oscillation amplitude, phase IV height, and phase IV volume, Guy et al. (8) showed that, during the SLS-1 mission, in sustained µG, the N2 phase III slope was reduced by ~22% of its 1-G value. This was attributed to the removal of gravitational CDI. Our predictions for the SLS-2 mission, in which He and SF6 were added to the test gas, were that the slopes of both He and SF6 would be decreased by approximately the same amount (~22% of their 1-G value), again due to the removal of their common gravitational CDI. Surprisingly, although the phase III slope of N2 was decreased by ~27%, the phase III slope of He was decreased by 28% and the phase III slope of SF6 was decreased by 46% (17). As a result, the phase III slope for SF6 in sustained µG was the same as that for He. Furthermore, when the subjects held their breath at TLC for 10 s, the SF6 slope became smaller than that of He. Only one other case has been reported in the literature in which, in 1 G, the slope of SF6 becomes flatter than that of He and that is in heart-lung transplant patients with rejection episodes (18). In the transplantation patients, an increase in the He slope was observed and attributed to conformational changes near the entrance of the acinus, possibly resulting from acute inflammation. Decrease in He phase III slope in short-term vs. sustained µG. It can clearly be seen from Fig. 3 that the major difference between the short-term and sustained µG results is the very large decrease in the He phase III slope during this study. This large decrease in the He phase III slope compared with that of SF6 accounts for the increase in SF6-to-He phase III slope difference in short-term µG. Because the diffusion front of He is situated in a more proximal region of the lungs than the diffusion front of SF6, we can speculate that the physiological phenomenon introducing this large decrease in the He phase III slope in short-term µG occurs predominantly in the proximal region of the acinus or between acini. Theoretical mechanisms of phase III slope generation. The steeper slope of SF6 than He seen in normal humans has been studied extensively and was attributed to two mechanisms, both of which are thought to be gravitationally independent. The first of these mechanisms is that the greater diffusivity of He compared with SF6 enhances its homogeneous distribution (7), resulting in a smaller He phase III slope. The second mechanism is DCDI, which originates at the acinar level, at branch points subtended by unequal volumes, or at unequal cross-sectional areas (14). To illustrate this second mechanism, we will consider the example of a branch point subtended by unequal volumes. In a homogeneously expanding lung, the amount of gas brought into a unit by diffusion is proportional to cross-sectional area and concentration gradient, whereas, by convection, the amount of gas brought into a unit is proportional to the volume of that unit. In units of unequal volume but similar cross-sectional area, the amount of gas diffusing to each unit is the same because the concentration gradient is initially the same. The concentration is, however, larger in the smaller unit because of the smaller volume. Therefore, at the end of inspiration, even though the gas concentration in each unit brought in by convection is the same, the concentration of the inspired gas will be higher in the smaller unit because of diffusion. Conversely, at the end of inspiration the concentration of the resident gas will be higher in the larger unit. During the subsequent exhalation, there will be back diffusion of the resident gas into the small unit but very little back diffusion of the inspired gas into the large unit because of its large convective expiratory flow. This back diffusion of the resident gas retards its appearance at the mouth and results in a positively sloping alveolar plateau (the opposite reasoning applies for the inspired gas). DCDI occurs in that zone of the lung where diffusion and convection are of similar magnitude, i.e., where the Peclet number (Pe) is between 0.1 and 1.0. [where Pe = ud/D (u = gas velocity, d = airway diameter, D = gas diffusivity)] (20). This zone is more distal for SF6 than for He because of its lower diffusivity. This results in DCDI occurring more peripherally for SF6 than for He, where the human lung is known to be more asymmetric (10). This generates a steeper slope for SF6 than for He. It is conceivable that pulmonary blood volume redistribution in µG alters airway luminal cross section or volume expansion at the acinar level, therefore changing the DCDI conditions from the 1-G state. Moreover, it is also possible that the blood volume redistribution would have preferentially affected the proximal acinar region during the short-term µG study, due to a longer time course required for the changes in the periphery to occur. Alternatively, the heart motion or the propagation of the cardiac pressure wave may be modified in µG, therefore altering cardiogenic mixing. Because the diffusion front is spread by cardiogenic mixing, changes in heart motion could also alter the DCDI conditions. For example, the number of units involved in the DCDI mechanism could be increased by enhanced spreading of the front. This would serve to reduce the inhomogeneity present and lower the phase III slope. Possible physiological mechanisms of changes in SF6-He slope. The major difference between sustained µG and the µG periods produced by parabolic flights is the 1.8-Gz phase immediately preceding µG during the parabolic flights. The 1.8-Gz phase could, for example, affect the distribution of the inspired gas through distortion of the lung parenchyma. However, because the lung parenchyma exhibits viscoelastic properties, which are known to have a time constant in the vicinity of 3 s (2), the effects of the 1.8-Gz period on the lung tissues themselves should have disappeared within a few seconds. This suggests that, if the 1.8-Gz period is responsible for the differences we observed between short-term and sustained µG, it must be through an external factor having a time constant longer than the ~27 s of µG generated by the parabolic flights. To address the issue of external influence on ventilation distribution, we have looked at physiological parameters that have previously been measured in both short-term and sustained µG. All the short-term µG measurements reported here were done during parabolic flights and, therefore, incorporate both the influence of the short period of µG and that of the 1.8-Gz period. External factors such as pulmonary blood volume distribution altering acinar conformation or cardiogenic mixing changing the position of the diffusion front could, conceivably, be responsible for the different results observed in short-term vs. sustained µG. Some physiological parameters reflecting blood volume distribution and cardiogenic mixing have been measured in both short-term and sustained µG, e.g., central venous pressure (CVP), cardiac output, and heart rate. CVP was seen to decrease within 60 s on entry into sustained µG and to remain low for the rest of the measurement period (1). In contrast, CVP has been shown to increase during the µG period of parabolic flights (13). The long time constant (compared with ~27 s of µG available in the KC-135 aircraft) of the changes in diffusional mixing suggests that changes in blood filling of the lung may play a significant role. It is, however, difficult to conceptualize how changes in CVP and, presumably, pulmonary blood volume distribution can alter the diffusive distribution of He and SF6 at the acinar level. Furthermore, such changes were not seen in a comparison of the SF6-to-He phase III slope difference for subjects in 1 G in standing and supine positions (17), whereas increases in CVP were observed by both Buckey et al. (1) and Norsk et al. (13) in their supine vs. sitting subjects in 1 G. Moreover, as reported in our previous study (17), the behavior of the phase III slopes of He and SF6 has been examined in upright and upside-down subjects. If blood volume redistribution were an important factor, it would have been expected to have been seen in this extreme situation, but this was not the case. Cardiogenic mixing could also conceivably be different during long- vs. short-term µG exposure due to changes in stroke volume or heart rate. In long-term exposure to µG, an increase in stroke volume and transient changes in heart rate were observed (1, 16). In short-term µG, Lathers et al. (11) reported in their sitting subjects a statistically significant increase in cardiac stroke index during the µG phase of parabolic flights. In short-term µG, neither Norsk et al. (13) nor Lathers et al. (11) could show a statistically significant change in heart rate. The heart rate from our subjects did not change significantly, either (65.4 ± 2.3 beats/min in 1 G and 70.2 ± 3.2 beats/min in µG). It is unlikely, therefore, that changes in stroke volume could explain the differences we observed between the space missions and the parabolic flights because stroke volume increased in both conditions. It may be, however, that changes in cardiac motion and in pulmonary vascular filling alter the propagation of the cardiac pressure waves through the lung, altering the cardiogenic mixing at the acinar level, as suggested by Engel and Macklem (3). Technical differences between SLS-2 and KC-135 studies. The major difference between the test performed during short-term µG and the one performed in sustained µG is the G-load during the initial expiration to RV. Whereas the G-load was constant during the sustained µG tests, during the parabolic flights the preliminary exhalation was performed during the transition between the 1.8-Gz and the µG phases. Michels and West (12) have investigated the effects of performing the preliminary expiration in µG while executing the remainder of a N2 SBW test in 1 G during parabolic flight. They observed a decrease in the amplitude of the N2 cardiogenic oscillations, a decrease in the phase IV height, a decrease in the closing volume, but no change in the N2 phase III slope compared with the 1-G data. They suggested that the regional distribution of the inspired O2 (and hence the N2 concentration) was dependent on the regional RV/TLC at the start of inspiration, which becomes more uniform when the preliminary expiration takes place in µG. Furthermore, they suggested that the regional RV/TLC was probably not a very important contributor to the N2 phase III slope. In the present study, although the initial expiration occurred under G-loading, inspiration was not started until µG was reached, and this should have minimized the RV/TLC differences. In any event, RV/TLC differences represent a convective contribution to lung inhomogeneity and should therefore affect He and SF6 equally. Despite minor technical differences between the two studies, the methodologies are comparable because baseline data collected on subject 8 produced virtually identical results (Fig. 5). Thus we are confident that we are observing significant physiological alterations in gas mixing within the periphery of the lung and not some artifact. Conclusion. Even though the slopes of He and SF6 decrease during both short-term and sustained µG, their pattern of decrease is very different in the two conditions. An increase in the SF6-to-He phase III slope difference was seen in short-term µG in sharp contrast to the decrease observed in sustained µG. In a comparison of the long- and short-term µG studies, the results suggest that changes in acinar-level gas mixing seen in sustained µG are primarily due to alterations in the diffusive-convective inhomogeneity of He. That we do not see a decrease in SF6-to-He phase III slope difference in short-term µG suggests that the time constant of the mechanism is larger than ~27 s and could therefore be affected by the period of 1.8 Gz. This points to alteration in blood volume distribution in the lung, which would necessarily be influenced by the state of the systemic circulation. Alterations in cardiogenic mixing through changes in cardiac motion and pressure wave propagation could also possibly be responsible for the results obtained. However, despite these observations, the mechanism of the changes in acinar- level gas mixing in sustained µG remains unclear.ACKNOWLEDGEMENTS
The authors thank Jeff Struthers, Raoul Ludwig, Janelle Fine, Bob Williams, Linda Billica, and Dave Wolf for collaborating on the manuscript. We also thank Mary Murrell, Marsha Dodds, and Brian Dubow for technical and administrative assistance.
FOOTNOTES
Address for reprint requests: G. K. Prisk, Dept. of Medicine, 9500 Gilman Dr., Univ. of California, San Diego, La Jolla, CA 92093-0931.
Received 26 June 1996; accepted in final form 28 October 1996.
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