Introduction
Parabolic flights performed in slightly modified passenger airplanes operating in the troposphere have been used extensively in past decades for space-related human physiological research. Most of these life science experiments have been conducted on parabolic flights in a KC 135 aircraft in the USA or in an Airbus A300 aircraft in Europe. Both aircrafts achieve parabolic trajectories of different sequences. The A300 performs 31 parabolas each flight day, with a 2-min break of level flight between two consecutive parabolas and with 4-min breaks after each group of five parabolas. After the 16th parabola, a break of 8 min represents half-time of the flight. The KC 135 performed 40 parabolas per flight day and took a so-called roller coaster flight path with 10 parabolas back-to-back. Typically a KC 135 flight had 5-min breaks after the 10th and the 30th parabola and a 10-min break after the 20th parabola. Extensive previous research was aimed at investigating the cardiovascular system in the context of changing gravity in general and weightlessness in particular (Liu et al.
2012; Mukai et al.
1991; Petersen et al.
2011). Most of these experiments focused on cardiovascular responses during gravity transitions (Limper et al.
2011; Mukai et al.
1994). Fewer studies have investigated longitudinal changes in these specific cardiovascular responses over the course of a parabolic flight day. Only Mukai et al. reported longitudinal changes in cardiac index (CI), although concrete CI differences were not reported. In particular, Mukai et al. used impedance cardiography during the first 10 parabolas of a parabolic flight. Mukai et al. (
1994) also demonstrated a decreased thoracic fluid index by thoracic impedance measurements, and they noted that such a decreased thoracic fluid index may indicate an increase in thoracic fluids during parabolic flight. However, to date, no research has investigated how the body fluid system is influenced by parabolic flights, although some evidence suggests that the intravascular volume may increase on the day of a parabolic flight, as stated by Schlegel et al. (
2001).
Another important factor that has not been adequately addressed in prior experiments is the changing ambient atmosphere of the airplane cabin on the day of a flight. This seems astonishing because of the tremendous amount of work which has been carried out on the effects of hypoxia of commercial air travel on the human body (Gradwell
2006; Mortazavi et al.
2003). An inflight cabin atmosphere that is more hypobaric, hypoxic and dry with respect to ground control may affect the responses of the cardiovascular system, particularly to changes in gravity. The ambient pressure of the European A300 at cruising altitude is approximately 830 mbar, which is equal to the ambient pressure at 1,650 m above sea level (m. a. s. l.) (Lehot
2012). The ambient pressure of the KC 135, which is no longer in service, was 751 mbar, which is equal to an altitude of 2,438 m. a. s. l. (Lehot
2012).
Even the mild hypobaric hypoxia (HH), equivalent to 2,400 m. a. s. l., of a typical airplane cabin has been associated with a reduction of baroreflex sensitivity (Sevre et al.
2002), which is one of the most important cardiovascular control mechanisms under changing gravity. In contrast, hypoxemia with an arterial oxygen saturation of 90–95 % causes pulmonary vasoconstriction, leading to a 20 % increase in pulmonary pressure in healthy subjects during air travel (Smith et al.
2012). Hypoxic pulmonary vasoconstriction (HPV) leads to a reduction of the arterial and venous blood volume in the lungs (Sylvester et al.
2012). Consequently, we can expect opposing mechanisms to act on the pulmonary blood volume during parabolic flight: a cephalic volume shift under microgravity bouts would increase pulmonary blood volume, whereas the persistent HPV would decrease it. Furthermore, it is known today that even slight hypobaric hypoxic conditions at quite low altitudes, from 1,000 m. a. s. l., induce changes in blood volume (Bartsch and Saltin
2008). However, the effects of HH on baroreflex sensitivity, pulmonary blood volume and the body fluid system during parabolic flights have not yet been examined.
We therefore measured cardiovascular, pulmonary, hormonal and fluid volume parameters during parabolic flights and repeated these measurements in a hypobaric chamber. Our specific hypotheses were the following: (1) cardiac output in a state of weightlessness is not constant during a parabolic flight but rather increases over time because of an increase in intravascular volume; and (2) the cephalic blood volume shift in weightlessness overrules the hypoxic pulmonary vasoconstriction and leads to an increase in lung tissue volume.
When designing this study, we also considered the commercial airplane parabolic flights and upcoming suborbital commercial parabolic flights. We believe that more research must be done to clarify potential health issues that may arise from the combined effect of moderate hypobaric hypoxia and intense gravitational transitions, particularly for flight surgeons responsible for future, most likely elderly, customers of airplane and suborbital parabolic flights.
Discussion
The major findings of the study are fourfold.
First, confirmation of the observations of the studies of Iwase et al. (
1999a) and Beckers et al. (
2003) who found that cardiovascular responses to the transition into weightlessness in a standing position are different between the early parabolas of a parabolic flight and the later parabolic phases. Our results give new insights into the mechanisms of those differences by showing that, in the early phase of the flight, there is no distinct blood pressure decrease after the injection of 0 G
z, which would have been expected. However, SVR is decreased at 0 G
z from the early phase of the flight on. Thus, blood pressure is kept elevated by a lack of heart rate decrease after injection together with an already increased stroke volume. Over the course of a parabolic flight day, the heart rate at 0 G
z decreases and through decreased cardiac output leads to a pronounced blood pressure drop at 0 G
z in the later phases.
Second, the plasma volume response pattern in the hypobaric chamber and during parabolic flight is comparable. With respect to the baseline, an increase in PV during outbound was observed in both facilities, followed by a decrease after the 16th and 31st parabola and an increase after recompression. This pattern suggests that changes in plasma volume depend mainly on changes in body position and changes in ambient and oxygen partial pressure and depend to a lesser degree on gravity changes produced by parabolic trajectories.
Third, differences in hormonal responses occur between the two facilities. Whereas the combination of hypobaric hypoxia and gravity changes in parabolic flight induces an increase in aldosterone, the opposite is the case after the hypobaric chamber run. NT-
proBNP shows a strong tendency to increase during parabolic flight maneuvers but not in hypobaric hypoxia in a hypobaric chamber alone. Renin
active is increased in the hypobaric chamber but is not affected by parabolic flight.
Fourth, the lungs and the cardiovascular system interact differently in the two facilities. Whereas in the hypobaric chamber, lung tissue volume is decreased by hypoxic pulmonary vasoconstriction, lung tissue volume is increased at 0 and in 1.8 G
z in parabolic flight.
Our results show that the cardiovascular response to microgravity transitions in the standing position differs between the early and later parabolas. This finding is of importance for the design and the interpretation of cardiovascular experiments on parabolic flights. Our results suggest that data collected during the initial five parabolas of a parabolic flight should be discarded to increase the homogeneity of the cardiovascular results. The observed variability may be partly derived from the administration of scopolamine, which has a serum elimination half-life of approximately 2 h (Stetina et al.
2005). This point may suggest that half-elimination of scopolamine from the circulation has already occurred after an early parabolic flight phase. However, the increased level of psychomotor excitement is also certainly of importance. In contrast, changing interactions of the baroreflex and a “Bainbridge-like Reflex” may explain changes in cardiovascular responses over the parabolic flight. Whereas the Bainbridge-like reflex induces tachycardia triggered by a central volume increase by a volume shift at 0 G
z (Petersen et al.
2011), the baroreflex would induce bradycardia. It is possible that the Bainbridge-like reflex predominates in early parabolic flight because the vagotropic blocking capability of Scopolamine suppresses the vagal efferent outflow of the baroreflex. The sympathetic withdrawal effect of the baroreflex at 0 G
z seems to be unaffected, as indicated by a decreased SVR at 0 G
z from the very first parabola (Fig.
3) and as found by Iwase et al. (
1999b). However, whether factors other than scopolamine, e. g., hypobaric hypoxia, influence arterial and cardiac regulation remains unclear. Systolic and diastolic blood pressure was unaffected in the hypobaric chamber, whereas heart rate decreased, which could indicate a resetting of the baroreflex. However, the neutral, rather tedious environment of the confined hypobaric chamber experiment could well have contributed a further decrease in heart rate. How the baroreflex behaves in hypoxia and hypobaric pressure has been inconsistently defined in the literature. Halliwill and Minson (
2002) present data supporting that hypoxia resets the baroreflex and muscle sympathetic nerve activity (MSNA) to higher levels without changing the baroreflex sensitivity, whereas Sevre et al. (
2002) found evidence for reduced baroreflex sensitivity in a hypobaric chamber experiment simulating an airplane cabin atmosphere with a pressure equivalent to an altitude of 2,400 m (Sevre et al.
2002; Halliwill and Minson
2002). Finally, heart rate increases typically in hypoxia caused by decreased oxygen partial pressure in the blood (West et al.
2007), which was contrary to the findings of our hypobaric chamber runs.
We found a slight intermittent decrease in plasma volume over both parabolic flight and hypobaric chamber courses. This finding was contrary to our expectations. Schlegel reported that the 16 subjects of the parabolic flight experiment had on average a larger stroke volume in the supine position when compared between and after the flight, suggesting an increase in blood volume (Schlegel et al.
2001). During the parabolas, the subjects had been in an upright sitting position, which allowed a certain value of volume shift through gravity transitions. Schlegel did not measure intravascular volume and hormone concentrations directly but actually focused on the question of whether changing levels of arginine vasopressin (AVP) and renin–angiotensin–aldosterone could lead to an increase in intravascular volume during parabolic flights. Schlegel suggested, based on previous work, that the predominance of hyper G
z during the flight with respect to μG
z may have led to the expansion of intravascular volume. Indeed, the overall durations of the μG
z and hyper G
z phases during a parabolic flight were approximately 1,000 and 2,000 s, respectively, on the KC 135 and approximately 700 and 1,400 s, respectively, on the A300 Zero-G, and therefore twice as long under hyper than under μG
z. Those longer micro- and hypergravity phases and the different flight profile on KC 135 parabolic flights may be an explanation for the different findings between Schlegel’s and our work. Nevertheless, we found, in accordance with the concept of a modification of the Starling–Landis pressure under changing gravity as noted by Hargens and Richardson (
2009), a plasma volume loss during parabolic flight and a recovery to baseline values after re-pressurization. Again, we would have expected that such a contraction of intravascular volume through the effects of hyper G
z and μG
z on the Starling–Landis equation during the parabolic flight day would have been aggravated by hemoconcentration because of the hypobaric hypoxia of the airplane cabin inflight. It is well known that hypoxia induces a reduction in plasma volume that increases the hematocrit and thereby improves tissue oxygenation (Bartsch and Saltin
2008). This finding is already accounted for from just slight hypobaric hypoxia, i.e., in an ambient pressure equivalent to an airplane cabin inflight. However, in contrast to our expectation, Yamashita et al. were not able to find a significant effect of 130 min of quiet sitting in a hypobaric chamber in an ambient pressure equivalent to the pressure at 2,000 m and a low relative humidity of 20 % on hematocrit levels with respect to the regular ambient pressure of sea level (Yamashita et al.
2005). However, they did find a significant decrease of body weight (100–200 g) after the chamber test with respect to baseline values. This finding may indicate a loss of extracellular water with a concomitant preservation of intravascular volume. Yamashita et al. concluded that low humidity conditions may have a higher effect on fluid loss than the hypobaric hypoxia itself. However, we found more pronounced changes in plasma volume over the course of the hypobaric chamber testing than during the parabolic flight, whereas the response pattern for the plasma volume in both facilities seemed to be similar. An explanation for the greater plasma volume changes in the hypobaric chamber, in addition to the smaller subject collective, may involve a different volume status of the subjects during the chamber runs as indicated by a slightly lower average osmolality during the chamber runs. The high average osmolality of approximately 310 mosmol/kg in the subjects during the parabolic flights is a strong indicator for a dehydrated state on the flight days. AVP is known to be increased in volume-contracted subjects, and CT-
proAVP shows a similar pattern for changes in blood volume (Szinnai et al.
2007). The reduced fluid volume in parabolic flight may be explained by the participants’ overnight fasting and then only having a slight breakfast without much morning fluid intake. The lower humidity in the airplane cabin inflight with respect to the chamber may have been an additional factor in the differences in osmolality, but the difference was already apparent during the baseline measurements. However, it should be taken into account that high osmolality has an impact on cardiovascular reflexes. Charkoudian et al. reported that hyperosmolality of even 290 mosmol/kg increases the baroreflex sensitivity in young subjects and has a sympathoexcitatory influence in general (Charkoudian et al.
2005).
In the present study, hormones related to volume regulation and their precursor peptides responded differently to scopolamine, standing position, gravity changes and HH in the airplane cabin on the one hand and to scopolamine, standing position and HH in the hypobaric chamber on the other hand.
Whereas aldosterone values increased in HH in combination with changing g-loads during the parabolic flight, they decreased in HH in the hypobaric chamber. Aldosterone levels are expected to decrease after a move to higher altitude and in hypoxia (Slater et al.
1969; Shigeoka et al.
1985). However, an aldosterone increase at altitude was reported by Humperler et al. (
1980) and attributed by Richalet (
2001) to the physical exercise in the study. Under orthostatic stress, aldosterone levels are known to increase (Laszlo et al.
2001). Taken together, these studies underpin the following interpretation of our own results: in the hypobaric chamber, the serum aldosterone concentration decreased in response to HH. In contrast in parabolic flight, increased orthostatic stress and muscular load of standing upright during hyper-g phases, and increased postural muscular work due to turbulent flight phases, and potentially increased muscular work, induced by the airplane’s whole-body vibrations, increased aldosterone release. This finding could be interpreted as supporting the effects of orthostatic and exercise stress on the effect of the stress of HH during parabolic flight on aldosterone release.
Indeed, renin
active did not show a parallel response with aldosterone. The renin
active post 16th measurement during hypobaric chamber testing showed a slightly significant increase with respect to pre. However, renin
active did not show any further significant response, neither in parabolic flight nor in hypobaric chamber. This implies a dissociation of the aldosterone level and renin response under the particular conditions of parabolic flight. Interestingly, dissociation of plasma aldosterone levels and plasma renin activity has previously been reported in subjects experiencing presyncope and in subjects undergoing repeated orthostatic challenges by tilt table testing and lower body negative pressure (LBNP) tests (Roessler et al.
2011; Hinghofer-Szalkay et al.
2011). The works of Roessler et al. and Hinghofer-Szalkay et al. indicate furthermore that during orthostatic challenge aldosterone is rather controlled by adrenocorticotropic hormone (ACTH) than by renin, which may serve as an explanation of the dissociated aldosterone–renin response in parabolic flight.
NT-
proBNP shows a strong tendency toward a different response in the chamber with respect to parabolic flight (
p = 0.0524). Parabolic flight induces an increase, whereas only hypobaric hypoxia and a standing position do not affect NT-
proBNP. This finding is in agreement with the literature, which reports that NT-
proBNP does not increase with an acute ascent to altitude (Toshner et al.
2008) and during tilt table orthostatic tests, but does increase after an increase in thoracic blood volume-by-volume loading in healthy volunteers (Heringlake et al.
2004). This finding may indicate that the trend toward increased NT-
proBNP during parabolic flight is triggered by reiterative increasing in the thoracic blood volume at 0 G
z. With subjects 0AT, 0AP and 0AD excluded from the analysis of the parabolic flight data for cortisol because of possible stress responses arising from motion sickness, cortisol showed a significant decrease over the day in both facilities. This finding underpins the observation of a decreased heart rate during the flights and shows that the stress level decreases. However, this response results not only from decreasing excitement during the experiments but also from the distinct circadian rhythm of cortisol. The blood cortisol concentration shows a physiological peak between 8 and 9 a.m. and a continuous decrease thereafter. Peak values in healthy subjects are approximately 16 μg/dl and decrease to approximately 12 μg/dl at noon (Debono et al.
2009). The baseline measurements before the flights and the chamber runs were obtained between 8 and 9 a.m., i.e., during the physiological cortisol peak, and post-intervention measurements were obtained between noon and 1 p.m. The measured cortisol values at these time points were similar to the circadian values of these day phases given in the literature by Debono et al. (
2009)
Opposing alterations of pulmonary tissue volume in hypergravity and microgravity compared with hypoxia have been shown in different experiments. Snyder et al. (
2006) showed a decrease in lung water and lung tissue volume under moderate hypoxia of 12.5 % inspired oxygen in resting healthy subjects. Rohdin and Linnarson found increased lung tissue volume in healthy subjects during 2 and 3 G
z centrifugation in a sitting position. Furthermore, they reanalyzed the parabolic flight data of Vaida et al. and noted an increase in lung tissue volume in weightlessness (Vaida et al.
1997; Rohdin and Linnarsson
2002). Vaida had performed the experiment during parabolic flights in the former European Caravel parabolic flight airplane under a hypobaric ambient pressure of 793 mbar. Thus, the results of Snyder, Rohdin and Vaida are in line with our observations of decreased Vt in the hypobaric chamber and increased Vt during weightlessness and hypergravity in parabolic flight. However, we are the first to show in the same subjects that the reduction in blood volume in hypobaric hypoxia of the airplane cabin is reversed by a central volume shift in weightlessness and by sequestration, as suggested by Rohdin and Linnarsson, of blood in the dependent parts of the lung circulation in the hypergravity phases. This finding could be of benefit for potential parabolic flight candidates suffering from pulmonary hypertension, which would be aggravated by the hypobaric hypoxia of the airplane cabin and which may be attenuated by the pulmonary response to hyper- and microgravity.
Limitations
The study design included some limitations that we tried to consider in our interpretation of the results.
First, temperature, humidity, noise level, vibrations and light conditions in the hypobaric chamber were not fully comparable to parabolic flight because of a lack of air-conditioning in the hypobaric chamber, and because of a fixed installed non-changeable illumination system in the hypobaric chamber. It seems unlikely that the slightly higher temperature in the hypobaric chamber of approximately 23 °C, with respect to approximately 19 °C in the cabin of the A300 inflight, led to changes in the orthostatic or volume-regulating behavior of the cardiovascular system for instance by skin vasodilation or even by increase of the core body temperature (Allan and Crossley
1972). There was a 10 dB difference in the noise level during parabolic flight with respect to hypobaric chamber runs. Thus, in both facilities the noise level was comparable and below 90 dB which is known to increase the degree of physiological arousal (Harding and Mills
1983) and therefore we do not assume a significant effect of differences in the noise levels of the two facilities on our data. On the other hand, vibrations which appeared only inflight and not in hypobaric chamber might have had a certain minor impact on our results. Although exposure to moderate levels of whole-body vibrations does not lead to consistent changes in basic measures of the cardiovascular system, there may be an increase in muscle activity to maintain body posture which may again lead to peripheral vasoconstriction (Rollin Stott
2006). Furthermore, whole-body vibration induces a slight increase in metabolic rate which is comparable with that seen in light exercise and to hyperventilation with a reduction in CO
2 (Rollin Stott
2006). However, forced hyperventilation due to vibrations inflight, with respect to the hypobaric chamber, would have led to an increase in SO
2 of the arterial blood inflight with respect to SO
2 in the hypobaric chamber, which indeed cannot be found in our data. The differences in illumination between the hypobaric chamber and the cabin of the A300 were approximately 650 lux in brightness and 600 K in light color temperature. Noguchi investigated the influence of 50 and 150 lux of light brightness and 3,000 and 5,000 K of light color temperature on the activity of the autonomic nervous system. They could not find any difference in the activity of the autonomous nervous system under these conditions what makes us doubting a significant effect of the differences in light characteristics in our study on our data (Noguchi and Sakaguchi
1999).
Second, it is known that vestibular–autonomic interactions (Yates
1996) and cardio-postural interactions (Goswami et al.
2012; Blaber et al.
2009) affect cardiovascular responses during orthostatic stress. Therefore, subjects were instructed to avoid head movements during the hypergravity phases to minimize potential vestibular–autonomic interactions. However, minor differences in cardio-postural interactions in parabolic flight with respect to hypobaric chamber can be considered possible because in parabolic flight subjects were standing on a floor covered with soft padding and trying to adjust their upright body posture for turbulences using their postural muscles. Furthermore, large muscle groups may have been activated by airplane whole-body vibrations during flight. These advanced postural adjustments, which almost did not occur in hypobaric chamber, may have led to increased muscle pumping and increased venous return inflight with respect to the hypobaric chamber.
Third, only 11 of the 18 subjects of the parabolic flights were available to participate thereafter in the hypobaric chamber tests
. Fourth, three of the 18 subjects developed motion sickness in parabolic flight, which affects cardiovascular and hormonal regulation and removes the homogeneity of the subject population. It is well known that levels of AVP and cortisol are extensively increased in motion sickness; therefore, the CT-
proAVP and cortisol values of the motion-sick subjects were excluded from the statistical analysis of the blood hormones, and individual data are shown instead. Furthermore, we did not analyze blood levels of ACTH what might had allowed us to identify a close relationship between ACTH and aldosterone in parabolic flight as it is known for orthostatic stress during tilting and LBNP (Roessler et al.
2011; Hinghofer-Szalkay et al.
2011).
Fifth, rebreathings at 0 G
z fell into the early 0 G
z phases, which are characterized by a sympathetic withdrawal and acute activation of the vagal nervous system. Later in the 0 G
z phase, there would be an increasing dominance of the sympathetic nervous system. We did not perform most of the rebreathings in this phase, and thus our results mainly represent the cardiovascular responses in the early 0 G
z phases.
Sixth, forced breathing, as performed for the rebreathing maneuvers for CI
rb determination, modulates cardiovascular regulation during gravity transitions (Schlegel et al.
1998; Iwase et al.
1999b). However, using a breathing frequency of 20 breaths per minute and a rebreathing volume between 1.5 and 2.5 L, we were in the range of the low effect of breathing parameters on CO
rb influencing noted by Damgaard and Norsk (
2005).