Vol. 89, Issue 1, 385-396, July 2000
HIGHLIGHTED TOPICS
Physiology of a Microgravity
Environment
Invited Review: Microgravity and the lung
G. Kim
Prisk
Department of Medicine, University of California, San Diego, La
Jolla, California 92093
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ABSTRACT |
Although environmental physiologists are readily able to alter
many aspects of the environment, it is not possible to remove the
effects of gravity on Earth. During the past decade, a series of
spaceflights were conducted in which comprehensive studies of the lung
in microgravity (weightlessness) were performed. Stroke volume
increases on initial exposure to microgravity and then decreases as
circulating blood volume is reduced. Diffusing capacity increases
markedly, due to increases in both pulmonary capillary blood volume and
membrane diffusing capacity, likely due to more uniform pulmonary
perfusion. Both ventilation and perfusion become more uniform
throughout the lung, although much residual inhomogeneity remains.
Despite the improvement in the distribution of both ventilation and
perfusion, the range of the ventilation-to-perfusion ratio seen during
a normal breath remains unaltered, possibly because of a spatial
mismatch between ventilation and perfusion on a small scale. There are
unexpected changes in the mixing of gas in the periphery of the lung,
and evidence suggests that the intrinsic inhomogeneity of the lung
exists at a scale of an acinus or a few acini. In addition, aerosol
deposition in the alveolar region is unexpectedly high compared with
existing models.
ventilation; perfusion; ventilation-perfusion ratio; lung volumes; diffusing capacity; gas exchange; aerosol deposition; aerosol
dispersion; hypoxia; hypercapnia
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INTRODUCTION |
THE LUNG IS AN UNUSUAL ORGAN in that it
comprises little actual tissue mass in a relatively large volume. It is
an expanded network of air spaces and blood vessels designed to bring
gas and blood into very close proximity to each other to facilitate efficient gas exchange. As a direct consequence of this architecture, the lung is highly compliant and is markedly deformed by its own weight.
Although there is little, if any, structural difference between the top
and bottom of the normal human lung, there are marked functional
differences caused by the effects of gravity. For example, there are
significant differences in regional lung volumes, ventilation, parenchymal stress, blood flow, ventilation-to-perfusion ratio (
A/
), and gas exchange (9,
42, 52, 93, 94,
95).
Numerous studies have examined the influence of gravity on the lung, by
using either postural change as the alteration in gravity or
hypergravity as a means of increasing the gravitational effect.
However, data obtained in the absence of gravity have only recently
become available. This review summarizes the results of some of those studies.
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MAKING PULMONARY FUNCTION MEASUREMENTS IN MICROGRAVITY |
There are only two practical methods of achieving microgravity
suitable for human experimentation: parabolic flight in aircraft and
spaceflight. Parabolic flight has the advantage of being relatively accessible and (in comparison to spaceflight) inexpensive. However, it
provides only short periods of microgravity (~20-25 s), and these are usually sandwiched between periods of hypergravity because of
the maneuver the aircraft must fly. Although spaceflight provides sustained microgravity (~1 wk to more than 1 yr at present), flight opportunities are infrequent at best.
Since 1983, the US Space Shuttle has, at times, carried the
European-built Spacelab in the cargo bay. Spacelab provided a large
increase in the habitable volume of the normally cramped Shuttle and
gave researchers a normoxic, normobaric environment in which to conduct
research. Space Shuttle flights are limited to missions of short
duration (the maximum currently is 17 days); therefore, only acute
phases of the adaptation to microgravity can be studied. Missions of
longer duration have, to date, been limited to the Mir space station
and before that to Salyut and Skylab, although there have been few
studies in those settings.
Both head-down tilt and water immersion have been used as analogs of
microgravity. However, these methods do not adequately simulate
microgravity in terms of lung function, and they are not discussed in
this review. There are, however, reviews that may prove useful for
comparison purposes (e.g., see Refs. 32 and 55).
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PULMONARY BLOOD FLOW AND FLUID REDISTRIBUTION |
Total pulmonary blood flow and fluid distribution.
The first direct measurements of pulmonary blood flow were made during
Spacelab Life Sciences-1 (SLS-1) in 1991. Seven subjects were studied
over the course of a 9-day mission. Cardiac output rose by ~35%
above preflight standing levels 24 h after the onset of
microgravity and then decreased during microgravity exposure. There was
a slight bradycardia, and, as a result, stroke volume was increased by
60-70% early in flight and also showed a subsequent decrease
(Fig. 1) (66). Similar
results were obtained using an independent technique on SLS-1 and SLS-2
and showed an overall 26% increase in cardiac output at rest in
microgravity (77) and a 55% increase in cardiac stroke
volume. Subsequent measurements on Spacelab D-2
(82) confirmed the SLS-1 measurements.
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Fig. 1.
Cardiac stroke volume during 9 days of exposure to
microgravity (µG). Data are expressed as percentage of preflight
standing. # P < 0.05 compared with preflight
standing. + P < 0.05 compared with preflight
supine. [From Prisk et al. (66).]
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Echocardiographic measurements made during SLS-1 (10)
showed increases in cardiac dimensions and stroke volume of a similar magnitude. Of particular interest, however, is the fact that these increases occurred in the face of significant decreases in cardiac filling pressures, inferred from central venous pressure (CVP). Measurements made on SLS-1 and SLS-2 (10) and
independently on D-2 (29) show convincingly that, contrary
to expectations, CVP falls in microgravity. Because the changes in CVP
occur within seconds of the removal of gravity, it seems highly
unlikely that there is any change in cardiac muscle performance per se.
Thus the change implies that transmural pressure must have increased, presumably due to a decrease in extracardiac pressure. The fact that
lung volume actually decreases slightly on entry into microgravity (implying an overall increase in pleural pressure) suggests that local
pressure changes must be considered when considering cardiac performance. Similar changes in intravascular pressures have been seen
in parabolic flight (45), although a clear understanding of the seemingly contradictory results is not yet available
(97, 98). Recent observations
(87) support the suggestion of a decrease in extra cardiac
pressure during parabolic flight.
Measurements of pulmonary CO-diffusing capacity
(DLCO) and the membrane component (Dm) both
show increases in microgravity of ~25% (66), with no
change in either during a 9-day flight. These changes likely stem from
a more uniform filling of the pulmonary vasculature in microgravity
with recruitment of capillaries near the apices that are unperfused in
1 G. The possibility of pulmonary edema formation in microgravity was
suggested by Permutt (60); however, evidence suggests that
this does not occur. If edema had occurred, a decrease in
DLCO and Dm would have been expected early in
flight, with possible increases later as the edema resolved. Pulmonary
tissue volume, which is sensitive to extravascular fluid in the lungs
(61), was unchanged after 24 h of microgravity and
was 20-25% lower after 9 days (82) despite increases
in thoracic blood volume (4, 43,
56). These results are consistent with observations of the
low compliance of the pulmonary interstitium (53), which,
in the presence of a pressure fall (10), would be expected
to result in a gradual reduction in fluid in the pulmonary tissue.
Distribution of pulmonary perfusion.
Gravity has long been known to have a strong influence on the
distribution of pulmonary perfusion (94, 95).
More recently, studies have shown that, at least in some species,
nongravitational factors are also important (6,
31, 88, 92) and that there is
also nongravitational inhomogeneity of pulmonary blood flow in human
lungs (38).
There are no direct measurements of the distribution of pulmonary blood
flow during spaceflight. Imaging was performed after parabolic flights
in F-100 jets in which radioactively labeled microaggregated albumin
was injected into the subjects during the weightless portion of the
flight (79). These studies showed some increase in apical
blood flow in microgravity compared with that shown in the upright
position in 1 G.
Because of the difficulties associated with radioactive imaging
techniques in flight, an indirect technique allowed inferences to be
made about the distribution of pulmonary blood flow (50). Subjects hyperventilated for 20 s, reducing the overall
PCO2 in all regions of the lungs. They then
rapidly inhaled to total lung capacity (TLC) and held their breath for
15 s. During this breath-hold period, CO2 evolved into
the alveoli at a rate proportional to the blood flow per unit alveolar
volume. Because the lung was at TLC, any interregional differences in
lung volume were minimized; therefore, the CO2 level in a
lung region became a marker of the perfusion of that region. At the end
of the breath-hold period, the subject exhaled in a controlled fashion
to residual volume (RV). During the exhalation, markers of
interregional inhomogeneity such as cardiogenic oscillations and a
terminal fall in CO2 after the onset of airways closure
provided indications of the degree of inhomogeneity of perfusion.
In 1 G, there were prominent cardiogenic oscillations and a marked fall
in CO2 toward the end of exhalation (68). In
supine in 1-G tests, the heights of both the cardiogenic oscillations and the terminal fall were decreased to ~60% of that seen standing (Fig. 2). These observations are
consistent with the known vertical gradient of pulmonary blood flow and
its reduction in the supine position.
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Fig. 2.
Relative size of cardiogenic oscillations in
CO2 and height of phase IV. Values are means ± SE;
n = 4 subjects. For purposes of comparison, height of
phase IV (which is negative in 1 G) has been inverted. Note that, in
µG, height of phase IV becomes disproportionately small compared with
that at 1 G standing and 1 G supine. * Significantly different
(P < 0.05) compared with standing. [From Prisk et al.
(68).]
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In sustained microgravity, the cardiogenic oscillations persisted,
whereas the terminal fall was absent. Because airway closure still
occurs in microgravity (see PULMONARY VENTILATION, below), the absence of a terminal fall of CO2 means that blood flow
in the regions of lung behind airways that close, and in the regions of
lung behind airways that remain open, must be similar. This is
consistent with the removal of the top-to-bottom gradients in blood
flow that are present in 1 G and with the increase in DLCO and its components seen in microgravity
(66).
The persistence of cardiogenic oscillations in microgravity, however,
implies that there is persisting inhomogeneity of pulmonary blood flow.
Although microgravity would be expected to abolish apicobasal
differences in perfusion, it would not necessarily affect other
nongravitational interregional mechanisms of inhomogeneity (6, 38). Microgravity also would not
necessarily affect the variability in lung compliance within small
regions of the lung (57), which may contribute to
differential gas flows from different areas of the lung during the
cardiac cycle. The residual inhomogeneity must, however, be on a scale
larger than the acinus because concentration differences on that scale
would be obliterated due to the fact that small differences in the
distance between different acini and the mouth would result in
cardiogenic oscillations being "smeared out" by the time the gas
was expired and to diffusional mixing, which would reduce differences
in CO2 between closely spaced regions.
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PULMONARY VENTILATION |
The inhomogeneity of pulmonary ventilation results from two major
sources. The first is commonly recognized and is termed convective-dependent inhomogeneity (CDI). CDI results from two regions
of the lung having different amounts of ventilation per unit lung
volume (specific ventilation) and may be gravitational and
nongravitational. The second is diffusion-convective-dependent inhomogeneity (DCDI). This is a complex interaction between the convective and diffusive transport of gas in the branching structure of
the lung (58, 86). Because it depends on the
interaction between convection and diffusion, DCDI is only operative
when these two mechanisms are of a similar magnitude. In humans, DCDI is only operative at about the level of the first acinar generations. Thus DCDI can be thought of as small-scale inhomogeneity, whereas CDI
is necessarily observed at a larger scale (since if it were present within the acinus, diffusive transport would abolish the concentration gradients set up by CDI).
Convective inhomogeneity.
Single-breath washouts (SBWs) have been performed several times in
microgravity. The first was in parabolic flight: Michels and West
(50) showed that there were marked reductions in the main
markers of interregional inhomogeneity, cardiogenic oscillation size,
and the terminal rise in nitrogen concentration following a vital
capacity (VC) inspiration of pure oxygen. Such reductions are
consistent with a reduction or removal of top-to-bottom differences in
ventilation. However, Michels and West showed that some inhomogeneity persisted, based on the continued presence of cardiogenic oscillations and a terminal rise. The question that could not be resolved was whether the preceding period of hypergravity necessary to fly the
parabolic maneuver resulted in residual inhomogeneities in the
microgravity phase.
During SLS-1, VC SBW nitrogen tests were performed on the seven-member
crew (34). These tests also included the inhalation at RV
of a small argon bolus to provide information on airway closure. The
results largely confirmed those from parabolic flight, with marked
reductions in the height of the terminal rise in N2 and in
cardiogenic oscillations but a clear persistence nevertheless. This
suggested a strong role of gravity in CDI with considerable influence
from nongravitational factors. Airway closure measured with the argon
bolus, often considered a gravitational phenomenon, still occurred at a
similar lung volume in microgravity in most subjects, although clearly
this was not closure of the gravitationally dependent regions of the
lung seen in 1 G. The onset of airway closure occurred at the same
absolute lung volume in 1 G and in microgravity, suggesting that some
units reach the point of zero elastic recoil at a similar absolute lung
volume regardless of the gravitational distortion of the lung.
In the multiple-breath washout (MBW) technique, N2 is
eliminated over a series of breaths. This is potentially advantageous because the breaths are much smaller and more closely approximate those
of normal breathing compared with the VC maneuvers used in the
single-breath tests. MBW tests performed during SLS-1, analyzed in six
different ways, showed few significant changes between the data
collected standing and those collected in microgravity (67). This surprising result led to the conclusion that
the primary determinants of CDI during tidal breathing in the upright posture were not gravitational in origin. Similarly, analysis of the
data collected during rebreathing tests performed on D-2 (83) showed that the degree of gravity-independent
inhomogeneity of specific ventilation was at least as large as the
gravity-dependent inhomogeneity of specific ventilation in 1 G.
Diffusive inhomogeneity.
The SBW performed in SLS-1 (34) also confirmed the
previous observation made in parabolic flight (50),
namely, that phase III slope was only slightly reduced by the removal
of gravity. Although CDI in conjunction with asynchronous emptying had
been shown to contribute to phase III slope, various studies (e.g., Ref. 18) had suggested that only about one quarter of the observed phase III slope in normal subjects was due to CDI. Other studies (15) showed that the continued exchange of respiratory
gases in the lung made an additional ~10% contribution to phase III slope, leaving the bulk of the slope being due to DCDI effects. Consistent with these estimates, the observations in SLS-1 showed that
phase III slope for N2 in microgravity was ~75% of that
seen standing in 1 G (34).
Diffusive effects can be studied by performing washouts in which trace
quantities of He and sulfur hexafluoride (SF6) are included
in the test gas used for inspiration. Because of the wide difference in
molecular weight (4 vs. 146) between these gases, He diffuses
about six times more readily than SF6. In 1 G, this
difference in diffusivity results in the phase III slope for
SF6 being considerably steeper than that for He. There are two causes for this. The transport of the more diffusible He becomes dominated by diffusion at a point in the airways more proximal (central) than does the less diffusible SF6, and the human
acinus is more asymmetric in the periphery (37). Second,
the more rapid diffusion of He serves to abolish concentration
gradients established either by CDI or DCDI, flattening the He slope
(86).
During D-2 and SLS-2, SBWs using He and SF6 were performed.
In both cases, there was a flattening of the phase III slopes for both
gases, but, surprisingly, the He and SF6 slope became the
same in microgravity (69, 84). When a
breathhold was also performed, the phase III slope for SF6
actually became flatter than that for He (Fig.
3). The only other known example of the SF6 slope becoming flatter than the He slope was in
heart-lung transplant recipients undergoing acute rejection episodes.
In that case, conformational changes near the entrance of the acinus, possibly as a result of acute inflammation, steepened the He slope (81). Inflammation was clearly not the cause in
microgravity, since the phase III slope difference had returned to
preflight values within 6-10 h of landing. The results from
microgravity suggest that a conformational change in the acinus such as
asymmetric narrowing of daughter airways at branch points, perhaps due
to peribronchial cuffing, was responsible. Alternatively, changes in
cardiogenic mixing may have altered the position and/or extent of the
quasi-stationary concentration front developed by the interaction between convective and diffusive transport. However, no specific mechanism could be identified. When the same tests were performed in
the 25 s of microgravity available in parabolic flight, the phase
III slope difference between SF6 and He actually increased, as opposed to the decrease seen in sustained microgravity
(47). This suggests that fluid shifts, which take longer
than 25 s to occur, likely play a role. Because the changes all
resulted from differences in the behavior of the more diffusible He, it
seems that the changes in peripheral gas mixing occur at the level of the entrance of the acinus, where DCDI dictates the behavior of He.
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Fig. 3.
A: normalized phase III slopes of He
( ) and SF6 ( ) from subjects
standing in 1 G and during sustained µG. Note that, whereas all data
collected in 1 G have significantly steeper slopes for sulfur
hexafluoride (SF6) than for He, this difference is
abolished in µG and is actually reversed after a breath hold.
B: same data as A separated into breath-hold and
non-breath-hold conditions. * SF6 slope significantly
different from that of He, P < 0.05. [From Lauzon et
al. (47).]
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During SLS-2, MBWs using He and SF6 were also performed
(64). CDI in these near-tidal-volume breaths was largely
unaltered between 1 G and microgravity, in line with the previous MBW
study (67). The SF6 
He slope
difference was also reduced (although, in these smaller volume breaths,
not abolished), similar to that seen in the SBW study
(69). The data were partitioned into the effects of CDI
and DCDI (17, 18, 85). This
partitioning showed that for N2 and SF6, both
of which have relatively distal quasi-stationary diffusion fronts,
there was little difference in the contribution of CDI to overall
inhomogeneity between 1 G and microgravity. However, for He, with a
more proximal front, the CDI contribution was abolished in microgravity
(Fig. 4). This suggests that the CDI seen
to persist in microgravity (34, 67) must be
located between units that are sufficiently close to each other, so
that diffusion of He, but not of N2 or SF6, is
an efficient means of abolishing the concentration gradients it
produces (i.e., between acini or between groups of a few
acini). This is the first instance in which it was possible to
estimate the size of the structures responsible for the inhomogeneity
of ventilation in microgravity. The recent parabolic flight study of
inhaled gas boluses also suggests that airway closure in microgravity
occurs in very close proximity to airways that remain open
(23), again providing a similar scale for the intrinsic
inhomogeneity of the lung.
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Fig. 4.
Contribution of convection-dependent inhomogeneity to the
normalized slope of phase III
( SCDI) of SF6, He,
and N2 measured during multiple-breath washouts. Filled
bars, standing position; open bars, µG. [From Prisk et al.
(64).]
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PULMONARY GAS EXCHANGE AND THE DISTRIBUTION OF
 A/ |
Measurements made during SLS-1 and SLS-2 showed that oxygen
consumption and CO2 production were unchanged by exposure
to microgravity (63). Tidal volume decreased by ~15%,
and there was a compensatory increase in breathing frequency (9%). The
increase in frequency did not completely compensate for the change in
tidal volume, and total ventilation decreased by ~7%. However, when
the reduction in physiological dead space, which presumably results
from the removal of areas of high A/, was
factored in, alveolar ventilation remained unchanged in microgravity
compared with that measured standing in 1 G. The selection of a
different combination of tidal volume and breathing frequency appears
to result from the removal of the weight of the abdominal contents and
shoulder girdle, placing the inspiratory muscles in a different
configuration. There was no evidence of significant changes in
respiratory drive based on the absence of large changes in inspiratory
time and mean inspiratory flow.
There have been no direct measurements of A/
distribution in microgravity. No imaging techniques have been used in
flight that would allow such measurements, and techniques such
as the multiple inert gas elimination technique (89) are
too complex and time consuming for spaceflight at this time. Even such
indirect but invasive methods such as alveolar-arterial oxygen gradient measurements have not been performed in microgravity. There is a brief
report of a decrease in arterial saturation measured from arterialized
capillary blood sample, (36), but this has not been confirmed.
During a controlled, slow exhalation from TLC to RV, there is a slope
to the CO2 expirogram, cardiogenic oscillations, and a
terminal fall, all of which are markers of inhomogeneity of gas
exchange. During the exhalation, the intrabreath respiratory exchange
ratio can be measured, and, by comparing this with a mathematical model
of gas exchange in a comparable lung, the deviation from a perfect lung
can be determined (33). Thus the range in the intrabreath
respiratory exchange ratio can be converted to a range of
A/ (96), and this has been shown
to reflect the degree of A/ inequality in the
lung (48, 72). The technique is indirect at
best and relies on a comparison between observed behavior and
(theoretical) ideal behavior of the lung. Other effects may also
intrude, such as changes in sequential emptying between different
parallel regions, which might introduce changes into the expirograms
even in the absence of a change in A/
distribution. Nevertheless, it is the only information on the range of
A/ in the lung in microgravity available to date.
During SLS-1 and SLS-2, there were significant cardiogenic oscillations
seen in the CO2 expirogram in microgravity. Their continuing presence is strong evidence for continued interregional differences in A/ in microgravity, since
cardiogenic oscillations largely reflect regional differences in gas
concentration (28). These regional differences in this
case result from differences in gas exchange.
There was a marked reduction in the A/ range
during phase IV of a prolonged exhalation (Fig.
5), consistent with the idea that the
top-to-bottom gradient in A/ had been
abolished in microgravity. The result is consistent with the
observation that alveolar dead space was reduced in microgravity
because of a reduction in the high A/ regions
of the lung.
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Fig. 5.
Range of ventilation-perfusion ratio
(A/) seen over phase III and phase IV of
prolonged exhalations in 8 subjects studied standing (vertically lined
bars), supine (horizontally lined bars), and in µG (open bars).
Values are means ± SE. Significantly different (P < 0.05) compared with * standing and + supine. [From Prisk et
al. (63).]
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There was no change in the range of A/
between standing and microgravity over phase III of the prolonged
expiration, the portion approximating the volume range used during
tidal breathing. This result was surprising given the prior
observations in which microgravity resulted in a reduction in the
topographical gradients of both ventilation (34) and
perfusion (68). It would seem that the different behaviors
seen between 1 G and microgravity in phase III and phase IV of the
expiration point to a different basis for the inhomogeneity in
A/. It may be that gas exhaled during phase
IV (in 1 G) is more reflective of top-to-bottom gradients in
A/, since, in 1 G, airway closure occurs
predominately in gravitationally dependent lung regions. However,
during phase III, expired gas concentration differences may be more
reflective of nongravitational interregional differences in
A/. Certainly, the data suggest that, before
the onset of airway closure, the principal determinants of
A/ inequality in normal subjects are not
gravitational in origin, although whether the primary cause is residual
inhomogeneity of ventilation or perfusion remains unclear.
Lauzon et al. (46) examined the phase relationships
between the cardiogenic oscillations in the expired gas signals
measured during the single-breath tests performed on SLS-2. The phase
relationship between CO2 (a gas that is added to the
alveolar space at a rate dependent on the A/)
and He (a gas added during inspiration and dependent on ventilation)
reversed between 1 G and microgravity. In 1 G, CO2 was in
phase with He (high CO2 was associated with high He),
consistent with the gravitational model in which high ventilation (the
bases of the lungs) is associated with low A/ (resulting in high CO2, also in the bases of the lungs).
However, in microgravity, this phase relationship was reversed, and
high ventilation was now associated with high
A/. This suggests that, in microgravity,
areas of high ventilation are associated with areas of low perfusion
and vice versa. Although other nongravitational gradients in blood flow
are present in the lung (6, 31,
38), the phase reversal seen between 1 G and microgravity
provides direct evidence of a role of gravity in the distribution of
A/ in the normal human lung. It was
hypothesized that, although the topographic gradients in both
ventilation and perfusion may be reduced in microgravity, the lack of
spatial correlation between ventilation and perfusion results in a
wider distribution of A/ than might otherwise
be expected.
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LUNG VOLUMES AND PULMONARY MECHANICS |
Vital capacity.
The first study of lung volumes in microgravity was performed in Skylab
in the early 1970s (75), with VC showing an ~10% decrease. However, ground controls that used the same hypobaric atmosphere also showed a 3-5% reduction, confounding the
spaceflight results (74). Michels and West
(50) showed no consistent differences in VC in
microgravity during parabolic flight, except an increase was noted when
the initial push to RV was during microgravity and the remainder of the
inspiration occurred in 1 G. They suggested that this might be due to a
lower RV in microgravity due to an increase in intrathoracic blood
volume. Radiographic measurements also performed in parabolic flight
(49) showed a nonsignificant decrease in apical-to-basal
height and an increase in lung width. Paiva et al. (59)
showed an ~8% reduction in VC during microgravity compared with
during 1 G. Forced vital capacity (FVC) measured in parabolic flight
was reduced by a small amount (100-200 ml) (35). This
result contradicted that of a previous study of FVC in parabolic flight
(30), but the difference appears to be the failure to
account for a falling cabin pressure during the microgravity phase of
the flight in the earlier study.
During the SLS-1, VC was measured in seven subjects over the course of
a 9-day flight (26). After ~24 h in microgravity, VC was
reduced by ~5% compared with that standing in 1 G. By 72 h, the
reduction had been abolished, and values later in flight were not
different from control values (Fig. 6).
Similar results were seen in FVC (25). The suggestion is
that an early inflight increase in intrathoracic blood volume is
responsible, with a subsequent increase in VC as plasma volume is
reduced (3).
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Fig. 6.
Inspiratory and expiratory vital capacities (IVC and EVC)
for 4 payload crew members of Spacelab Life Sciences-1. Vital capacity
on flight day 2 (FD-2) was intermediate between standing and
supine values and was reduced compared with flight days 4 (FD-4) and 9 (FD-9). Values are means ± SE
* Significantly different from standing (P < 0.05).
[From Elliott et al. (26).]
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Functional residual capacity.
Agostoni and Mead (2) predicted that microgravity would
reduce functional residual capacity (FRC) by ~10%. This was based on
a cranial shift of the diaphragm and abdominal contents as gravity was
removed (an effect that would decrease FRC), an outward movement of the
rib cage as the weight of the abdomen was removed, and an upward
movement of the shoulder girdle (effects that would increase FRC).
Their prediction was largely confirmed by measurements performed during
SLS-1 (26), in which FRC decreased by ~15% in
microgravity compared with that shown in standing subjects in 1 G but
was higher than that measured supine. These results have subsequently
been confirmed by measurements in other flights (82).
Results from short periods of microgravity in parabolic flight are
consistent with orbital studies, which showed a reduction in FRC of
~400 ml in microgravity compared with 1 G in seated subjects
(59).
Residual volume.
RV is generally quite resistant to change. Transitions between upright
and supine positions (1, 26, 80)
and water immersion (11, 12, 73)
resulted in no significant decrease in RV. Similarly, central vascular
engorgement produced by G-suit inflation does not reduce RV
(11).
In sustained microgravity, RV was shown to decrease by ~18% (310 ml)
compared with that shown in standing subjects and was also
significantly below that measured in supine subjects (by ~220 ml)
(26). A likely explanation is that, in microgravity, the
large, apicobasal gradients in regional lung volume present in 1 G are
abolished (Fig. 7). In 1 G, when lung
volume is reduced below FRC, airway closure begins in the more
gravitationally dependent lung regions (because of distortion of the
lung by its own weight), and this airway closure progresses up the lung
until RV is reached (51). Thus the regional RV of basal
lung units is dependent on airway closure, whereas the regional RV of
apical lung units is dependent on the balance of local static forces.
The result is a large difference in regional RV between the top and
bottom of the lung in 1 G. In microgravity, however, the apicobasal
gradients in regional lung volume due to gravity are abolished. The
result is that regional volume of lung units is much more uniform, and no region reaches its trapped gas volume, resulting in an overall reduction in the RV of the lung (Fig. 7).
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Fig. 7.
A theoretical model of the lung at residual volume (RV)
during 1-G conditions and in µG. At RV, alveolar size increases from
base of lung to apex in 1 G and is uniform in µG. If area
2 is less than area 1, total sum of alveolar volumes
may be less at µG than at 1 G (depending on shape of chest wall).
Graph of distribution of alveolar size at RV (A) has been
modified from Ref. 52. TLCr, regional total lung capacity.
B and C: regional alveolar volumes at different
vertical distances during 1 G and µG, respectively. [From Elliott et
al. (26).]
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Forced expirations.
Castile et al. (14) demonstrated that postural changes
altered the position and magnitude of the sudden changes in flow that
characterize an individual's maximum expiratory flow volume (MEFV)
curve. These changes were consistent with wave speed theory (22) in which changes in local airway stresses could alter
the location of airway choke points. In parabolic flight, there was a
reduction in FVC and, at high lung volumes, a reduction in the lung
volume at which a given expiratory flow occurred in microgravity (35). These effects were consistent with an increase in
intrathoracic blood volume, which would engorge the lung with blood and
increase elastic recoil. At low lung volumes, there was a scooping out of the MEFV curve similar to that seen in recumbency (14)
and immersion (62) attributed to vascular engorgement.
In an orbital study that eliminated the periods of hypergravity
preceding microgravity, Elliott et al. (25) found an early inflight reduction in FVC that disappeared by the fourth day in microgravity. In addition, the reduction in lung volume at which a
given expiratory flow occurred was seen in the early flight data, but
this also disappeared later in flight, suggesting that intrathoracic
blood volume increases may have been responsible. However, at low lung
volumes, there were no discernible changes in the shape of the MEFV
curve as were seen in parabolic flight.
Peak expiratory flow was significantly reduced early in flight but was
back to control values after 9 days of microgravity. These reductions
were largely in the absence of parallel changes in lung volumes (e.g.,
FVC), suggesting that the change was not simply a consequence of
scaling (as was seen supine). It was suggested that the lack of a firm
platform to push against during the maneuver compromised the ability of
the subjects to generate maximum flows, with the recovery being due to
improved subject performance as they adapted to operating in a
microgravity environment.
Shape and movement of chest wall.
In parabolic flight, microgravity caused an inward displacement of the
abdominal wall, thus elevating the diaphragm and reducing lung volume
(59). There was no corresponding change in the rib cage,
consistent with the radiographic observations (49). The results are consistent with an increase in abdominal wall compliance, which was confirmed by Edyvean et al. (24) who showed an
increase in the abdominal contribution to tidal volume from 33% in 1 G to 51% in microgravity. By measuring gastric pressures, they
demonstrated that abdominal compliance increased from 43 to 70 ml/cmH2O between 1 G and microgravity. Importantly, their
data led them to suggest that there may be small, residual pleural
pressure gradients present in microgravity as a result of shape changes
in the chest wall, which may result in some residual inhomogeneity of ventilation.
In spaceflight, the measurements have been limited to noninvasive
studies of pulmonary mechanics. In the D-2 and Euromir-95 studies
(91), the abdominal contribution to tidal volume was seen
to increase from 31 to 58%, consistent with the results from parabolic flight.
| |
CONTROL OF VENTILATION |
Hypoxic response.
During the Neurolab mission, the hypoxic ventilatory response was
measured using an isocapnic rebreathing technique (71). In
microgravity, the slope of the increase in ventilation with decreasing
arterial oxygen saturation was only about one-half that measured when
the subjects were standing (Fig. 8).
Furthermore, this reduction was unchanged for the duration of the
16-day mission (65). The reduction was almost identical to
that seen when the hypoxic ventilatory response was measured in supine
subjects. Some studies reported changes in hypoxic response in humans
(76, 78, 99) and showed a
substantial reduction in hypoxic response in the supine position
compared with that in the upright position, although this is not well
known. This is probably because, in both microgravity and in the supine
position, there is a substantial increase in blood pressure at the
level of the carotid bodies because of the removal of the hydrostatic
pressure difference between the heart and neck. In cats, the arterial
chemoreceptors respond markedly to changes in blood pressure when they
are hypoxic, becoming less active as blood pressure increases, but no
such response is seen when conditions are hyperoxic (44).
Similar observations made in dogs suggest that the pathway for the
changes in the hypoxic response is central, as an isolated alteration in carotid distending pressure on one side of the animal results in
changes in chemoreceptor output on the contralateral side
(39, 40). These studies provide an
explanation of why there is a reduction in the hypoxic response both in
microgravity and supine, in the absence of changes in the pattern of
ventilation breathing air (63) and of changes in the
inspiratory occlusion pressures during air breathing (65).
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Fig. 8.
Slope of the hypoxic ventilatory response (HVR) measured
standing (vertically striped bars) and supine (horizontally striped
bars) in 1 G and in µG (open bars). HVR is approximately halved in
µG and supine. SaO2, arterial O2
saturation. Open brackets, P < 0.05 between adjacent bars.
* P < 0.05 compared with preflight standing. [From Prisk
et al. (65).]
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|
Hypercapnic response.
In sharp contrast to the ventilatory response to hypoxia, microgravity
resulted in no overall change in the ventilatory response to inhaled
CO2 (65), measured using a rebreathing
technique (70). Results collected during an earlier flight
also failed to show any change in the ventilatory response to
CO2 (65). Similarly, there was no change in
the response for supine subjects, consistent with previous studies on
the ground (78, 99). However, there was an
indication that the slope of the response steepened somewhat in both
microgravity and supine subjects and that this was accompanied by a
concomitant increase in the PCO2 at a
calculated ventilation of zero (a steeping and shift to the right of
the response). There was also a small increase in the resting end-tidal PCO2 of the subjects measured during quiet
breathing from 36 to 39 Torr (similar to that between standing
and supine of 36-41 Torr), raising the possibility of a shift in
the set point of the PCO2. Measurements made in
an environmental chamber study in which the
PCO2 was elevated to 1.2% (8.6 Torr) also
showed an early increase in the set point (27) that
gradually abated over the 21 days of that study. However, there were no
significant alterations when the environmental
PCO2 was controlled at 5.0 Torr. In the case of
Neurolab, environmental PCO2 averaged only ~2.3 Torr, a level below that in the chamber studies, and it remains unclear whether the ambient CO2 in the spacecraft is
responsible for the small changes seen in the CO2 response.
| |
INHALED AEROSOLS |
Long-term spaceflight represents a situation in which aerosol
deposition may be an important health consideration. In the spacecraft
environment, the potential for significant airborne particle loads is
high because the environment is closed and no sedimentation occurs.
Fires aboard the spacecraft, like that which occurred on the Mir space
station in 1997 (13), also produce large amounts of
airborne particles. Similarly, microgravity provides for potentially
high particle concentrations in the airways because particles that
normally sediment will not be removed from the airways, leaving them
potentially available for transport to the alveolar
regions.
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Fig. 9.
Comparison between experimental data of aerosol
deposition (DE) in short periods of microgravity and numerical data
obtained within a 1-dimensional model (see Ref. 18a).
A-C: µG, 1 G, and 1.6 G, respectively. For
each particle size, left bar of each pair represents experimental
value, and right bar of each pair represents numerical value with
contribution of each mechanism of deposition. Solid segments,
deposition by diffusion; hatched segments, deposition by sedimentation;
open segments, deposition by impaction. [From Darquenne et al.
(19).]
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|
There have been no studies of aerosol deposition in the human lung
during spaceflight. However, Hoffman and Billingham (41) studied the deposition of 2.0-µm particles during parabolic flights. They saw an almost linear increase in deposition with G level over the
range 0-2 G. They showed a lower deposition than that suggested by
Beekmans (7, 8) who had predicted a reduction in total deposition but an increase in deposition in the alveolar region in microgravity due to greater penetration of the particles into
the lung. Muir (54) made similar predictions.
In retrospect, it appears that the results of Hoffman and Billingham
(41) were because of their choice of particle size (2.0 µm). Darquenne et al. (19) studied the total deposition of 0.5-, 1-, 2-, and 3-µm particles in a series of parabolic flights. For measurements made in 1 or 1.6 G, the results correlated very closely with one-dimensional model predictions, with a tendency for the
models to slightly overestimate total deposition. However, in
microgravity, total deposition significantly exceeded predictions in
all particles below 3 µm in size. The effect was greatest for 1-µm
particles, for which total deposition in microgravity was more than
twice that predicted by existing models (18a) (Fig. 9).
Because, for 0.5- and 1-µm particles, deposition by impaction is
negligible and because in microgravity there is no sedimentation, only
diffusion is apparently left to account for the deposition. The
conclusion drawn was that some form of "enhanced diffusion," likely
due to nonreversibilities of flow in the branching airway structure,
must be playing a role. Importantly, there was nothing to suggest that
this process was exclusively related to microgravity, and it is likely
that the hypothesized effect was likely operating in 1 G as well.
Subsequently, Darquenne et al. (20) performed a series of
bolus deposition and dispersion studies in 0, 1, and 1.6 G. They found
a strong dependence of deposition on both gravity and on penetration
volume. Importantly, dispersion continued to increase with penetration
volume in microgravity, showing that gravity is not the only mechanism
responsible for dispersion in the human lung. It seems likely that the
previously hypothesized nonreversibility of flow plays a significant
role in this process.
Aerosols also play a useful role in the study of convective mixing in
the lung, especially in microgravity, in which there is no
sedimentation. Because the intrinsic motion of the particles is so
small, they behave as a nondiffusing gas. Recent studies by Darquenne
et al. (21) clearly show that convective ventilatory inhomogeneity increases toward the periphery of the lung and that these
inhomogeneities persist in the absence of gravity.
| |
FUTURE DIRECTIONS |
After the completion of the Neurolab flight in 1998, the National
Aeronautics and Space Administration mothballed the highly successful
Spacelab system. In August of 1999, the Russian Mir space station was
abandoned after more than a decade of continuous habitation. The
promise for future spaceflight research lies primarily with the
International Space Station (ISS), but, until that facility is fully
operational, which will likely not be before 2004, there are likely to
be few opportunities for pulmonary function studies in space. These
opportunities will exist on some SpaceHab flights planned to
occur irregularly until the ISS is fully operational and on some
limited studies on the fledgling ISS. One series of experiments planned
for the early stages of the ISS will study the effects of
extravehicular activity (EVA, space walk) on the lung. The protective
suits used during EVA operate at a very low pressure (~30 kPa) to
enable astronaut mobility. As a consequence, EVA carries with it the
risk of gas bubble formation in the venous circulation and possible
decompression sickness (90). As these bubbles form
microemboli in the lung, they disrupt the distribution of
A/ and can be detected using the test of
intrabreath respiratory exchange ratio (16).
Some might conclude that all that has been done in this area of
research is sufficient. Certainly, it is true that, unlike some areas
of physiology (such as bone and muscle metabolism), there is little to
suggest that changes in pulmonary function as a result of microgravity
will limit the presence of humans in space. However, we simply do not
know what happens to the lung when gravity is removed for a long period
of time. In addition, microgravity provides a valuable tool to study
the effects of gravity on the lung itself and on the behavior of
material within the lung (e.g., inhaled particles), and the lung
provides a convenient means of monitoring cardiac function. A Pulmonary
Function System, part of the Human Research Facility for the ISS, is
under development, which may provide a means of continuing the study of
the effects of gravity on the lung.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: G. K. Prisk, Dept. of Medicine, Univ. of California, San Diego,
9500 Gilman Drive, La Jolla, CA 92093-0931 (E-mail:
kprisk{at}ucsd.edu).
| |
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TOP
ABSTRACT
INTRODUCTION
