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1 Swedish Defence Research Agency, Defence Medicine, S-580 13 Linköping, and Karolinska Institutet, S-171 77 Stockholm; and 2 Department of Pediatric Clinical Physiology, Queen Silvia Children's Hospital, S-416 85 Göteborg, Sweden
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study assessed the effects of increased gravity in the head-to-foot direction (+Gz) and anti-G suit (AGS) pressurization on functional residual capacity (FRC), the volume of trapped gas (VTG), and ventilation distribution by using inert- gas washout. Normalized phase III slope (SnIII) analysis was used to determine the effects on inter- and intraregional ventilation inhomogeneity. Twelve men performed multiple-breath washouts of SF6 and He in a human centrifuge at +1 to +3 Gz wearing an AGS pressurized to 0, 6, or 12 kPa. Hypergravity produced moderately increased FRC, VTG, and overall and inter- and intraregional inhomogeneities. In normogravity, AGS pressurization resulted in reduced FRC and increased VTG, overall, and inter- and intraregional inhomogeneities. Inflation of the AGS to 12 kPa at +3 Gz reduced FRC markedly and caused marked gas trapping and intraregional inhomogeneity, whereas interregional inhomogeneity decreased. In conclusion, increased +Gz impairs ventilation distribution not only between widely separated lung regions, but also within small lung units. Pressurizing an AGS in hypergravity causes extensive gas trapping accompanied by reduced interregional inhomogeneity and, apparently, results in greater intraregional inhomogeneity.
functional residual capacity; gas trapping; helium and sulfur hexafluoride; multiple-breath washout; normalized phase III slope analysis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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AFTER THE INTRODUCTION of the 133Xe scintigraphy technique in the early 1960s (1), several studies designed to assess the effects of gravity on regional distribution of lung expansion, ventilation, and perfusion were undertaken in human centrifuges. Gravitational force in the head-to-foot direction (+Gz) produces a pleural pressure gradient that results in greater expansion of the apical than the basilar alveoli and ventilation to be directed preferentially to the basilar lung zones (4, 12). The pleural pressure gradient has been found to rotate around an isopressure point, which corresponds to an isovolume point at which ventilation does not change with acceleration (4). In four test subjects, this isovolume point was located on average 18 cm from the top of the lung. During breathing at functional residual capacity (FRC) level or higher, regional ventilation has been shown to decrease linearly in the apical direction above the isovolume point and with increasing +Gz, whereas the opposite occurs below this point (4). During breathing at lung volumes below FRC, this linear relationship is abolished because of the positive basilar pleural pressure leading to increasing airway closures. This phenomenon is further accentuated with increasing +Gz, resulting in extensive basilar airway closures and ventilation to be directed more apically (15). Increasing gravity up to +3 Gz has been shown to affect vital capacity (VC) and residual volume (RV) little, whereas FRC has been shown to increase by ~300 ml at +2 Gz, and by another 150 ml at +3 Gz (15). This increase results from a downward movement of the diaphragm by ~1 cm at +2 Gz and by 2 cm at +4 Gz (15, 23). Pressurization of an anti-G suit (AGS) at increased +Gz load is known to counteract the gravity-induced descent of the diaphragm (15) and cause pulmonary vascular congestion, i.e., an increased volume or filling of the pulmonary blood vessels, as well as extensive gas trapping (14).
Studies that used multiple-breath washout (MBW) of inert tracer gases of differing molecular mass, applying the Paiva-Engel lung models, have significantly increased the knowledge about the mechanisms of ventilation distribution in the lungs (11, 31, 33). During normal breathing in upright seated subjects, inhomogeneity of gas mixing within small lung regions, caused by the interaction between diffusive and convective gas mixing, is the greatest contributor to overall inhomogeneity, whereas convection-dependent, interregional inhomogeneity is only a minor contributor (8, 31). This contrasts with VC breaths during which interregional inhomogeneity occurring near RV and close to total lung capacity (TLC) is the main contributor to overall inhomogeneity (9, 17). Studies in sustained weightlessness (microgravity; µG), using multiple-breath washin or MBW of inert tracer gases such as He, N2, or SF6, indicate that reduced gravity has relatively little influence on interregional ventilation inhomogeneity (34, 35). Prisk et al. (34) did, however, find a marked reduction in the difference between the normalized phase III slopes (SnIII) for SF6 and He, indicating reduced intraregional, intra-acinar inhomogeneity in sustained µG.
Previously, no results have been published from inert-gas MBW studies that assessed the effects of hypergravity and AGS inflation on ventilation distribution during tidal breathing. The present MBW study was, therefore, designed to assess the influences of increased +Gz and compression of the lower body half on FRC, overall ventilation distribution, inter- and intraregional ventilation inhomogeneity, and gas trapping during normal tidal breathing. In a previous He/SF6 VC single-breath washout (SBW) study, our laboratory found that moderate hypergravity resulted in greater overall ventilation inhomogeneity, whereas AGS pressurization was associated with greater SF6 than He phase III slopes (SIII) (19). Because VC SBW tests and MBW tests give weight to different aspects of ventilation distribution (8, 9, 17), the MBW test findings in hypergravity and after AGS pressurization might come out differently than those from the He/SF6 VC SBW test (19). We hypothesized that this MBW study would show that increased +Gz results in a small increase of interregional ventilation inhomogeneity and in a greater increase of intraregional inhomogeneity and that these effects would be aggravated when the AGS was pressurized.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Test subjects. Twelve male test subjects participated in the study. They were part of a pool of volunteers trained for physiological experiments in the human centrifuge and were well familiar with the equipment used. Their mean age was 31 yr (range 23-39), their mean height was 178 cm (range 169-189), and their mean weight was 78 kg (range 70-91), and they were all healthy nonsmokers.
Equipment. The study was performed in the human centrifuge at Karolinska Institutet, Stockholm, Sweden. The centrifuge gondola was equipped with a replica of the seat in the Swedish jet fighter SAAB 39 Gripen, which has an angle of 28° between the support for the back and the vertical plane. The test subjects were dressed in an individually adjusted full-coverage AGS and were strapped into the seat in the gondola. The Swedish full-coverage AGS used in this study consists of inflatable bladders covering the legs but not the feet and an abdominal bladder reaching just above the umbilicus.
Gas concentrations were measured at the mouth by using a respiratory mass spectrometer (AMIS 2000, Innovision A/S, Odense, Denmark) placed in the center of rotation of the centrifuge. The washin (4% SF6, 4% He, 21% O2, balance N2) and washout (21% O2, balance N2, i.e., air) gas mixtures used were stored in two compressed gas cylinders placed close to the center of rotation of the centrifuge. In the gondola, the gases were administered to the test subject through a remote-controlled two-way solenoid valve, allowing the selection of either of the two gas mixtures. The solenoid was connected to a demand valve (OTWO-systems, Toronto, ON), which in turn was applied to the inspiratory port of a two-way nonrebreathing valve (model 2630; Hans Rudolph, Kansas City, MO). Inspiratory and expiratory flows and volumes were measured by using a heated Fleisch no. 2 pneumotachometer (PTM) applied to the Hans Rudolph valve. During the tests, the subjects used a nose clip and breathed through a mouthpiece connected to the PTM. The dead space of the breathing system was ~70 ml. Recorded inspiratory and expiratory flows and volumes were converted to BTPS conditions. The PTM was calibrated with separate calibration constants for inspiratory and expiratory flow rates by using a 3,000-ml precision syringe (Hans Rudolph) at a flow rate of ~0.5 l/s. The membrane differential pressure transducer used for the flow measurements (model DP45, Validyne Engineering, Northridge, CA) was positioned in the midline of the centrifuge gondola to minimize potential effects of increased gravity on the offset and gain of the pressure signal. To ascertain the correct positioning, a 2,000-ml syringe was manually operated up to +3 Gz. No significant effects of changes in level of gravity on offset or gain were found. The technique described by Brunner et al. (3) was used to align the gas concentration and flow signals. To validate the mass spectrometer signals when using the 10-m-long capillary in hypergravity, the transit and rise times for SF6 and He were measured when increasing gravity in 1-G steps up to +5 Gz. No changes in lag or rise time with gravity were found for either gas. The tip of the mass spectrometer capillary was positioned in the center of the airstream, between the mouthpiece and the PTM. The sample flow rate of the mass spectrometer was 20 ml/min, and the gas concentration signals were updated at a rate of 33.3 Hz. The mass spectrometer measured the concentrations of all respiratory gases used (SF6, He, N2, O2, and CO2) as dry gas concentrations. The SF6 signal was averaged over 10 ms, whereas the other four gas signals were averaged over 5 ms, resulting in a duty cycle of 30 ms. All signals were recorded by a Pentium computer at 100 Hz through a 16-channel analog-to-digital conversion board (DAS-1602, Keithley Metrabyte, Taunton, MA) by use of custom-made software based on a commercially available data-acquisition software pack (TestPoint, Capital Equipment, Billerica, MA). The software corrected the flow signal sample by sample for changes in dynamic viscosity caused by the variations in gas composition. The recording system was validated before and after the recordings in each test subject were completed. The validation consisted of a simulated FRC measurement by a MBW using the 3,000-ml precision syringe. The accuracy of the measured syringe volumes was within 3% of the geometric volume, and the repeatability was also within 3%. Tidal volumes (VT) and inspiratory and expiratory flows were monitored on a computer screen placed in front of the test subjects for visual feedback.Test procedures. For each subject, the MBW procedure was carried out at +1 and +3 Gz, with AGS inflation pressures of 0, 6, or 12 kPa at each +Gz level. Recordings at +2 Gz were undertaken only with an AGS inflation pressure of 0 kPa. Because of the 28° reclined seat, the gravitational effect in the head-to-foot direction was +0.88, +1.77, and +2.65 G when in the +1.0-, +2.0-, and +3.0-Gz situations, respectively. Consequently, there was also an additional gravitational effect in the anterior-posterior direction (Gx) of +0.47, +0.94, or +1.41 G at the three levels of gravity. In the following text, we will, however, refer to the gravitational load as +1, +2, or +3 Gz. The order of these seven test situations was balanced among the subjects to minimize time effects. The test subjects were instructed to breathe with normal tidal breaths of ~1 liter, to relax during expirations, and to keep inspiratory volumes similar in all test conditions. Three MBW tests were performed in each test situation, resulting in a total of 21 washouts. Each test started with a tidal breathing washin of the tracer gas mixture at +1 Gz. Washin continued until the inspiratory and expiratory end-tidal concentrations of the SF6 tracer had equilibrated. The AGS pressure was set to the predetermined level after the test subject had taken three VC breaths of the tracer gas mixture, a procedure undertaken to ensure that all lung spaces had the same tracer gas concentrations. The centrifuge was then started, and gravity was increased with a rate of 0.1 Gz/s until the desired Gz level was reached. After 20-30 s at this Gz level, when the test subjects had a regular tidal breathing, the washout started by switching the solenoid valve during an expiration to provide air during the subsequent inspirations. Tidal breathing washout continued until the end-tidal SF6 concentration was below 0.1%, i.e., 1/40 of the starting concentration. At this moment, the AGS pressure was released, and the test subject took three slow VC breaths and then started tidal breathing again. The centrifuge was then halted, and a 2- to 5-min-long rest was taken before the next washin-washout round was started. The VC breaths taken at the end of MBW were used to estimate the volume of trapped gas (VTG) in the lungs. The VTG results were possible to calculate in only 10 subjects because of technical problems.
Calculation of breathing-pattern variables, FRC, and lung-volume turnover. Each variable was calculated as the mean from the three washouts in each test condition for each test subject. FRC was determined from the cumulative volume of SF6 expired divided by the difference in end-tidal gas concentration at the start of the washout and the end-tidal concentration at completion of the washout. The expiratory VT, FRC, and VT-to-FRC ratio (VT/FRC) were calculated from the complete tidal breathing washout curves. The VT/FRC was included because it has been suggested to influence some variables of ventilation distribution calculated from inert-gas washout studies (6, 7, 18, 25, 32). The respiratory rate (RR) was calculated from the number of breaths during the washout divided by the washout time for each test, and the ventilatory rate was calculated from the cumulative expired volume (CEV) divided by the washout time. The number of lung volume turnovers (TO) for each breath during the washout was calculated as the CEV at that point divided by the FRC. The external dead space (70 ml) was subtracted from the reported VT, VT/FRC, CEV, TO, and ventilatory rate results.
Calculation of the VTG. The VTG,SF6 was defined as the volume of SF6 that does not communicate with the atmosphere during tidal breathing expressed as the corresponding volume of air. It was measured as the amount of SF6 mobilized by three large breaths after a tidal breathing washout of the tracer gas performed until the end-tidal concentration was 1/40 of the starting concentration (20). It was assumed that after tidal breathing washout the concentration of tracer gas in the closed-off lung spaces was similar to the end-tidal concentration at the start of washout (i.e., ~4%).
Equation 1 shows how the VTG was calculated for SF6
![V<SUB>TG</SUB> = [V<SUB>SF<SUB>6exp</SUB></SUB> − FRC · (C<SUB>SF<SUB>6ewo</SUB></SUB> − C<SUB>SF<SUB>6emv</SUB></SUB>)]](/content/vol94/issue4/fulltext/1353/img001.gif)
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(1) |
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Indexes of overall ventilation inhomogeneity. Several indexes of overall ventilation inhomogeneity were calculated because these indexes may be sensitive to variations in VT and FRC to a variable degree (25). The lung clearance index was calculated as the CEV needed to lower the end-tidal SF6 concentration to 1/40 of the starting concentration divided by the FRC, i.e., the number of TO (25). The mixing ratio was calculated as the ratio between the actual and the ideal number of breaths needed to lower the end-tidal SF6 concentration to 1/40 of the starting value (10). For calculation of the slope index, the logarithm of the end-tidal SF6 concentration was plotted as a function of TO (35). Two slopes from this curve were calculated, from 50 to 100% (A) and from 10 to 50% (B) of the washout, respectively. The slope index was obtained from the ratio between these slopes (i.e., A/B). The moment analysis is a method of presenting the inhomogeneity of ventilation distribution as described by the inert-gas washout curve (25). The first and second moments give more weight to the latter part of the washout curve, which means that the higher these indexes are, the more skewed is the washout curve. This in turn indicates that a greater portion of the lungs is slowly ventilated. A brief explanation is given of how the moment ratios were calculated. First, the end-tidal SF6 concentration was plotted as a function of TO. The area under this curve was denoted the zeroth moment (µ0). Then each end-tidal SF6 concentration value was multiplied with the corresponding TO value, and this new parameter was plotted as a function of TO. The area under this curve was denoted the first moment (µ1). In the next step, the end-tidal SF6 concentration value was multiplied with the square of the corresponding TO value (i.e., TO · TO). Again this new variable was plotted as a function of TO. The area under this curve was denoted the second moment (µ2). The ratios between the first and zeroth moments (µ1/µ0) and between the second and zeroth moments (µ2/µ0) were then calculated over the first eight TO.
SIII and SnIII determinations. For each breath, the SF6 and He concentrations were plotted as a function of expired volume. The slope of the alveolar phase (SIII) was calculated by the least square fit in the interval of 65-95% of the expired volume. When cardiogenic oscillations produced obvious distortions of the slopes, a manual best fit was done. The SIII was then normalized by the mean tracer gas concentration over the phase III interval of interest (65-95% of expired volume), to account for the dilution of the tracer gas, giving the concentration SnIII for SF6 and He, respectively. The difference between the SF6 and He concentrations (SF6-He) was calculated sample by sample and plotted as a function of expired volume. The SIII for (SF6-He) was calculated between 65 and 95% of expired volume and normalized by the mean concentration in this interval, giving the (SF6-He)SnIII.
Calculation of inter- and intraregional inhomogeneity. Inter- and intraregional ventilation inhomogeneities were assessed by using a previously presented linear fit technique (34, 41). The SnIII for each washout were plotted as functions of TO. A linear fit procedure utilizing these plots was undertaken to delineate the two underlying mechanisms of ventilation distribution contributing to total inhomogeneity: convection-dependent inhomogeneity (CDI) and diffusion-convection-dependent inhomogeneity (DCDI) (6, 11, 13, 33). This in turn is based on previous lung modeling and experimental studies (8, 30, 31, 39). The CDI and DCDI are reported as the first-breath SnIII(CDI) and the first-breath SnIII(DCDI), respectively, and together they form the first-breath SnIII(total). Further background to this theory is given in the DISCUSSION section.
The increase in SnIII per unit TO was calculated by linear regression between 1.5 and 6.0 TO, and the result was termed
SCDI in the present study. We then utilized
the method described by Verbanck and colleagues (40, 41)
and calculated the first-breath SnIII(CDI) value
by multiplying the SCDI with the first-breath TO value. The first-breath SnIII(DCDI) value
was determined by subtracting the calculated first-breath
SnIII(CDI) value from the first-breath
SnIII value measured [i.e.,
SnIII(total)].
In a previous study (18), our laboratory showed that the
magnitude of the first-breath SnIII(DCDI) is to
a large extent determined by the ratio of the VT to the
preinspiratory lung volume, i.e., the VT/FRC, during a MBW.
In the upright position, increasing VT values for a given
FRC resulted in a proportional reduction of the first-breath
SnIII(DCDI). On the basis of the results of that
study, we undertook a normalization procedure aiming to obtain SnIII(DCDI) results corrected for alterations in
VT/FRC and that would allow for a comparison to the
baseline situation (+1 Gz and 0 kPa AGS pressure). To
accomplish this, the first-breath SnIII(DCDI)
was first multiplied by the VT/FRC of the first washout breath in each test situation for each subject. The obtained
value was then divided by the first-breath VT/FRC measured
in the baseline situation, for each subject. For
SnIII(CDI), no correction was made because we
previously did not see any changes in SnIII(CDI) with changed VT/FRC in the upright posture
(18). No correction was made for the
(SF6-He)SnIII variable
either, because the relationship between the VT/FRC and the
(SF6-He)SnIII was not conclusive
(18).
Data presentation and statistical analysis. For each subject, average values of the obtained variables from the three recordings in each of the seven test situations were used for analysis and presentation. Two-way ANOVA was used to assess the overall effect of G load (+1, +2, or +3 Gz) and gas species (SF6 or He) and their interaction on the lung function variables without pressurized AGS, because no AGS pressure was applied at +2 Gz. Three-way ANOVA was used to estimate the overall effects of gravity (+1 or +3 Gz), AGS pressure (0, 6, or 12 kPa), and gas species (SF6 or He), and their interaction on lung function variables. Post hoc comparisons were undertaken by using the Tukey's honest significant difference test when ANOVA indicated a significant effect. When the distribution of a variable deviated significantly from normal distribution (Shapiro-Wilk W test), it was analyzed using a nonparametric test (Wilcoxon's matched-pairs test). P values <0.05 were regarded as statistically significant. Results are given as means ± SE. The statistical analysis was performed by use of the Statistica 6.0 (StatSoft, Tulsa, OK).
Ethics. The study was approved by the Ethics Committee for Human Research at Karolinska Institutet, Stockholm, Sweden.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Breathing pattern, FRC, VTG, and
VT/FRC.
Increasing gravity was associated with larger VT, minute
ventilation, and FRC (Table 1).
VT increased by ~5% from +1 to +3 Gz. When
the AGS was not inflated, FRC increased by 9% (280 ml) when going from
+1 to +2 Gz and by 14% (420 ml) when going from +1 to +3
Gz. AGS pressurization did not influence the breathing pattern but was associated with marked reductions of FRC (Table 1).
Pressurization of the AGS to 12 kPa caused a 31% (920 ml) reduction in
FRC at +1 Gz and a 31% reduction (1,050 ml) at +3 Gz. Pressurization to 6 kPa caused a 21% (620 ml) fall in
FRC at +1 Gz and a 14% (490 ml) fall in FRC at +3
Gz. The VT/FRC tended to decrease when going to
+3 Gz (P = 0.052) when there was no pressure in the AGS and increased significantly when the AGS was pressurized to 12 kPa, irrespective of gravity level (Table 1). The
first-breath VT/FRC used for the adjustment of first-breath SnIII(DCDI) showed similar changes.
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Indexes of overall ventilation inhomogeneity.
All five conventional variables of overall ventilation distribution
indicated significantly greater inhomogeneity with increasing gravity
(Table 2). Inhomogeneity also increased
after pressurization of the AGS at +1 Gz but not at +3
Gz.
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SnIII vs. breath number.
Figure 2, A-B,
presents the group average-measured SF6 and He
SnIII plotted vs. breath number at +1, +2, and
+3 Gz with uninflated AGS. The corresponding plots obtained
at +1 and +3 Gz with different inflation pressures in the
AGS (0, 6, and 12 kPa) are given in Fig. 2,
C-D and E-F,
respectively. These diagrams show that the SF6
SnIII were on average greater than the He slopes
throughout. With the AGS uninflated, SnIII were
markedly greater at +3 Gz than at +1 or +2 Gz
and also slightly greater at +2 Gz than at +1
Gz. These differences were small during the beginning of
the washouts but more marked after several breaths. Pressurization of
the AGS had opposite effects on SnIII at +1 and
+3 Gz. In normogravity, SnIII
increased slightly, whereas in hypergravity
SnIII decreased markedly when the AGS was
inflated, particularly when the AGS was pressurized to 12 kPa.
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First-breath SnIII(total).
The first-breath SnIII(total) results for
SF6 are given in Fig. 3.
SnIII(total) was significantly greater for
SF6 than for He in all test situations (P < 0.001; data not presented). First-breath SnIII(total) increased significantly with
gravity. In normogravity, SnIII(total) increased
significantly with AGS pressure, whereas in hypergravity it did not
change when the AGS was pressurized to 6 kPa and declined significantly
(P < 0.001) when the AGS pressure was increased
further to 12 kPa.
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First-breath SnIII(DCDI). When no adjustments were made for the influence of the VT/FRC on the first-breath SnIII(DCDI) (see METHODS and DISCUSSION), this variable (no figure) was similar to the first-breath SnIII(total) results given in Fig. 3. In hypergravity, however, the unadjusted first-breath SnIII(DCDI) increased significantly when the AGS was pressurized to 6 kPa (P = 0.049) and decreased significantly when the AGS pressure was further increased to 12 kPa (P < 0.001).
The first-breath SnIII(DCDI) results calculated for SF6 after adjustment for the assumed influence of the first-breath VT/FRC are given in Fig. 4. The corresponding values for He were significantly lower than for SF6 in all test situations (P < 0.001), but the pattern was similar (data not given). The adjusted first-breath SnIII(DCDI) increased significantly with gravity and also with higher AGS pressures, irrespective of gravity level (Fig. 4).
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First-breath SnIII(CDI) and SCDI.
Because the first-breath SnIII(CDI) and the
SCDI results diverged significantly from a
normal distribution, the Wilcoxon's matched-pairs test was used for
statistical analysis. The results from these two variables were
similar, and, therefore, only the SCDI
results are reported (Fig. 5). Increased
gravity from +1 to +2 or +3 Gz resulted in significantly
greater SCDI for both gases. The
SCDI was significantly greater for
SF6 than for He at +2 and +3 Gz when the AGS
was not pressurized and also at +1 Gz when the AGS was
pressurized to 6 or 12 kPa. When the AGS was pressurized to 12 kPa,
SCDI increased significantly for
SF6 in normogravity, whereas it decreased significantly for
both gases in hypergravity.
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First-breath (SF6-He)SnIII.
When the AGS was not pressurized, the first-breath
(SF6-He)SnIII increased
significantly from +1 to +3 Gz and from +2 Gz
to +3 Gz (Fig. 6). At +1
Gz, the first-breath
(SF6-He)SnIII tended to increase
after the AGS was pressurized to 12 kPa (P = 0.071). There was, however, no significant effect of AGS pressure on this variable at +3 Gz. On the whole, the first-breath
(SF6-He)SnIII results showed a
greater scatter than the other SnIII variables calculated in the study.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Breathing pattern and lung volumes. The effects of hypergravity and AGS pressurization on breathing pattern, FRC, overall ventilation distribution, and gas trapping reported here agree largely with results obtained previously by using other methods (15, 23). Minute ventilation increased on average by 3% at +2 Gz and by 26% at +3 Gz compared with normogravity (Table 1). The latter increase was caused by a combined increase of VT (+5%) and RR (+17%). The test subjects were, however, instructed to keep VT constant, which may have affected the way by which minute ventilation increased. Glaister (15) reported a ventilation increase by only ~15% during short-term exposure to +3 Gz and that it was the result of a combined increase of VT and RR. Greater increase has been reported after longer exposures, however (37). The causes of the greater ventilation at +3 Gz have not been established. Subjects accustomed to exposures to hypergravity report little if any respiratory discomfort at +3 Gz (15), but pressure-volume curves suggest that the work of displacing the abdominal viscera in the caudal direction during inspiration is doubled (15). An increased work of breathing is also expected as a result of an overall rightward shift on the lung pressure-volume curve in hypergravity (15). We do not, however, know of any reports on energy expenditure at +3 Gz confirming these suggestions. Additional possible stimuli to the greater ventilation at +3 Gz are greater CO2 dead space ventilation due to hypoperfusion of apical lung regions and hypoxemia due to shunting in the basilar lung regions (16). It is notable that the increase in ventilation was not linear from +1 to +3 Gz but showed a marked increase above +2 Gz.
The magnitude of the FRC increase in hypergravity reported here agrees well with the FRC increment previously reported by Glaister (~300 ml at +2 Gz and another 150 ml at +3 Gz; Ref. 15). The mechanism is a downward movement of the diaphragm in hypergravity, for which 1 cm is estimated to correspond to a 300-ml increase in lung volume (42). In the present study, FRC was markedly reduced during AGS pressurization, both in normogravity and in hypergravity (Table 1). There are only a few previous reports in the literature on the effects of the AGS on lung volume. Already in 1948, Lombard et al. (26) found that compression of the legs, thighs, and abdomen by pressurization of an AGS in hypergravity reduced the lung volume. Bondurant et al. (2) found that inflation of an AGS to 2 psi (13.8 kPa) at +1 Gz decreased FRC by 500 ml and caused pulmonary vascular congestion as demonstrated by radiography. Glaister (15) reported a reduction in FRC by 500 ml when the AGS was pressurized to 3 psi (20.7 kPa), with a concomitant upward movement of the diaphragm by ~1 cm. We found that airway closures increased significantly in hypergravity. The trapped gas volume index calculated by using SF6 as marker gas increased on average by 63% at +2 Gz and by 122% at +3 Gz when the AGS was not inflated (Fig. 1). Interestingly, a doubling of the closing volume during exposures to +3 Gz has been reported previously (16). Combined inflation of the AGS to 12 kPa and exposure to +3 Gz resulted in an increase of the VTG,SF6 by 321% over the baseline normogravity situation. As further discussed below, the VTG figures reported here presumably underestimate the true volume of the noncommunicating lung spaces by far in hypergravity when the AGS is inflated. For instance, Glaister (15) reported a more than halved VC after exposing a test subject to 100% O2 at +3 Gz with inflated AGS, whereas lesser VC reductions were seen in other subjects. The present VTG method cannot report where gas trapping occurs, but the 133Xe study by Glaister clearly showed that the gas trapping occurs in the basilar lung regions (15). Several mechanisms work in concert to produce airway closures in hypergravity and/or while pressurizing the AGS. The gravity-dependent pleural pressure gradient is three times greater at +3 Gz compared with normogravity, resulting in a significant positive pleural pressure around the lung bases in hypergravity. In addition, hypergravity accentuates the proportion of lung blood volume located in basilar pulmonary vessels, further decreasing regional lung volume and facilitating airway closures. Pressurization of the AGS adds to these effects by moving the diaphragm upward and also by increasing the intrathoracic blood volume. The VTG assessed with SF6 was found to be significantly greater than that obtained with He in all test situations involving increased gravity (Fig. 1). The reasons for this have not been established, but the finding could possibly reflect a greater loss of the more diffusive He gas through collateral ventilation. It might also result from a greater loss of He than SF6 to the bloodstream in the congested basilar lung regions in hypergravity, because He is more soluble than SF6 in plasma and blood (22). The true volume of trapped gas is unknown, and the VTG reported in the present study can serve only as an indicator of it. The present method presumably underestimates the gas trapping, particularly in situations in which extensive airway closures are present. This suspicion is based on observations made in a previous N2-washout study (20), in which the VTG,N2 was found to increase after inhalation of a bronchodilator in patients with asthma who had severe peripheral airway obstruction. Furthermore, when calculating the VTG,SF6, for example, we assumed that the SF6 concentration in the noncommunicating lung spaces at the end of the tidal breathing washout was the same as that in the communicating lung volumes at the start of washout, i.e., ~4% in the present study. If, however, the true tracer gas concentration in the poorly communicating lung spaces was on average only one-half of that figure, i.e., 2%, because of losses via collateral ventilation, then only one-half of the true VTG,SF6 would have been reported. The VTG can thus be seen as a theoretical volume, reflecting the size of lung spaces, which are ventilated extremely slowly or not at all during tidal breathing and which are parts of the true FRC.Theoretical background to SnIII analysis. To a large extent, regional lung expansion and ventilation distribution are determined by the magnitude of the gravity-dependent pleural pressure gradient, but ventilation distribution is also influenced by other factors not related to gravity. The mechanisms responsible for inhomogeneity of ventilation distribution have been summarized (36) as follows. 1) Gravitational CDI is produced by differences in expansion between the top and the bottom of the lung and sequential lung emptying (13, 28). VC SBW studies in µG suggest that gravitational CDI causes ~25-30% of all inhomogeneity (21, 27). 2) Nongravitational CDI results from inhomogeneities within and between separate regions because of variations in mechanical properties that are not caused by gravity (24, 29, 43). 3) The DCDI is at the diffusion-convection front in the distal airways and air spaces, i.e., intraregional inhomogeneity. The DCDI is the major contributing mechanism to inhomogeneity during normal breathing in healthy subjects (11, 31, 33).
Lung modeling (30, 39) and experimental studies (8) have shown that the contributions of DCDI and CDI to total inhomogeneity can be estimated from the progression of the SnIII plotted vs. breath number or TO. Interaction between diffusion and convection in the vicinity of the diffusion-convection front for a particular gas results in inhomogeneity manifested as increased SnIII, which reaches an asymptote because of a dynamic equilibrium after approximately five normal breaths or 1.5 TO (8). Differences in specific ventilation between sequentially emptied lung regions with branch points proximal to the diffusion-convection front result in additional inhomogeneity (increased SnIII) all through the washout (11). In the normal human lung, the diffusion-convection front for SF6 is believed to arise within the acini. Consequently, the SF6 SnIII reflects the ventilation inhomogeneity that exists within the acini plus that between parallel regions that branch more proximally (30, 33). For He, this front is believed to form some airway generations proximal to the SF6 front, at the terminal bronchiole and/or more mouthward. Therefore the He SnIII reflects inhomogeneous ventilation between groups of acini (31) in addition to CDI occurring in the proximal airways (30, 33). The (SF6-He) phase III slope will thus reflect where in the peripheral airways ventilation inhomogeneity predominates: close to the acinar entrance or within the acini. The CDI is assumed to be similar to a large extent whether assessed with He or SF6, because CDI occurs mainly between lung regions with branch points located well mouthward of the respective diffusion-convection fronts. Interestingly, Prisk et al. (34) reported that CDI for He disappeared in sustained µG, whereas it remained for SF6, suggesting that there is nongravitational CDI between lung units located closely enough to allow He diffusion to reduce concentration differences generated by CDI. A recent VC SF6-He washout study also indicated the existence of intraregional CDI (17), presumably between groups of acini. Gas exchange contributes an additional 10% heterogeneity during exhalation (5), but this effect is equal for SF6 and He and is, therefore, not accounted for in this study.Expected effects of hypergravity and AGS pressurization on inter- and intraregional ventilation distribution. Hypergravity has previously been shown to accentuate the interregional differences in lung expansion and specific ventilation already seen in upright subjects in normal gravity (4), and gravity was, therefore, thought to be the main cause of interregional ventilation inhomogeneity. More recent studies performed in sustained µG indicate that intrinsic properties of the human lung contribute to a significant degree to interregional ventilation inhomogeneities as evidenced by a persisting CDI in weightlessness (34). In our previous SF6 and He VC SBW study, a greater overall inhomogeneity was found in hypergravity as demonstrated by greater SnIII for SF6 and He, whereas the (SF6-He) SnIII did not change. With this background, we expected to find greater CDI with increasing gravity in the present MBW study.
The methods used in previous studies on ventilation distribution in hypergravity (4) did not carry the potential to assess effects on ventilation distribution within small lung units. Using the MBW method, Prisk et al. (34) demonstrated reduced overall SIII and reduced (SF6-He) slopes in µG, indicating decreased intraregional inhomogeneity in weightlessness. On the basis of these µG findings, intraregional inhomogeneity would be expected to increase during tidal breathing in hypergravity. In our laboratory's previous VC SBW study (19), we did not find a greater increase of the SIII for SF6 than for He. This finding would suggest that either intraregional intra-acinar inhomogeneity did not increase in hypergravity or that inhomogeneity did actually increase within the acinar region but was accompanied by increased inhomogeneity of similar magnitude in the vicinity of the entrance to the acini. The VC SBW test, however, reflects to a great extent events near RV and TLC (9), in contrast to the tidal MBW test, which explores ventilation distribution in the normal range of breathing, and different findings with the two methods could, therefore, not be excluded. The VT/FRC decreased only marginally, from 28.1% at +1 Gz to 25.9% at +3 Gz, and the potential effect of hypergravity on SnIII(DCDI) would, therefore, be negligible (18). Gas trapping increased significantly in hypergravity, an event previously shown to occur in the basilar lung regions (15). We would expect this gas trapping to be accompanied by changes in the mechanical properties and expansion of the still-communicating peripheral lung units in the lung bases, resulting in greater inhomogeneity within small units. Previous studies have demonstrated that AGS pressurization, particularly in hypergravity, results in extensive gas trapping in the basilar lung regions (15). Marked gas trapping after AGS pressurization was seen also in the present study. Our previous VC SBW study showed evidence of greater intraregional inhomogeneity (greater SF6 vs. He slopes) when the AGS was pressurized in hypergravity (19), and we might consequently expect similar findings with the MBW method in the present study. The changes in interregional inhomogeneity when the AGS was pressurized in hypergravity were difficult to predict. On the one hand, the greater intrapleural pressure gradient in hypergravity is expected to remain to a large extent, suggesting that interregional inhomogeneity would persist also during pressurization of the AGS. On the other hand, the reduction in FRC and the marked airway closures, both presumably occurring in the basilar lung regions, are likely to force a greater portion of ventilation to go in the apical direction, reducing the vertical differences in specific ventilation as a whole (4). Slower filling and emptying of the most basilar lung spaces due to partial airway closures is expected to occur in hypergravity, and this would further contribute to increasing interregional inhomogeneity. Whether this phenomenon would be further accentuated when the AGS was pressurized was not readily predicted. The VT/FRC was markedly increased after pressurization of the AGS. In a previous study (18), our laboratory found that the SnIII(DCDI) will decrease with a greater VT/FRC, giving an impression of improved intraregional ventilation distribution. In the same study, we also found that increasing the VT/FRC results in a greater SnIII(CDI) when subjects are supine, but not when upright. The latter findings would suggest that moving the diaphragm in the cranial direction (as when going supine or when pressurizing the AGS) would accentuate interregional inhomogeneities. RR was slightly higher in hypergravity than in normogravity, but this increase was probably too small to have any discernible influence on gas mixing. Theoretically, however, the location of the diffusion-convection front is moved somewhat in the distal direction into more geometrically complex airway structures when inspiratory flow is increased, which in turn is expected to increase intraregional inhomogeneity.Findings with the conventional gas-mixing indexes. The conventional MBW indexes of ventilation inhomogeneity reflect regional differences in specific ventilation, which need not be accompanied by sequential filling or emptying. This contrasts to indexes derived from the SIII, e.g., the VC SBW test or SnIII analysis of MBW recordings, which, in addition, require sequencing. All conventional gas-mixing indexes except the slope index indicated significant stepwise increase in ventilation inhomogeneity with increasing gravity (Table 2). The relative change in these indexes from +1 Gz varied between 6 and 14% at +2 Gz and between 11 and 24% at +3 Gz. Results from previous tidal breathing washout studies in hypergravity are lacking, but the present findings are in general concordance with the 133Xe findings by Bryan et al. (4) demonstrating increasingly greater preference of ventilation to basilar lung regions during breathing at a lung volume above 45% TLC in hypergravity. In normogravity, all conventional indexes of ventilation inhomogeneity except the mixing ratio indicated greater inhomogeneity when the AGS was pressurized to 6 kPa, but only one index (µ2/µ0) showed further increase of inhomogeneity in 12 kPa (Table 2). Pressurization of the AGS at +3 Gz had no significant effect on overall ventilation inhomogeneity as assessed by these indexes. This finding is somewhat surprising when we consider the extensive, presumably basilar, airway closures. The absence of change in the conventional markers when the AGS is pressurized in hypergravity indicates, however, that interregional differences in specific ventilation did not change as a whole when the AGS was pressurized in hypergravity. In our group's previous study in normogravity (18), changes in VT/FRC had inconsistent effects on the different indexes. The contribution of changes in VT/FRC on the conventional indexes in the different test situations in the present study was thus difficult to estimate.
SnIII findings. To determine the contribution of SnIII(DCDI) and SnIII(CDI) to the SnIII(total), either a linear-fit technique (40, 41) or a two-component exponential curve-fit technique can be used (38). We have found that the two methods produce similar results, and we have chosen to use the linear-fit method in the present study because it was used previously in a similar µG SF6 and He MBW study (34).
The first-breath SnIII(total), an SnIII index of overall ventilation inhomogeneity, increased with the level of gravity (Fig. 3) in similarity with the conventional gas-mixing indexes, and it increased also with increased AGS pressure in normogravity. In hypergravity, however, pressurizing the AGS to 6 kPa did not change SnIII(total), and when the AGS pressure was further increased to 12 kPa the SnIII(total) was significantly reduced. The latter finding might be due to the extensive basilar airway closures discussed above, resulting in reduced sequencing between regions, and/or it might be due to the increased VT/FRC. The primarily obtained, not adjusted, first-breath SnIII(DCDI) results, which reflect intraregional ventilation distribution, were similar to the first-breath SnIII(total) findings. Unadjusted SnIII(DCDI) demonstrated stepwise greater inhomogeneity with increasing gravity. In normogravity, the first-breath SnIII(DCDI) also increased in a stepwise fashion when the AGS was pressurized to 6 or 12 kPa. In hypergravity, this index decreased when the AGS pressure was increased from 6 to 12 kPa. After adjusting the first-breath SnIII(DCDI) for the influence of changes in VT/FRC (18), a marked increase of intraregional inhomogeneity after AGS pressurization was, however, evident even in hypergravity (Fig. 4). These findings might be the result of distortion of the most peripheral airway units, such as changes in the geometry and/or mechanical properties of single acini or small groups of acini. When gas trapping becomes extensive, as occurs when the AGS is pressurized in hypergravity, the most distorted and/or unevenly ventilated acini or groups of acini in the basilar lung regions have presumably ceased to participate in ventilation because of airway closures. The fact that intraregional inhomogeneity appears to persist and even increase suggests that the still ventilated units have become geometrically or mechanically distorted to a large extent. By the adjustment of the first-breath SnIII(DCDI) for the increased VT/FRC, this phenomenon can be disclosed in these presumably relatively overventilated lung units. The adjustment of the first-breath SnIII(DCDI) results for the change in first-breath VT/FRC from the baseline situation (+1 Gz, AGS not pressurized) in the present study was performed to allow more adequate comparisons between the different test situations. In their MBW study performed on Earth and in sustained µG, Prisk et al. (34) solved this problem by keeping the expiratory reserve volume identical to that in the standing position on Earth, assuming a constant RV. This approach was, however, not feasible in the present study. Because of the marked variations in FRC between the different test situations in the present study, we felt that an adjustment based on the previously shown effects of variations in VT/FRC on SnIII would provide a more realistic and comparable picture of the changes in intraregional ventilation distribution, especially when the AGS was pressurized. Whereas the SnIII(total) reflects changes in interregional as well as intraregional inhomogeneity, i.e., SnIII(DCDI), it is likely that the true changes in SnIII(total) follow those of the adjusted SnIII(DCDI) to a large extent, but on the basis of our laboratory's previous study (18) we could not justify an adjustment of the SnIII(total) variable. Our adjustment procedure is, however, novel, and the validity and limitations of the procedure in different situations need to be confirmed in future studies. TheSCDI, the index used for assessing CDI,
increased significantly by 50% from +1 to +2 Gz, but at +3
Gz the further increase was only ~10% (Fig. 5). No
effects on CDI were seen when the AGS was inflated to 6 kPa in
normogravity, but it increased by 100% on average for SF6
when the AGS was inflated to 12 kPa. In contrast, CDI was approximately
halved when the AGS was inflated to a pressure of 12 kPa at +3
Gz. A similar marked reduction in inhomogeneity when the
AGS was inflated to 12 kPa at +3 Gz, as found with the SCDI, was not seen with the conventional
gas-mixing indexes, suggesting that the lesser inhomogeneity was
related to reduced sequencing. Interestingly, in the previous VC SBW
study, the SIII for He was significantly reduced
when the AGS pressure was increased from 6 to 12 kPa at +3
Gz, whereas the SF6 slope did not change (19). This difference in response between the gases could
be interpreted as evidence of somewhat reduced interregional
inhomogeneity paired with greater intraregional intra-acinar
inhomogeneity. It is also interesting to note that
SCDI was greater for SF6 than for
He in situations with moderately increased gas trapping, i.e., at +2
and +3 Gz with uninflated AGS and also in normogravity with
pressurized AGS (Fig. 5). We, therefore, speculate that the SF6-vs.-He difference in SCDI
reflects intraregional CDI occurring in basilar lung regions, possibly
as a result of pulmonary vascular congestion and the positive pleural
pressure surrounding the most dependent lung zones. When the AGS is
inflated in hypergravity, these unevenly ventilated basilar lung units
become noncommunicating, paradoxically resulting in improved
convection-dependent ventilation distribution.
The first-breath (SF6-He)SnIII
increased significantly with increasing gravity (Fig. 6) in accordance
with the first-breath SnIII(DCDI), indicating
distorted acinar geometry and/or mechanics in hypergravity. It is
likely that such distortion also occurred when the AGS was inflated,
although no significant changes were seen, because this possible effect
was masked by the airway closures, as previously discussed. In the
previously quoted study on the effects of VT/FRC on
SnIII (18), the
(SF6-He)SnIII variable was found to
decrease with increasing VT/FRC in the upright position, but there was a large scatter of data, suggesting that there may be
marked interindividual differences. Therefore, we did not make any
adjustments in the present study to this variable for the observed
changes in VT/FRC.
MBW findings in µG.
Two MBW studies performed in sustained µG have been reported
previously (34, 35). On the Spacelab Life Sciences (SLS)-1 mission, multiple-breath N2 washouts were
undertaken by four subjects with VT of ~700 ml or
~1,250 ml, the latter being used for SnIII analysis
(35), whereas on the SLS-2 mission the same number of
subjects performed multiple-breath N2 washouts and
simultaneous washins of He and SF6 (34). In
the SLS-2 study, the washouts were done with a VT of
~1,250 ml and a fixed preinspiratory lung volume, corresponding to
the FRC in the standing position. This allowed for a fixed
VT/FRC in all test situations. The SLS-1 study showed that
the inhomogeneity measured by MBW in normogravity remained essentially
unchanged when in µG, and the authors concluded that the mechanisms
determining inhomogeneity during almost-normal breathing are not
gravitational in origin (35). However, in the SLS-2 study,
the SnIII for SF6, He, and
N2 over the course of the washout were reduced in µG
compared with the standing position in normogravity, and the
(SF6-He) SnIII was also reduced in
µG (34). These findings suggest less overall and less
intra-acinar inhomogeneity in weightlessness. Interregional
inhomogeneity as measured by SCDI was not
significantly reduced in µG (34), but a relatively
greater reduction in CDI for He than for SF6 or
N2 was observed and interpreted as evidence that the
nongravitational inhomogeneity occurs between closely located lung
units. These units must consequently be close enough for the highly
diffusible He gas to reduce the CDI-generated concentration differences
within the time of a normal breath, suggesting that they comprise small groups of acini or a single acinus. Surprisingly, the slope index of
end-tidal inert-gas concentrations over the washout was significantly reduced for SF6 in µG, indicating increased inhomogeneity
(34). This index is thought to reflect mainly
interregional inhomogeneities, and the authors suggested that this
finding supports the view that CDI persists in µG (34).
|
Summary and conclusions. During normal breathing, moderately increased gravity in the head-to-foot direction results in airway closures and produces greater inter- and intraregional ventilation inhomogeneity in the communicating lung. Moderate compression of the abdomen and the lower limbs by pressurization of an AGS in normogravity also produces gas trapping and inter- and intraregional ventilation inhomogeneities. Pressurization of the AGS in hypergravity results in extensive gas trapping, presumably in the most basilar lung zones, and significant reduction of FRC. As a consequence, a greater proportion of inspired gas will probably be directed to the middle and the upper lung zones, with an accompanying improvement in interregional ventilation distribution, whereas intraregional ventilation inhomogeneity appears to increase.
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ACKNOWLEDGEMENTS |
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We acknowledge the skillful technical assistance given by Roger Kölegård and Bertil Lindborg.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Grönkvist, Swedish Defence Research Agency, Defence Medicine, PO Box 13 400, S-580 13 Linköping, Sweden (E-mail: mikgro{at}foi.se).
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.
First published December 6, 2002;10.1152/japplphysiol.00612.2002
Received 9 July 2002; accepted in final form 26 November 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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E in 12 test subjects and
VTG,SF6/FRC in 10 test subjects in
different test situations defined by gravity and anti-G suit pressure
