G.

Kim Prisk
J Appl Physiol 89:385-396, 2000. You might find this additional information useful... This article cites 84 articles, 60 of which you can access free at: http://jap.physiology.org/cgi/content/full/89/1/385#BIBL This article has been cited by 2 other HighWire hosted articles: Effect of changing the gravity vector on respiratory output and control R. L. Dellaca, D. Bettinelli, C. Kays, P. Techoueyres, J. L. Lachaud, P. Vaida and G. Miserocchi J Appl Physiol, October 1, 2004; 97 (4): 1219-1226. [Abstract] [Full Text] [PDF] Effects of hypergravity on the distributions of lung ventilation and perfusion in sitting humans assessed with a simple two-step maneuver M. Rohdin, P. Sundblad and D. Linnarsson J Appl Physiol, April 1, 2004; 96 (4): 1470-1477. [Abstract] [Full Text] [PDF]
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J Appl Physiol 89: 385396, 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
Prisk, G. Kim. Invited Review: Microgravity and the lung. J Appl Physiol 89: 385396, 2000.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 spaceights 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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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 efcient 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 signicant differences in regional lung volumes, ventilation, parenchymal stress, blood ow, ventilation-to-perfusion ratio (VA/Q), and gas exchange (9, 42, 52, 93, 94, 95).

Numerous studies have examined the inuence 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.
MAKING PULMONARY FUNCTION MEASUREMENTS IN MICROGRAVITY

Address for reprint requests and other correspondence: G. K. Prisk, Dept. of Medicine, Univ. of California, San Diego, 9500 Gilman Drive, La Jolla, CA 920930931 (E-mail: kprisk@ucsd.edu). http://www.jap.org

There are only two practical methods of achieving microgravity suitable for human experimentation: parabolic ight in aircraft and spaceight. Parabolic ight has the advantage of being relatively accessible and (in comparison to spaceight) inexpensive. However, it provides only short periods of microgravity ( 2025 s), and these are usually sandwiched between periods of hypergravity because of the maneuver the aircraft must y. Although spaceight provides sustained mi385

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crogravity ( 1 wk to more than 1 yr at present), ight 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 ights 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).
PULMONARY BLOOD FLOW AND FLUID REDISTRIBUTION

Total pulmonary blood ow and uid distribution. The rst direct measurements of pulmonary blood ow 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 preight 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 6070% early in ight and also showed a subsequent decrease (Fig. 1) (66).

Fig. 1. Cardiac stroke volume during 9 days of exposure to microgravity ( G). Data are expressed as percentage of preight standing. #P 0.05 compared with preight standing. P 0.05 compared with preight supine. [From Prisk et al. (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) conrmed the SLS-1 measurements. 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 signicant decreases in cardiac lling 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 ight (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 ight. 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 ight. These changes likely stem from a more uniform lling 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 ight, with possible increases later as the edema resolved. Pulmonary tissue volume, which is sensitive to extravascular uid in the lungs (61), was unchanged after 24 h of microgravity and was 2025% 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 uid in the pulmonary tissue. Distribution of pulmonary perfusion. Gravity has long been known to have a strong inuence 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 ow in human lungs (38). There are no direct measurements of the distribution of pulmonary blood ow during spaceight. Imaging

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was performed after parabolic ights in F-100 jets in which radioactively labeled microaggregated albumin was injected into the subjects during the weightless portion of the ight (79). These studies showed some increase in apical blood ow in microgravity compared with that shown in the upright position in 1 G. Because of the difculties associated with radioactive imaging techniques in ight, an indirect technique allowed inferences to be made about the distribution of pulmonary blood ow (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 ow 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 ow and its reduction in the supine position.

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 ow 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-tobottom gradients in blood ow 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 ow. 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 ows 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.
PULMONARY VENTILATION

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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 G, height of phase IV becomes disproportionately small compared with that at 1 G standing and 1 G supine. * Signicantly different (P 0.05) compared with standing. [From Prisk et al. (68).]

The inhomogeneity of pulmonary ventilation results from two major sources. The rst 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 (specic 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 rst 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 rst was in parabolic ight: 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 dif-

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ferences 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 y 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 conrmed those from parabolic ight, 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 inuence 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 signicant 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 specic ventilation was at least as large as the gravity-dependent inhomogeneity of specic ventilation in 1 G. Diffusive inhomogeneity. The SBW performed in SLS-1 (34) also conrmed the previous observation made in parabolic ight (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 hexauoride (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, attening the He slope (86). During D-2 and SLS-2, SBWs using He and SF6 were performed. In both cases, there was a attening 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 atter than that for He (Fig. 3). The only other known example of the SF6 slope becoming atter than the He slope was in heartlung transplant recipients undergoing acute rejection episodes. In that case, conformational changes near the entrance of the acinus, possibly as a result of acute inammation, steepened the He slope (81). Inammation was clearly not the cause in microgravity, since the phase III slope difference had returned to preight values within 610 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 cufng, 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 specic mechanism could be identied. When the same tests were performed in the 25 s of microgravity available in parabolic ight, the phase III slope difference between SF6 and He actually increased, as opposed to the decrease seen in sustained microgravity (47). This suggests that uid 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. 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 contribu-

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PULMONARY GAS EXCHANGE AND THE DISTRIBUTION OF VA/Q

Fig. 3. A: normalized phase III slopes of He (F) and SF6 ( ) from subjects standing in 1 G and during sustained G. Note that, whereas all data collected in 1 G have signicantly steeper slopes for sulfur hexauoride (SF6) than for He, this difference is abolished in G and is actually reversed after a breath hold. B: same data as A separated into breath-hold and non-breath-hold conditions. * SF6 slope signicantly different from that of He, P 0.05. [From Lauzon et al. (47).]

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 VA/Q, 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 conguration. There was no evidence of signicant changes in respiratory drive based on the absence of large changes in inspiratory time and mean inspiratory ow. There have been no direct measurements of VA/Q distribution in microgravity. No imaging techniques have been used in ight that would allow such measurements, and techniques such as the multiple inert gas elimination technique (89) are too complex and time consuming for spaceight 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 conrmed. 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,

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tion 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 sufciently close to each other, so that diffusion of He, but not of N2 or SF6, is an efcient means of abolishing the concentration gradients it produces (i.e., between acini or between groups of a few acini). This is the rst instance in which it was possible to estimate the size of the structures responsible for the inhomogeneity of ventilation in microgravity. The recent parabolic ight 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.

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, G. [From Prisk et al. (64).]

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Fig. 5. Range of ventilation-perfusion ratio (VA/Q) seen over phase III and phase IV of prolonged exhalations in 8 subjects studied standing (vertically lined bars), supine (horizontally lined bars), and in G (open bars). Values are means SE. Signicantly different (P 0.05) compared with * standing and supine. [From Prisk et al. (63).]

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 VA/Q (96), and this has been shown to reect the degree of VA/Q 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 expiro grams even in the absence of a change in VA/Q distribution. Nevertheless, it is the only information on the range of VA/Q in the lung in microgravity available to date. During SLS-1 and SLS-2, there were signicant cardiogenic oscillations seen in the CO2 expirogram in microgravity. Their continuing presence is strong evi dence for continued interregional differences in VA/Q in microgravity, since cardiogenic oscillations largely reect 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 VA/Q range during phase IV of a prolonged exhalation (Fig. 5), consistent with the idea that the top-to-bottom gradi ent in VA/Q 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 VA/Q regions of the lung. There was no change in the range of VA/Q 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 micro-

gravity 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 inhomoge neity in VA/Q. It may be that gas exhaled during phase IV (in 1 G) is more reective of top-to-bottom gradients in VA/Q, since, in 1 G, airway closure occurs predominately in gravitationally dependent lung regions. However, during phase III, expired gas concentration differences may be more reective of nongravitational interregional differences in VA/Q. Certainly, the data suggest that, before the onset of airway closure, the principal determinants of VA/Q 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 VA/Q) 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 VA/Q (resulting in high CO2, also in the bases of the lungs). However, in microgravity, this phase relationship was reversed, and high ventilation was now asso ciated with high VA/Q. 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 ow 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 VA/Q 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 VA/Q than might otherwise be expected.
LUNG VOLUMES AND PULMONARY MECHANICS

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Vital capacity. The rst 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 35% reduction, confounding the spaceight results (74). Michels and West (50) showed no consistent differences in VC in microgravity during parabolic ight, 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 ight (49) showed a nonsignicant de-

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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 ight day 2 (FD-2) was intermediate between standing and supine values and was reduced compared with ight days 4 (FD-4) and 9 (FD-9). Values are means SE * Signicantly different from standing (P 0.05). [From Elliott et al. (26).]

crease 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 ight was reduced by a small amount (100200 ml) (35). This result contradicted that of a previous study of FVC in parabolic ight (30), but the difference appears to be the failure to account for a falling cabin pressure during the microgravity phase of the ight in the earlier study. During the SLS-1, VC was measured in seven subjects over the course of a 9-day ight (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 ight were not different from control values (Fig. 6). Similar results were seen in FVC (25). The suggestion is that an early inight increase in intrathoracic blood volume is responsible, with a subsequent increase in VC as plasma volume is reduced (3). 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 conrmed 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 conrmed by measurements in other ights (82). Results from short periods of microgravity in parabolic ight 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 signicant decrease in RV. Similarly, central vascular engorgement produced by G-suit ination 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 signicantly 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). Forced expirations. Castile et al. (14) demonstrated that postural changes altered the position and magnitude of the sudden changes in ow that characterize an individuals maximum expiratory ow 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 ight, there was a reduction in FVC and, at high lung volumes, a reduction in the lung volume at which a given expiratory ow 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 inight reduction in FVC that disappeared by the fourth day in microgravity. In addition, the reduction in lung volume at which a given expiratory ow occurred was seen in the early ight data, but this also disappeared later in ight, 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 ight. Peak expiratory ow was signicantly reduced early in ight but was back to control values after 9 days of microgravity. These reductions were largely in the

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Fig. 7. A theoretical model of the lung at residual volume (RV) during 1-G conditions and in G. At RV, alveolar size increases from base of lung to apex in 1 G and is uniform in G. If area 2 is less than area 1, total sum of alveolar volumes may be less at G than at 1 G (depending on shape of chest wall). Graph of distribution of alveolar size at RV (A) has been modied from Ref. 52. TLCr, regional total lung capacity. B and C: regional alveolar volumes at different vertical distances during 1 G and G, respectively. [From Elliott et al. (26).]

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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 rm platform to push against during the maneuver compromised the ability of the subjects to generate maximum ows, 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 ight, 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 conrmed 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 spaceight, 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 ight.
CONTROL OF VENTILATION

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 substan-

Hypoxic response. During the Neurolab mission, the hypoxic ventilatory response was measured using an

Fig. 8. Slope of the hypoxic ventilatory response (HVR) measured standing (vertically striped bars) and supine (horizontally striped bars) in 1 G and in G (open bars). HVR is approximately halved in G and supine. SaO2, arterial O2 saturation. Open brackets, P 0.05 between adjacent bars. * P 0.05 compared with preight standing. [From Prisk et al. (65).]

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tial 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). 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 ight 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 3641 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 signicant 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

that normally sediment will not be removed from the airways, leaving them potentially available for transport to the alveolar regions. There have been no studies of aerosol deposition in the human lung during spaceight. However, Hoffman and Billingham (41) studied the deposition of 2.0- m particles during parabolic ights. They saw an almost linear increase in deposition with G level over the range 02 G. They showed a lower deposition than that suggested by Beekmans (7, 8) who had predicted a

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Long-term spaceight represents a situation in which aerosol deposition may be an important health consideration. In the spacecraft environment, the potential for signicant 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

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). AC: G, 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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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 m). Darquenne et al. (19) studied the total deposition of 0.5-, 1-, 2-, and 3- m particles in a series of parabolic ights. For measurements made in 1 or 1.6 G, the results correlated very closely with onedimensional model predictions, with a tendency for the models to slightly overestimate total deposition. However, in microgravity, total deposition signicantly exceeded predictions in all particles below 3 m in size. The effect was greatest for 1- m 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- m 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 ow 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 ow plays a signicant 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

fully operational and on some limited studies on the edgling 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 VA/Q 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 sufcient. 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.
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After the completion of the Neurolab ight 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 spaceight 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 ights planned to occur irregularly until the ISS is

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