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Section of Environmental Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Submitted 4 March 2005 ; accepted in final form 19 April 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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human; stroke volume; centrifuge; anti-gravity suit
COS[x] has been used to study intrapulmonary gas mixing and perfusion heterogeneity. Several investigations have studied COS[x] to assess the effects of gravity on the distribution of ventilation and perfusion in the lungs (14, 21, 23, 24, 27). COS[x] is generated from a combination of concomitant gas composition differences and heart-synchronous sequential emptying between units with different gas compositions. In many studies, COS[x] values are compared between different conditions of gravity, which may induce differences in the distribution of ventilation, perfusion, central blood volume, and stroke volume (SV). Gravity-induced changes in these hemodynamic variables may modify the mechanical agitation caused by cardiac action on the lungs, thereby altering COS[x] amplitude without necessarily reflecting a change in intrapulmonary gas concentration differences. Rohdin et al. (26, 27) addressed this issue by normalizing COS[x] amplitudes for SV. In an alternative approach, Montmerle et al. (23) compared conditions where central hemodynamics were likely to be similar.
This experiment was designed to study the effects of moderate hypergravity and changes in blood volume distribution imposed by use of an anti-G suit on COS[x]. In particular, we wanted to compare conditions where we knew from a parallel study (22) that SV was the same but, at the same time, there were differences in gravity and blood volume distribution. We assessed the mechanical action of cardiac pumping on the lung tissue from COSflow, because COS[x] is generated from a combination of heart-synchronous sequential emptying of pulmonary units and gas composition differences between these units.
We hypothesized that relatively small cardiogenic blood volume pulsations would suffice to cause sequential emptying and, thus, produce COS[x] because of the compliant nature of the lung tissue. As a consequence, we reasoned that COS[x] would reflect primarily the concentration differences between sequentially emptying lung units and would be modulated to only a small extent by the size of the intrathoracic blood volume pulsations.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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We studied 12 subjects (6 men and 6 women) recruited by an advertisement. All were healthy nonsmokers. Their mean ± SD ages, heights, and weights were 25.6 ± 4.5 yr, 1.78 ± 0.08 m, and 70.0 ± 10.9 kg, respectively. They received written information before the start of the experiment and provided verbal consent in accordance with the national Swedish ethical guidelines. The protocol adhered to the principles of the Declaration of Helsinki and had been approved by the Regional Research Ethics Committee of Karolinska Institutet, Stockholm, Sweden.
Equipment
Human centrifuge. Experiments were conducted in a 7.25-m-radius human centrifuge (ASEA, Västerås, Sweden) at Karolinska Institutet. The floor of the gondola was horizontal when stationary (1-G tests) and was perpendicular to the resultant normal and centrifugal G vectors when the centrifuge was spinning (2-G tests). The back rest of the seat of the gondola reclined at an angle of 28°. Thus the gravitational effect of 1- and 2-G exposures on the subject was 0.88 and 1.77 Gz, respectively (i.e., in the head to foot direction). For convenience, we refer to these Gz gravitational loads as 1 and 2 G.
Slip rings at the center of the centrifuge allowed audiovisual monitoring, power supply, and transmission of the physiological signals between the gondola and a control room. We used a dedicated respiratory monitoring system consisting of a quadrupole mass spectrometer for gas analysis (model AMIS 2000, Innovision, Odense, Denmark) located in the center of the centrifuge and coupled to a custom-made valve activated by a pneumatic rotary drive (type DSR-25-180-P, Festo Pneumatic, Esslingen, Germany) placed in the gondola. In turn, the rotary drive was powered by compressed air and an array of solenoid valves. From the rotary valve, the subject could, via a mouthpiece, breathe air or rebreathe from a 4-liter rubber bag. This valve was controlled remotely by an operator in the control room. A flowmeter (type 3719, Hans Rudolph, Kansas City, MO) coupled to a pressure transducer (model CD12, Validyne, Northridge, CA) was attached to the cabin air port of the rotary valve for measurement of expiratory flow. The membrane of the pressure transducer was mounted perpendicular to the direction of rotation to minimize the effects of the normal and centrifugal G vectors on pressure recordings. The volume of the instrumental dead space was 150 ml. Calibration of the flowmeter was performed daily with a 3-liter syringe (series 5530, Hans Rudolph) within the experimental flow range. Gases were sampled from an inlet located between the valve and the mouthpiece. This inlet was coupled to a 10-m sampling tube, connected to the mass spectrometer. The mass spectrometer was calibrated before each session with two mixtures with known compositions of all relevant gas components (Air Liquide, Malmö, Sweden). The delay of response of the mass spectrometer compared with the flowmeter signal was 7.37 ± 0.20 (SD) s. The 10–90% response time for a step change in the gas composition was 
180 ms. Data were recorded with a data-handling system (Biopac, Goleta, CA) at a sampling frequency of 200 Hz and stored digitally.
Anti-G suit. The pneumatic anti-G suit was the full-coverage model used by Swedish military pilots in the 9-G aircraft JAS 39 Gripen [anti-G ensemble 39 (AGE-39), Swedish Defense Material Administration, Stockholm, Sweden]. The upper edge of the suit was placed at the level of the iliac crest and the lower edge at ankle level. The suits were fitted snugly on each subject.
The suits were inflated manually with air from a cylinder fixed in the center of the centrifuge. Inflation took 1 min to complete, and the centrifuge was not started until the pressure was stable (target value ±2 mmHg on the manometer fixed to the suit). Two target pressures were used: 0 (control) and 85 mmHg (inflation). The subject could deflate the suit by opening a valve on the left side of the seat and did so when the test was completed. The total time with the suit inflated ranged from 2 min (1-G tests) to 4 min (2-G tests).
Instrumentation
The subjects sat in the gondola during all tests, with the right arm resting on a support approximately at heart level.
Three ECG electrodes were placed on the subject’s chest for monitoring of heart rate (type AS2, Datex, Helsinki, Finland). Arterial beat-by-beat blood pressure was measured with a volume-clamp technique (Portapres, TNO, Amsterdam, The Netherlands).
The operator monitored the subject continuously via voice communication and a video camera. Gz was measured by an accelerometer mounted in front of the subject approximately at heart level.
Procedures
Subjects were instructed to avoid caffeine intake for 24 h before the experiment and to have a light meal 2 h before the tests.
The subject sat in the centrifuge and was restrained by a seat belt. A rebreathing bag was filled with 2.5–4 liters of a gas mixture containing 21% O2 and 5% He (an inert blood-insoluble gas). The bag volume corresponded initially to 50% of the subject’s estimated total lung capacity at normal gravity and was then adapted slightly according to the subject’s preference. The subject donned a nose clip and took a few normal breaths with the valve in the nonrebreathing mode. After expiring to residual volume, the subject switched the valve to rebreathe the full bag volume back and forth five times starting from residual volume within 5 s, ending with a full inspiration from the bag, and then held his/her breath for 10 s with glottis open if possible. The subject then expired to residual volume at an individually adapted flow rate that corresponded to the volume of the rebreathing bag exhaled in 10 s. Expiratory flow was controlled by the subject viewing a screen in real time.
The experimental procedure was rehearsed on two or more occasions before the first recording. The rebreathing-breath-holding-expiration sequence was performed at 1 and 2 G, with and without anti-G suit inflation (1-G control, 1 G + inflation, 2-G control, and 2 G + inflation). Tests were randomized with regard to the G level and inflation pressure (IP). During the 1-G tests, the centrifuge was stationary. During the 2-G tests, the maneuver started at the onset of 2 G. The average time to reach 2 G was 8.5 ± 1.3 (SD) s. When the maneuver was completed, which took 30 s, the centrifuge returned slowly to 1 G. The mean time at 2 G was 50 s.
Subjects rested while sitting between tests. The tests were repeated until three usable maneuvers were obtained per combination of G level and IP. At least 9 min were allowed between tests to clear foreign gases from the lungs.
Data Analysis
Traces were studied with a proprietary interactive graphic analysis program developed with LabVIEW software (National Instruments, Austin, TX). Airflow oscillations were analyzed on the recordings when breath holding was performed with an open glottis (7 subjects). The software defined the oscillations as cardiogenic when they occurred between two R peaks of the simultaneous ECG recording, and nadir-to-peak amplitudes were determined to obtain the COSflow amplitude. A flow baseline was established as the mean value over that period and was approximately zero. The flow signal was integrated to compute the volume of air moved into or out of the thorax per cardiac cycle [pulsatile gas volume (PGV)].
Expirograms for O2 and He were plotted as a function of expired volume. Traces were then normalized, the mean concentration of He and O2 at the fifth inspiration of rebreathing being defined as 100%, to correct for the variability of lung volume-dependent inert gas dilution between subjects and to allow comparison of expirogram parameters obtained with He and O2. To correct for incomplete gas mixing after rebreathing, traces of the normalized blood-soluble gas O2 were divided by the normalized nonsoluble gas He. Thus the normalized O2-to-normalized He ratio (O2/He) was computed sample by sample and plotted as an expirogram. Henceforth, the terms O2, He, and O2/He refer to normalized values. We focus on the O2/He data, although we also report the parameters from the O2 and He expirograms for completeness. In the three types of expirograms (normalized traces and ratios), the start and end of the alveolar plateau (phase III) were visually identified and marked using a cursor. The slope of phase III was identified on each plotted curve using linear regression and subtracted from the curve. COS[O2], COS[He], and COS[O2/He] were defined, and their amplitudes were computed in an analog manner as for COSflow. All COS amplitudes and PGV values measured in each file were used.
Finally, system gas volume (Vsys) was computed from the equilibration of He between the rebreathing bag and the lungs. Median values were calculated for each subject and each G level and IP. We choose medians, instead of means, because of the large number of COS values obtained per test and condition (10 values per test, thus 30 per subject and condition); a median is more representative of the distribution of the values within a sample. Moreover, this enabled us to eliminate some random noise at the end of phase III, when there is no more COS; this random noise was computed as COS by the software, because it was part of phase III. For consistency, medians were computed also for the other parameters.
Medians were then used to compute a group mean for each G level and IP.
Statistical Analysis
For all parameters, prerequisites for a two-way repeated-measures ANOVA (factors = G level and inflation) were fulfilled apart from sphericity. Thus the critical F value was corrected with Greenhouse-Geisser and Huyn-Feldt epsilons (STATISTICA 6, Statsoft, Tulsa, OK). Significance was accepted at P < 0.05. Tukey’s honestly significant difference post hoc test was applied to locate the differences for pairwise comparisons. Unless otherwise indicated, values are means ± SD.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Figure 1 shows a typical recording of COSflow during breath holding. COSflow amplitude did not change with gravity but increased when the anti-G suit was inflated (Table 1). Values were 86% higher at 1 G + inflation than at 1-G control. In contrast with COSflow amplitude, PGV (Table 1) showed overall differences with G level and with IP in the Greenhouse-Geisser and Huyn-Feldt analyses, but these differences were small, and the post hoc test showed no differences between any of the four combinations of G level and IP.
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Vsys did not change with G level but decreased when the anti-G suit was inflated (P = 0.023), and there was an interaction between G level and IP (P = 0.028). Mean values were 4.84 ± 0.88 liters at 1-G control, 4.84 ± 0.94 liters at 1 G + inflation, 4.90 ± 0.83 liters at 2-G control, and 4.79 ± 0.85 liters at 2 G + inflation.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Cardiogenic Flow Oscillations
We observed a mean COSflow amplitude of 105 ml/s at 1-G control, which agrees with the value of 120 ml/s previously measured in seated humans (9) and with similar values obtained in supine subjects (7). Similar to previous studies in humans and animals (9, 33), we found large interindividual variability in COSflow and PGV.
Cardiovascular factors in COSflow generation.
During the cardiac cycle, the heart exerts a mechanical action on the emptying and filling of the lung alveoli (7, 10, 20). During breath holding with an open glottis, one can observe an outward movement of gas with each cardiac diastole and an inward movement of gas with each systole (10), which starts 100 ms after the R wave on the ECG (7, 9). Our recordings clearly showed an inflow during systole and an outflow during diastole (Fig. 1).
Two experiments in dogs have suggested that PGV is correlated with SV (15) and that PGV is equivalent to about one-third of SV (33). The present finding of a mean PGV of 24 ml at 1-G control is compatible with these studies, inasmuch as the SV of a seated human adult is 60–70 ml (8). However, the only other studies performed in humans found much lower PGV values, 7 ml (7, 9). An explanation for this discrepancy is that these subjects were not specifically instructed to keep their glottis open, as ours were; therefore, these subjects probably had a larger upper airway resistance than those of the present study (for discussion of the influence of airway resistance on COSflow, see Pulmonary factors in COSflow generation).
Rather than being a direct function of SV, COSflow is more likely to be initiated by cyclic changes in the overall intrathoracic blood volume (7, 10, 15), which are in turn is related to SV: During systole, there is a temporary systolic negative blood balance in the thorax. The volume of blood ejected from the left ventricle (i.e., SV) is only partly simultaneously compensated for by the effects of right ventricular systolic suction on thoracic inflow, and the remainder enters the thorax during diastole (8). This causes a transient volume reduction in the thoracic cavity, which in turn results in an inflow of air if the airways are open (7). The extent to which the intrathoracic parts of the large systemic vessels, the lung vessels, or the heart contribute to overall heart-synchronous blood volume changes is not known, and we will refer to such changes as intrathoracic blood volume pulsations.
Pulmonary factors in COSflow generation. The effect of thoracic blood volume movements on the parenchyma could be damped by stiffness of the lung tissue. This hypothesis is consistent with the results of Lichtwarck-Aschoff et al. (18), who observed that PGV decreases when lung compliance decreases in ventilated pigs. These authors also observed a decrease in compliance of the chest wall in a representative experimental animal (M. Lichtwarck-Aschoff, personal communication). Decreased compliance of the chest wall should augment COSflow amplitude for the following reasons: The blood leaving the thorax during systole tends to decrease intrathoracic pressure, and if the chest and diaphragm are flaccid enough, they will move inward, thereby reducing the need for air influx into the chest. Heckman and co-workers (15) reported lower COSflow amplitudes when the chest was open, an extreme case of low chest wall compliance. Opening the chest exposes the heart and the lungs to ambient air, radically diminishing the mechanical influence of cyclic thoracic blood volume changes on the pulmonary parenchyma. Thus, in the experiment performed by Lichtwarck-Aschoff et al., it appears that the potentially augmenting effects of decreased chest wall compliance on COSflow were masked by the damping effects of decreased lung compliance.
Differences in compliance between lung regions are probably also important; in their bronchoscopic experiments in supine humans, West and Hugh-Jones (34) observed that pulsatile flow variations were not present in each bronchus studied. However, this could also reflect differences in airway resistance between lung regions.
Colebatch et al. (9) found that COSflow amplitude decreases as airway resistance increases. In the closed upper airway, heart-synchronous compression rarefaction of the intrathoracic gas must be a major factor; accordingly, using a body plethysmograph, Bosman and Lee (7) found heart-synchronous volume variations with a closed airway in the external chest.
It is unclear from which alveolar populations COSflow originate, and our data do not give any topographical information. West and Hugh-Jones (34) studied this issue by using an argon-dilution technique to estimate variations in pulsatile gas flow in the bronchi of supine sedated patients. They found that "appreciable cardiac pulsations occur in all five lobar bronchi and, as might be expected, the largest pulsations are found in the left lung. However, the consistency with which large pulsations can be detected in the right middle-lobe bronchus is interesting." Our interpretation of these observations is that proximity to the heart is one, but not the only, factor that determines the extent of heart-synchronous airway flow oscillations.
Effects of anti-G suit inflation on COSflow. When the anti-G suit was inflated, COSflow amplitudes were 186% and PGV values were 255% of their 1-G control values; these responses were similar at the two gravity levels (Table 1, Fig. 2). When an anti-G suit is inflated, increases in central blood volume (32) may become large enough for systolic suction into the right heart to be accounted for to a larger extent by blood already in the thoracic cavity, which would attenuate the impact of systolic suction on the rate of influx of blood to the thorax. Acting in a similar direction, the venous blood volumes in the legs and abdomen decrease, dramatically reducing the blood volume accessible for systolic suction into the thorax. This would in turn increase the systolic negative blood balance in the thorax and, together with a 10–30% increase in SV (22), would increase COSflow amplitude and PGV. Such changes are consistent with previous data showing that COSflow amplitude increases in subjects moving from the seated to the supine posture, which increases SV and central blood volume (9).
Anti-G suits also affect the lungs: lung compliance decreases (6), probably because of the increased blood content in the lungs, which tends to decrease COSflow amplitude and PGV (18). We found no reports on the effect of anti-G suit inflation on chest wall compliance, but it seems logical that the chest wall would become stiffer because of the upward movement of the diaphragm (13). Consequently, COSflow amplitude and PGV should increase (7). The net outcome of these opposing actions of the lower lung compliance and the lower chest wall compliance on COSflow during anti-G suit inflation is uncertain.
Effects of increased gravity on COSflow. SV and central blood volume are lower at 2 G than at 1 G (4, 19). At 2 G, the compliance of the respiratory system is lower, the diaphragm moves downward (5, 12, 13), and the lung is distorted, leading to an increase in pleural pressure gradients. However, in the present study, COSflow amplitude and PGV did not differ between 1-G control and 2-G control or between 1 G + inflation and 2 G + inflation. Thus any effect of an increase to 2 G on the generation of COSflow, if it exists, is small, probably because the pulmonary effects of increased gravity compensate each other: decreased lung compliance decreases COSflow amplitude, whereas decreased chest wall compliance increases COSflow amplitude.
SV is similar at 1-G control and 2 G + inflation (22). In contrast, COSflow values were almost twice as large during 2 G + inflation as during 1-G control. This observation suggests that effects of anti-G suit inflation other than SV per se have a much greater impact on the outcome of COSflow.
Cardiogenic oscillations of O2/He
We present the mechanisms generating COS[x] only briefly here, because these have been discussed extensively elsewhere (10, 23). Laviolette and Cormier (17) showed that COS[x] represents intraregional (i.e., small-scale) differences in gas content. Whether these differences are caused by ventilation or perfusion differences depends on the maneuver performed before the slow expiration, which enables one to record COS: Laviolette and Cormier (17) focused on ventilation distribution. In the present experiment, we wanted to study perfusion distribution. Thus we used the blood-soluble gas O2, which was first distributed in the lungs as homogeneously as possible. In addition, we computed O2/He to correct for any incomplete homogenization. During the subsequent breath holding, O2 was taken up by the blood at a rate proportional to local perfusion. Thus changes in the concentrations of O2 observed subsequently, during the final expiration, represented perfusion differences that were primarily of intraregional origin.
Cardiovascular and pulmonary factors in COS[O2/He] generation. Studies in dogs have suggested that cardiac wall movements during the cardiac cycle act on the surrounding parenchyma (31), creating COS[x] (11, 15). It is likely that only a small part of COS[x] is generated by the direct mechanical action of the heart on lung units, because the changes in heart volume and cardiac rotation movements during the cardiac cycle are small (16, 31). The main mechanism probably relates to the sequential emptying of lung units during expiration as a result of differences in the time constants between lung units in their response to pressure waves generated by the heart (1) or the different locations of these lung units in relation to a pulsating vessel (3, 10).
The experiments of Wei et al. (31) in dogs suggested that the amplitude of COS[x] is related to SV, although these authors did not demonstrate significant correlations between these variables. SV probably influences the generation of COS[x] in two entirely opposite ways: 1) SV induces intrathoracic blood volume pulsations, which mechanically influence the emptying of compliant lung units. Thus, if all other factors remain constant, an increase in SV tends to increase COS[x]. 2) An increase in SV and, thereby, pulmonary blood flow increases capillary recruitment, which decreases the differences in pulmonary perfusion and lowers the amplitude of COS[x] of the blood-soluble gas studied.
Effects of anti-G suit inflation and gravity on COS[O2/He].
As for COSflow, the effects of anti-G suit inflation and gravity on COS[O2/He] were similar at the two gravity levels (Table 1, Fig. 2). Because COS[x] represents a product of concomitant sequential emptying of lung units and gas composition differences between such units, there was a striking dissociation between the responses of COS[O2/He] and those of COSflow. Anti-G suit inflation resulted in a 30% reduction in COS[O2/He] amplitudes at both gravity levels, whereas COSflow amplitudes nearly doubled. In contrast, inflation to 85 mmHg increases SV only by 10% at 1 G and by 30% at 2 G (22). Taken together, these findings show that the dominating factor behind COS[O2/He] amplitudes must be differences in gas composition between asynchronously emptying lung units, rather than the mechanical agitation of the lung tissue. It is of special interest to compare the data between 2-G control and 2 G + inflation: our previous study (22) showed that SV increased with inflation, but not with cardiac output, because of a concomitant bradycardia. Thus the tendency toward a reduction in COS[O2/He] in the present study (P = 0.053) cannot be explained by increased pulmonary blood flow. Instead, this trend might be explained by the generally elevated vascular pressures in the lung circulation (29, 30), which should improve capillary recruitment and cause less perfusion heterogeneity in the lungs, as reflected in the decreased COS[O2/He] amplitudes. Moreover, the decrease in lung compliance (6) and upward movement of the diaphragm (13) should reduce the number of compliant alveoli and, thus, further contribute to the decrease in COS[O2/He] amplitude.
We found no difference in COS[O2/He] between the 1- and 2-G conditions. This result agrees with the data reported by Rohdin et al. after 1 min of exposure to 2 G (27) and with previous experiments performed during parabolic flight (23). Thus any net cardiopulmonary effects of 2 G on COS[O2/He] must be small.
A likely explanation is that hypergravity has opposing influences on the generation of COS[O2/He]. On one hand, it reduces SV (19, 25, 28), which tends to reduce the mechanical impact of cardiac activity on the lungs. On the other hand, hypergravity tends to increase the differences in O2/He between sequentially emptying lung units by causing larger perfusion differences between these units.
Potential effect of lung volume changes. In the present experiment, Vsys changed with IP. However, the variations in Vsys measured when the anti-G suit was inflated compared with no inflation were +4 ml at 1 G and –115 ml at 2 G. Although statistically significant, such small changes are likely not biologically significant. Thus the present changes in Vsys between conditions are unlikely to have influenced our results.
Conclusions
SV is, by definition, the prime mover of the generation of any heart-synchronous event but does not appear to be the main factor influencing COSflow and COS[O2/He]. Instead, we found that COSflow depends primarily on intrathoracic blood volume, whereas COS[O2/He] reflects differences in intraregional pulmonary perfusion.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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) during a rebreathing-breath holding with open glottis-expiration maneuver performed in the sitting position at normal gravity without anti-G suit inflation (1-G control). Maneuver started from residual volume after a few normal breaths (left). There is no flow trace during rebreathing, because the flowmeter was connected to the cabin air port to minimize dead space. As soon as rebreathing is finished, the valve opens to the cabin air port, and flow oscillations can be detected. Expiration is upward. Flows exceed the displayed range during the initial normal breathing. Bottom: magnification of heart-synchronous air movements [cardiogenic oscillation of airway flow (COSflow)] measured at the mouth during breath holding from top: flow and simultaneous recording of ECG.