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J Appl Physiol 97: 827-834, 2004. First published April 16, 2004; doi:10.1152/japplphysiol.01379.2003
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Effect of 60° head-down tilt on peripheral gas mixing in the human lung

I. Mark Olfert and G. Kim Prisk

Department of Medicine, Division of Physiology, University of California, San Diego, La Jolla, California 92093

Submitted 22 December 2003 ; accepted in final form 15 April 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The phase III slope of sulfur hexafluoride (SF6) in a single-breath washout (SBW) is greater than that of helium (He) under normal gravity (i.e., 1G), thus resulting in a positive SF6-He slope difference. In microgravity (µG), SF6-He slope difference is smaller because of a greater fall in the phase III slope of SF6 than He. We sought to determine whether increasing thoracic fluid volume using 60° head-down tilt (HDT) in 1G would produce a similar effect to µG on phase III slopes of SF6 and He. Single-breath vital capacity (SBW) and multiple-breath washout (MBW) tests were performed before, during, and 60 min after 1 h of HDT. Compared with baseline (SF6 1.050 ± 0.182%/l, He 0.670 ± 0.172%/l), the SBW phase III slopes for both SF6 and He tended to decrease during HDT, reaching nadir at 30 min (SF6 0.609 ± 0.211%/l, He 0.248 ± 0.138%/l; P = 0.08 and P = 0.06, respectively). In contrast to µG, the magnitude of the phase III slope decrease was similar for both SF6 and He; therefore, no change in SF6-He slope difference was observed. MBW analysis revealed a decrease in normalized phase III slopes at all time points during HDT, for both SF6 (P < 0.01) and He (P < 0.01). This decrease was due to changes in the acinar, and not the conductive, component of the normalized phase III slope. These findings support the notion that changes in thoracic fluid volume alter ventilation distribution in the lung periphery but also demonstrate that the effect during HDT does not wholly mimic that observed in µG.

phase III slope; single-breath washout; multiple-breath washout; helium; sulfur hexafluoride

NONUNIFORMITY OF PULMONARY ventilation results from inhomogeneities in both convective and diffusive gas transport, sometimes referred to as convective-dependent inhomogeneity (CDI) and diffusion-convection-dependent inhomogeneity (DCDI) (7). CDI effects may be induced by either gravitational mechanisms, such as topographic differences in pulmonary ventilation resulting from regional differences in pleural pressure (2, 27), or nongravitational mechanisms, such as differing mechanical properties (e.g., lung compliance) among regional lung units (7, 37). DCDI effects involve a complex interaction between both convection and diffusion and are believed to occur in the branching structure of the lung when convective and diffusive transport mechanisms are similar in magnitude, which in humans is reported to be at or near the level of the entrance of the acinus (32). The effects of DCDI can be thought of as occurring on a small scale, i.e., intraregional, whereas CDI principally occurs between regions of the lung, i.e., interregional. Studies performed in microgravity (µG) have shown that a substantial portion (~75%) of ventilatory inhomogeneity (as evidenced by the phase III slope) is due to DCDI effects (20, 38–40). However, there is marked, and as yet unexplained, alteration in the homogeneity of gas mixing during µG (38, 39).

Single-breath (SBW) or multibreath washout (MBW) tests have been extensively used to assess ventilatory inhomogeneity in the lung. The slope of the alveolar plateau, also known as phase III slope (shown in Fig. 1), is a consequence of the unevenness of ventilation throughout the lung and thus provides a measure of the ventilatory inhomogeneity. The inclusion of two poorly soluble inert gases, e.g., sulfur hexafluoride (SF6) and helium (He), with widely differing diffusivities (diffusion for He being 6 times greater than that of SF6) results in differential mixing of these gases and provides a sensitive index of peripheral gas mixing (16). In healthy humans, the ventilatory inhomogeneity at the acinar level (DCDI) is responsible for the steeper phase III slope for SF6 than He (Fig. 1, inset) and thus results in a positive value for the SF6-He phase III slope difference (15). The absence of gravity was expected to result in an equal reduction in the phase III slopes of SF6 and He (due to the common loss of the gravitational CDI component on both gases), and thus no change in SF6-He slope difference was expected. However, studies performed during spaceflight (i.e., sustained µG) not only found that significant inhomogeneity in pulmonary ventilation persisted in µG but surprisingly that the SF6-He slope difference was abolished, which was due to a greater fall in the phase III slope of SF6 than He (39). In an attempt to elucidate the mechanism(s) responsible for the unexpected behavior in the SF6-He slope difference observed in space (i.e., sustained µG), SBW tests have been performed during transient µG on board a National Aeronautics and Space Administration KC-135 µG research aircraft (12, 26). However, in contrast to the results from spaceflight, those studies found a greater fall in phase III slope of He than SF6, which resulted in an increase of SF6-He slope difference. The findings from transient µG implicate airways near or proximal to the acinar entrance, as opposed to a more peripheral location. It was also concluded that the mechanism responsible for altering ventilatory inhomogeneity was of a time course greater than ~27 s (the length of time transient µG was obtained during these parabolic flights), thus possibly indicating the involvement of the pulmonary vasculature.



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  		Fig. 1. Idealized example of exhaled concentration of inert gas plotted against lung volume after a vital capacity breath. The resulting expirogram is divided into 4 phases. Phase I, dead space gas; phase II, transition between dead space and alveolar gas concentration; phase III (also known as the "alveolar plateau"), emptying of pure alveolar gas; phase IV, exhaled gas after the onset of airways closure. The phase III slope is obtained by the best fit line through the alveolar plateau and is an index of ventilatory inhomogeneity. Not shown in the alveolar plateau (phase III) are cardiac oscillations that are frequently present. TLC, total lung capacity; RV, residual volume. Inset: stylized examples of phase III slope (%/l) for sulfur hexafluoride (SF6) and helium (He). SF6 exhibits a steeper phase III slope than He because of the difference in each gas's diffusive properties.

 
To test the hypothesis that a sustained increase in thoracic fluid volume may be responsible for the changes in ventilatory homogeneity, we performed a series of single- and multiple-breath washin maneuvers on healthy volunteers placed in a 60° head-down tilt (HDT) position for 1 h. Historically, less severe 6° HDT has been used as a surrogate to spaceflight to simulate the cardiovascular effects of µG, i.e., redistribution of fluid volume from caudal to cephalic regions in the body (22). In this study, we used a steeper 60° HDT to elicit a more acute stimulus to elicit changes in fluid distribution over a shorter period of time. These data show the changes in gas mixing occurring during HDT were, in part, similar to those reported in µG and are compatible with the notion that redistribution of fluid volume (perhaps implicating an increase in lung water, e.g., pulmonary interstitial edema) may be involved with the alteration in peripheral gas mixing. However, in contrast to µG, the magnitude of the change in phase III slopes for SF6 and He during HDT were similar and therefore resulted in no change in the SF6-He slope difference.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This study was approved by the University of California, San Diego, Human Research Protection Program and was conducted with informed consent of all subjects.

Subjects and data collection.   Seven male subjects were recruited and screened for cardiac or pulmonary disease by self-reported medical history. Spirometric assessment of pulmonary function was used to verify the absence of lung disease.

A commercially available inversion table (Teeter Hang Ups F5000, STL International, Puyallup, WA) was used to place subjects in a 60° HDT position for 60 min. Subjects' body weight was supported by ankle boots and by a climbing harness positioned low across the hips, leaving the shoulders, chest, and abdomen to move freely. During HDT, subjects performed a single- and multiple-breath washin maneuvers at time points corresponding to 5, 10, 15, 25, 35, 45, and 60 min throughout HDT. Before HDT, SBW and MBW tests were performed twice at baseline and twice post HDT (i.e., 60 min after returning upright). Figure 2 provides a graphical time line of the testing procedure.



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  		Fig. 2. Experimental timeline depicting when tests were performed before, during, and after 60° head-down tilt (HDT). Each arrow denotes a time point when both single- and multiple-breath washout tests were performed. Baseline and post-HDT tests were performed in a standing position.

 
Equipment and experimental system.   All tests were performed on a system identical to that previously used to study ventilation inhomogeneity in µG studies (20, 25, 40, 43). Briefly, the system comprises of a bag-in-box system with separate bags for inspired and expired gases. The subject breathed either air or test gas, which consisted of 5% He, 1.25% SF6, and balance O2, through a nonrebreathing valve (volume {approx} 70 ml). Flow was measured with a linearized Fleisch no. 2 pneumotachograph housed in the wall of the bag-in-box system. Gas concentration was sampled near the lips of the subject and measured with a rapid-responding mass spectrometer (Perkin-Elmer MGA-1100, Pomona, CA). The system was calibrated before and after HDT for each subject, which consisted of gas calibrations with known gas concentrations, flowmeter calibration using a calibrated 3-liter syringe (Hans Rudolph) at a flow rate of ~0.5 l/s, and determination of mass spectrometer transit time (determined by measuring the time required for a sharp puff of gas containing CO2 to be detected by the mass spectrometer). The transit time was defined as the point at which flow was detected to the midpoint in the rise of CO2 measured by the mass spectrometer and thus includes the lag time and dynamic response time of components. Gas concentration signals were aligned with the integrated flow (i.e., volume) signal on the basis of measured transit time (~400 ms). Each subject wore a nose clip while performing the breathing maneuvers.

Data were recorded and logged at 100 Hz by use of a 12-bit analog-to-digital converter and were stored on a computer. These data were converted to our standard laboratory format, by using a personal desktop computer, and analyzed with the same techniques applied to data previously obtained during µG (20, 38, 40).

SBW maneuver and analysis.   After several breaths of air on the system mouthpiece, the subjects was asked to exhale to residual volume (RV). At RV, the subject turned a valve connecting him to a bag containing the test gas consisting of 5% He, 1.25% SF6, and balance O2. The subject inspired from RV to total lung capacity (TLC) while watching a flow display to maintain the inspiratory flow at 0.5 l/s. On reaching TLC, the subject immediately exhaled to RV at 0.5 l/s. The expiratory flow rate was also controlled by an active flow-regulating valve. Inspiratory and expiratory vital capacities were determined from maximum and minimum volumes measured and compared for consistency. The average volume difference between inspiratory and expiratory vital capacities for each subject is shown in Table 2.


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  		Table 2. Test quality parameters from single- and multiple-breath washout maneuvers

 
To account for differences in the inspired concentrations of He and SF6, gas concentrations were normalized by considering the pretest concentration of gas in the lung as 100% and the inspired concentration of gas as 0%. This results in positive phase III slopes for all gases (similar to that of N2). Each gas concentration was plotted against volume along the abscissa, and the phase III slope was determined by an iterative process, as previously described (20). Briefly, the beginning of phase III was marked by the choosing a point beyond the end of phase II. An estimate of the end of phase III was then made, and the least-squares best fit line of gas concentration as a function of volume (calculated between these two limits) was drawn. The end of phase III was repeatedly chosen in this manner until no further change in its position resulted. The phase III slope was then taken from this best fit line.

MBW maneuver and analysis.   The 12-breath washin maneuver started with the subject breathing air on the mouthpiece and, when comfortable, turning a valve to begin the test. The subject exhaled to RV. The volume at RV was detected by the system and used to set (by adding a predetermined volume) the preinspiratory lung volume (PILV) to be used for the remaining cycle of breaths. The volume added for each subject was predetermined so that PILV was approximately equal to subject's standing functional residual capacity (FRC). From RV, the subject inspired past PILV up to a preset tidal volume (VT) limit (set ~1,200 ml above PILV) and then expired to PILV. This cycle continued for a series of 15 breaths, in which the first 3 breaths were performed breathing air and the final 12 breaths were from a prefilled bag containing test gas. During the breathing cycle, system valves actively controlled the limits of each breath, thereby ensuring a very regular washout.

Before analysis, MBW data were treated in a similar manner to those used in the SBW test, i.e., pretest concentration of gas in the lung was considered to be 100% and the inspired concentration of gas as 0%. This resulted in an expired tracing that resembled a washout maneuver and accounts for differences in the inspired concentrations of He and SF6. The normalized phase III slope (SnIII) for each breath was determined using a least-squares best fit line of the mixed expired gas concentration fitted against volume over a range 700–1,200 ml of expired VT. To better compare subjects with different lung volumes, SnIII was plotted against lung turnover (TO), i.e., cumulative expired volume divided by the subjects PILV. This also allows partitioning into acinar (Sacin) and conducting (Scond) airway components by the technique described by Verbanck et al. (53). Briefly, Scond was determined by linear regression analysis of SnIII between lung TO ~1.5 to 6.0, i.e., the portion of SnIII where conductive effects dominate and contribute to the rise in SnIII. Sacin was determined by subtracting the part of SnIII attributable to the conductive airways from the slope of the first breath, i.e., Scond multiplied by the TO value of the first breath. PILV was determined by mass balance of inert gas concentration from the start to the end of the maneuver [i.e., PILV = FetHe (start) – FetHe (end)/{sum}V E(He), where FetHe is the end-tidal fraction of He concentration and {sum}V E(He) is the cumulative expired volume of He].

Statistical analysis.   This study was a repeated-measures design; therefore each subject served as his own control. Repeated-measures analysis of variance (rANOVA, StatView 5.0, SAS Institute, Cary, NC) was used for SBW data. ANOVA was used to determine significance within each 12-breath maneuver. In all cases, significance was set at P < 0.05, and unless otherwise indicated all values shown are means ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Physical characteristics and spirometric assessment of pulmonary function for each subject are shown in Table 1. Test quality parameters of the SBW and MBW maneuvers are shown in Table 2 and indicate well-performed maneuvers and a high degree of reproducibility between serial measurements.


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  		Table 1. Subject anthropometric and pulmonary function characteristics

 
Values obtained at the baseline and recovery (i.e., 60 min after HDT) time points were not significantly different for either SF6 or He (P = 0.87 and P = 0.54, respectively). Accordingly, these groups were averaged and treated as a single group (labeled as "upright") for all subsequent analyses. Time points corresponding to 5, 10, and 15 min; to 25 and 35 min, and to 45 and 60 min were grouped to yield mean time points at 10, 30, and 50 min (Fig. 2).

The data from the N2 washout were qualitatively similar to that of both He and SF6. We have chosen to not include the N2 findings in this paper because they do not significantly add information beyond that which is collectively seen from He and SF6.

SBW.   As expected, we observed SF6 to have a steeper phase III slope compared with He, thus resulting in a positive number for SF6-He difference in the upright position (Fig. 3). Seen in Fig. 3A, the phase III slope for both SF6 and He tended to decrease with time (reaching nadir at 30 min) in HDT. However, the fall in phase III slope was similar for both SF6 and He, and therefore no significant change in the SF6-He difference was observed (Fig. 3B).



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  		Fig. 3. Normalized phase III (PIII) slope data from single-breath vital capacity washout (SBW) maneuver. A: change in PIII occurring over time from a change in upright, i.e., standing, position to 60° HDT. B: difference in the PIII slope between SF6 and He (i.e., SF6-He). Because the decline in PIII slope during HDT was similar for both SF6 and He, SF6-He slope difference did not change.

 
MBW.   Seen in Fig. 4, SnIII for each of the 12 breaths performed during the MBW was significantly lower during all time point groups (i.e., 10, 30, 50 min) in HDT compared with the upright position (P < 0.001). However, no significant differences were observed between any time point groups during HDT.



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  		Fig. 4. Normalized phase III slope (SnIII) for SF6 (A) and He (B) obtained during a 12-breath washout maneuver (MBW) in an upright position and during 60° HDT. Lung turnover (TO) is determined by dividing cumulative expired volume by the subject's preinspiratory lung volume.

 
In Fig. 5, changes in Scond and Sacin components of SnIII are shown. Sacin for He progressively decreased (P < 0.05) during HDT, and although a similar trend in Sacin was observed for SF6 this did not prove statistically significant (P = 0.44). No significant differences in Scond were observed during any of the time points.



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  		Fig. 5. Changes in acinar (Sacin) and conductive (Scond) components responsible for phase III slope obtained from MBW maneuvers performed upright and during 60° HDT (see text for details). *Significantly different compared with upright position, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Theoretical background.   Distribution of ventilation in the normal lung is largely determined by the branching structure of the airways and the pattern of breathing (33), but external factors, such as the chest wall, pleural pressure, intrathoracic blood volume, and even the position of the heart can also affect the uniformity of ventilation distribution (14). CDI mechanisms are largely at play as air is drawn into the lung, but as the geometry of airway branching becomes increasingly asymmetric more distally in the lung (21, 33) a combination of diffusive and convective gas transport (i.e., DCDI) mechanisms take over. The diffusion-convection front, or so-called diffusion front (35), occurs over a range of airways where diffusive and convective transport are of similar magnitude. The location of the diffusion front depends largely on the diffusivity of the gas and the pattern of breathing (33), but in humans it is typically found at or near the level of the acinus (34, 37). The slope of the alveolar plateau, i.e., phase III slope, of insoluble gases (such as SF6 and He) is a consequence of asymmetrical airway geometry and unequally and sequentially ventilated parallel airways within the lung (32, 34). In the normal upright lung, the phase III slope for SF6 is steeper than for He. This is because, although both gases are subject to the same convectional mixing (i.e., CDI), their widely different diffusivities (6:1 ratio) result in markedly different behavior at the diffusion front, where DCDI effects occur. For SF6 (a more dense gas than He), the diffusion front occurs deeper in the lung and is believed to be located at or near airway generation 16 (34, 51). The diffusion front for He resides two or three generations proximal in the airways (mouthward) than that of SF6 (33). The combination of a more distal diffusion front for SF6 and greater asymmetry of airways toward the periphery of normal human lungs results in a steeper phase III slope for SF6 than He. This is seen in our data, in which the control, i.e., upright, values for phase III slope of SF6 are greater than for He (Fig. 3A).

Single-breath maneuver.   When switching from an upright to 60° HDT position there was a tendency for phase III slope of He and SF6 to decline (i.e., rANOVA: P = 0.06 and P = 0.08, respectively, Fig. 3). Although the change in phase III slope did not prove statistically significant, the relative declines of 44 and 32% at the 10-min HDT time point, and 57 and 42% decline at the 30-min HDT time point in the phase III slope of He and SF6 (Fig. 3A), respectively, are comparable to the declines of ~38% previously reported in 1G studies (7) and ~25% in studies performed in µG (20). The lack of statistically significant outcome, in the present study, is likely due the combination of large intersubject variability and relatively small number of subjects in our study. Although this could limit our interpretation of these data, we would note that an independent paired t-test analysis (similar to that performed in the previous studies just cited) does in fact reveal a significance difference between the upright and 30-min HDT time groups (P < 0.05, for both SF6 and He).

The present finding of no change in SF6-He slope difference is consistent with that when transitioning from upright to a supine position (18, 19). The lack of SF6-He difference indicates that either 1) changes occurring in the phase III slope as a result of HDT were upstream of DCDI effects and thus primarily involved CDI mechanisms, or 2) changes in the lung periphery occurred in a manner that affected He and SF6 similarly. In contrast to HDT, overall ventilatory inhomogeneity is increased in the supine position (18, 19, 29). The increase in ventilatory inhomogeneity in the supine position appears to be largely, if not solely, related to CDI transport mechanisms (18, 19). In our study, the observation that the phase III slope of both inert gases tended to decline is consistent with a change in CDI and is also consistent with the observed response (decline) of phase III slope during both transient (12) and sustained µG (26). However, in contrast to that seen during sustained µG (where the SBW SF6-He slope difference was abolished) and transient µG (where SBW SF6-He slope difference was increased) (12, 26), we saw no change in the SF6-He slope difference (Fig. 3B).

The immediate or acute decline in phase III slope with HDT was not itself of great interest, as such changes could be expected during HDT (10). Indeed, a change in the phase III slope (as influenced by CDI) would be expected to occur with the transition from upright to HDT position as a result of changing the gravitational vector (e.g., changing chest wall configuration and shifting abdominal structures toward the thoracic cavity with HDT). However, these acute effects on CDI would not be expected to develop over time. More interesting is the time-dependent manner in which phase III slope tended to decline (reaching nadir at ~30 min, Fig. 3A), which suggests the involvement of an evolving mechanism affecting ventilatory inhomogeneity.

Multiple-breath maneuver.   Compared with an upright position, SnIII was consistently lower during HDT with the exception of the last He breath (Fig. 4B). Nongravitational CDI mechanisms (such as lung regions with differing compliance and/or changes in chest wall configuration) might be postulated to be responsible for the SnIII changes we observed during HDT. This, however, seems somewhat unlikely given the healthy pulmonary status of our subjects (Table 1). Changes in chest wall configuration during HDT may have had a mechanical effect and could perhaps have changed regional volume distribution within the lung, but previous studies have shown that neither HDT (11) nor voluntary changes in thoracoabdominal shape (17) greatly influence regional lung volumes. Moreover, differences in regional ventilation have been shown to remain constant relative to the vertical axis irrespective of body position (24), which is due to the continued persistence of intrapleural pressure gradients when body posture changes from upright to HDT (5, 9, 28). Furthermore, esophageal pressure (obtained during vital capacity maneuvers) with 90° HDT appear not to be related to chest wall configuration (4), but whether the same is true for esophageal (or intrapleural) pressures when smaller VT breaths are performed during a MBW maneuver is less certain. Nevertheless, the evidence suggests that it is unlikely that nongravitational CDI mechanisms, such as lung compliance or changes in chest wall configuration, underlie the changes in peripheral gas mixing we observed.

When SnIII was partitioned into Sacin and Scond components, a significant change was seen in Sacin, but not in Scond (Fig. 5), indicating that the changes seen during the MBW test during HDT were due to DCDI and not CDI effects. The change in Sacin was only significant for He and not SF6. It is tempting to speculate that the preferential effect of HDT on He, which coincidentally is consistent with that observed during transient µG (26), could mean that the alteration in ventilatory inhomogeneity is due to changes occurring at a point near or proximal to the entrance of the acinus. However, given the very similar magnitude of decline in both gases (Fig. 5), it is more likely that the greater intersubject variability in the SF6 data (seen by the larger standard errors shown in Fig. 5) resulted in the nonsignificant decline. The VT we use (~1,200 ml) in this study is also greater than what would be expected for tidal breathing in our subjects at rest. Because an increased VT has been shown to substantially decrease DCDI and increase CDI in the intact chest (13, 18), it may be that we actually underestimated the effect of DCDI during HDT. It is interesting to note that using a smaller VT would be expected to result in a larger magnitude of change (decrease) in DCDI and lessen the (already nonsignificant) change in CDI and thus would strengthen our MBW data.

Comparison of single- and multiple-breath tests.   On initial inspection the results of SBW and MBW appear to be contradictory. The SBW results show no apparent change in intraacinar heterogeneity (i.e., SF6-He difference, Fig. 3B), whereas MBW shows a decrease in the acinar component of SnIII (Fig. 5). However, these two tests do not measure the same aspect of ventilatory inhomogeneity. The small-VT breaths performed during the MBW are more representative of ventilation inhomogeneity as it occurs during normal (or physiological) breathing, whereas the vital capacity maneuver during a SBW is dominated by events occurring at extreme end of the lung volumes, i.e., RV and TLC (12). Therefore, the apparent discrepancy between effect of HDT on uniformity of ventilation as seen separately by SBW and MBW maneuvers does not necessarily negate their respective interpretation but rather provides data under conditions of two very different lung volumes.

It is also worth noting, we determined SnIII using a linear-fit technique (52, 53). It has also been shown that these data can be described by using a two-exponential curve-fit method (46), which tends to produce larger Scond values because it accounts for all the breaths in the washout and not just those fitting in the linear range. We have chosen to use the linear-fit technique described by Verbanck et al. (53) because this is the technique that has been most frequently used in the studies that look at ventilation inhomogeneity in µG and with respect to changes in body position. Although our choice might affect the absolute values we obtained, it is unlikely to affect the overall pattern we observed, especially since our study is based on a repeated-measures design and each subject served as his own control.

Potential limitations and factors influencing alveolar plateau (phase III slope).   The factors determining and affecting the alveolar plateau have been well described (2, 6, 8, 27, 32, 36). Among these, the PILV at which the maneuver is performed is an important determinant in the resulting phase III slope (6, 36, 37). Likewise, altering VT or even ventilatory flow rate also affects the resulting phase III slope (8, 13, 36). Although it is well known that FRC is reduced during HDT, in our study PILV was set on the basis of fixed volume above each individual's RV. Interestingly, if RV were reduced as a result of HDT and lowered PILV compared with upright, then SnIII might be expected to increase (36, 37). Although we did not measure RV, Demedts et al. (11), using 90° HDT, as well as other studies using water immersion (3) and inflation of antigravity suit (3), have not found significant changes in RV. Unlike the other lung volumes (e.g., FRC), RV appears to be the most stable and resistant to change. As seen in Table 2, the coefficient of variation in PILV between successive MBW maneuvers, within each subject, was small (~5%), indicating that these changes in SnIII due to PILV would have had only minor, if any, effect. Subjects also controlled inspiratory and expiratory flows (at 0.5 l/s) by monitoring flowmeter display, and the fact that system valves actively control the limits of each breath throughout the breathing cycle ensured very regular washin results. The system we used is especially designed to maximize the uniformity and consistency between repeated maneuvers and to minimize and/or eliminate the potential confounding effect of VT and PILV. Altogether, the reproducibility and successive quality of each test (Table 2) give us confidence in the data obtained during HDT.

Potential role for lung water in the alteration of gas mixing in the lung periphery.   A common feature between HDT and µG is an increase in fluid volume in the thoracic cavity. Unfortunately, we did not measure thoracic fluid volume or lung water. There is, however, very little question that HDT results in a redistribution of body fluid from caudal to cephalic regions in the body (1, 22). The observation that significant reductions in the diffusing capacity for carbon monoxide (DLCO) occur during long-term 6° head-down bed rest (23, 30, 44) is compatible with the notion of greater lung water during HDT. However this may not provide a straightforward explanation, because acute changes in body position, e.g., upright to supine, are more generally found to increase DLCO (42, 45). However, the acute increases in DLCO appear primarily due to an increase in pulmonary capillary blood volume and to a lesser extent to changes at the membrane level (42, 45). Thus it is possible, despite evidence of acute increases in DLCO, that an increase in lung water content, i.e., fluid retention in the pulmonary interstitium, could occur without overt clinical symptoms over the 60 min of steep HDT. This is supported by a recent observation that the pulmonary interstitium pressure, which is central to determining lung water content, is increased in spontaneously breathing anesthetized rabbits after 1 h of only 20° HDT (31). However, whether a similar change in pulmonary interstitium pressure occurs in humans during HDT, or even during spaceflight, is presently not known. In fact, during both transient (47) and sustained µG (42, 50), DLCO is increased. Under both conditions, the increase in DLCO in µG was the result of significant increases in pulmonary capillary blood volume and at the membrane level. However, the longest period of time for which µG DLCO data are available is 10 days (50); whether an elevated DLCO will persist after several weeks or months in µG is not presently known. It does not seem unreasonable to speculate that "subclinical" fluid accumulation in the pulmonary interstitial matrix may be reflected in the changes in SBW and MBW observed during steep HDT, and perhaps those observed during µG. However, this is not to say that either HDT or spaceflight results in alveolar fluid accumulation (e.g., pulmonary edema), for indeed the evidence to date does not indicate that pulmonary edema occurs in humans during either HDT or spaceflight (42).

Perhaps the simplest mechanism by which an increase in thoracic blood volume could alter ventilation inhomogeneity may involve engorgement of pulmonary and other (e.g., superior and inferior vena cava) vessels within the chest, which in turn press against the lung structure and may change the geometry of the distal airway. Demedts and Clarysse (10), using 90° HDT, found that apicobasal volume differences were significantly reduced in the lower half of the lung at RV. This, to some extent, could explain the fall in phase III slope we observed during HDT, as the sequestration of blood within the chest could alter regional lung volumes. On the other hand, the study by Demedts and Clarysse also found that apicobasal volume differences were greater at higher lung volumes; consequently, ventilation between 0 and 50% vital capacity was more sequential in HDT than upright. Nevertheless, they too observed a decline in the SBW phase III slope. The continued presence of an esophageal (or intrapleural) pressure gradient during HDT (4, 5, 9, 28) does makes it difficult to envisage how any mechanism (elicited by HDT position) would result in greater uniformity of ventilation in the lung. However, we would reemphasize that, to the extent that we saw a decline in the phase III slope of SF6 and He, these results are similar to those of studies performed in both transient (12, 26) and sustained µG (39). They do, however, differ from µG in that we did not see a change in SF6-He slope difference, whereas a decrease in SF6-He slope difference occurred during µG. Interestingly, the only other case in which a decrease in the SF6-He slope difference has been observed in the terrestrial environment (i.e., on Earth) is in heart-lung transplant patients. In this case, the decrease in SF6-He slope difference appears only in transplant patients' experiencing acute episodes of infection and organ rejection (48, 49), suggesting a mechanism that may involve small airway inflammation and/or bronchoconstriction. It is hard to draw similarities between this unique patient population and a healthy lung in µG (or even HDT), except to say that both conditions point toward an alteration occurring in the periphery (distal airways) of the lung. The observation that long-term 6° HDT results in a significant decrease in forced expiratory flow between 25 and 75% of forced vital capacity, but not other spirometric parameters (30), would also tend to implicate medium- to small-sized airways and suggest involvement of airways in the lung periphery.

In summary, we have found that steep HDT reduces the phase III slope for both SF6 and He during MBW and a similar trend is seen during SBW, a result consistent with that observed in µG. The progressive decline in phase III slope during the HDT implies a mechanism evolving with time (up to 30 min) and thus may involve changes in thoracic fluid volume and perhaps increasing lung water. However, unlike that previously observed in sustained µG, the magnitude of the change for SF6 and He was similar; thus no change in the SF6-He slope difference occurred. Although similarities existed between µG and HDT, it is apparent from these data that the effect of HDT on pulmonary ventilation does not wholly mimic that which is observed during either sustained µG or transient µG (whose results are themselves paradoxical).


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study was supported by grants from National Aeronautics and Space Administration contract NAS9-98124 and National Heart, Lung, and Blood Institute Grant HL-07212.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank all the subjects who participated in this study and endured 1 h of head-down tilt. We also gratefully acknowledge the expert technical assistance provided by Janelle Fine, Assistant Development Engineer, and Trevor Cooper, Programmer Analyst.


   FOOTNOTES
 

Address for reprint requests and other correspondence: I. M. Olfert, Univ. of California, San Diego, Dept. of Medicine 0623A, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail: molfert{at}ucsd.edu).

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.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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 ACKNOWLEDGMENTS
 REFERENCES
 

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A. C. Henderson, D. L. Levin, S. R. Hopkins, I. M. Olfert, R. B. Buxton, and G. K. Prisk
Steep head-down tilt has persisting effects on the distribution of pulmonary blood flow
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