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1Unité de Médecine et Physiologie Spatiales (UMPS), Centres Hospitaliers Universitaires Trousseau, Tours, France; 2Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario; and 3School of Kinesiology, University of Western Ontario, London, Ontario, Canada
Submitted 26 September 2007 ; accepted in final form 11 January 2008
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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leg vein; lower body negative pressure; head-down bed rest; echography; Women International Space Simulation for Exploration 2005
The increase in leg vein cross-sectional area (CSA), measured by echography, in response to a fluid shift toward the legs during a stand test was found higher in those unable to complete a 10-min stand [nonfinishers (NF)] after a 90-day head-down bed rest (HDBR) (5) but there was no difference between subjects who performed no countermeasures during HDBR and those who performed regular resistive (flywheel) exercise. In the same study, it was observed that venous plethysmography failed to detect significant changes (5), confirming that only direct visualization of the vein and surrounding tissue by echography provides appropriate information on the response of these targets to HDBR and orthostatic test.
The objectives of the present study were to evaluate the effect of two countermeasures [exercise + lower body negative pressure (LBNP) (Ex-Lb) and nutrition (Nut)] in women participating in a long-duration (60-day) HDBR on the calf vein CSA and surrounding superficial tissue thickness (STth) at rest and in response to LBNP of –45 mmHg and to determine the impact on orthostatic tolerance. It was hypothesized 1) that the "Ex-Lb" countermeasure combining aerobic and resistive exercise and LBNP (1, 28) would prevent changes in vein and tissue liquid storage during an LBNP test on HDBR day 55. Furthermore, it was hypothesized 2) that subjects, regardless of their countermeasure group, who had the smallest increase in vein and tissue liquid storage measured during the LBNP test on day 55 would finish the 10-min tilt test after 60-day HDBR. Direct visualization and measurement of the vein CSA and STth by echography during LBNP were used to try to answer these questions.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The 60-day at 6° HDBR was organized by the Institute for Space Physiology and Medicine (MEDES) Space Clinic, located at Rangueil Hospital, Toulouse, France, in 2005. The experiment was approved by a French Committee for health (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale, Midi-Pyrénées).
Twenty-four healthy women signed a consent form after having been informed of the risks and benefits of this long-term bed rest study. The population were randomly assigned to three groups: Ex-Lb (n = 8) and Nut (n = 8) countermeasure groups and controls (Con, n = 8). Ex-Lb subjects performed flywheel (resistance exercise) (1) every third day, and 3–4 days per week with interspersed rest days they performed 40 min of treadmill aerobic exercise within the LBNP chamber with an interval training pattern (28) followed by 10-min passive LBNP. Nutrition subjects consumed a daily protein supplement during meals corresponding to 0.6 g·kg–1·day–1, i.e., between 30 and 40 g of additional protein per day.
LBNP
Subjects were placed in a supine position then instrumented with the calf echographic probe. They were studied at rest and at –45 mmHg LBNP for 3 min.
Echographic Parameters
The calf veins and tissue were investigated using a 7.5-MHz ultrasound "T-shaped probe" attached to the upper posterior level of the left calf by an adhesive patch, and connected to the echograph by a 2-m-long cable (Logic book GE France). The ultrasound probe was placed, to visualize in a transverse cross section the upper part of the posterior tibial vein (Tib) and one or two gastrocnemius veins (Gast) depending on the subject's anatomy. Echographic views were digitized and recorded continuously during the LBNP test and processed on a program designed by our laboratory (Fig. 1). The contours of the Tib and Gast veins were outlined on the images, and the vein CSA was expressed in centimeters squared.
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CSA at rest and maximal CSA at LBNP –45 mmHg, and the percent changes in CSA and STth from 0 to LBNP –45 mmHg, were analyzed according to the countermeasure used and considering the fact that the subject finished [finisher (F)] or not (NF) the post-HDBR 10-min tilt test. The percent change in Tib and Gast CSA and STth from LBNP 0 to –45 mmHg was considered to be proportional to the vein and tissue capacity to stow liquid (capacitance).
Measurement Schedule
LBNP test. The vein CSA and STth parameters were measured pre-HDBR and after 55-day HDBR on the subject supine at 0 mmHg and at LBNP –45 mmHg.
Orthostatic tolerance test. Orthostatic tolerance was evaluated by comparing the ability to complete a 10-min 80° head-up tilt test before HDBR and as the very first upright activity after 60-day HDBR. All subjects completed the 10-min test pre-HDBR, whereas in the post-HDBR test, two of eight Ex-Lb (25%), five of eight Con (63%), and six of eight Nut (75%) subjects failed to complete the full 10-min tilt test. Based on these results, we further subdivided the subjects as F and NF of the 10-min tilt test for additional comparison of the hypothesis that completion of the 10-min tilt test was related to smaller increases in vein and tissue liquid storage during LBNP at HDBR day 55 compared with NF.
Statistical Analysis
Values are expressed as means ± SD, and changes were considered statistically significant for P < 0.05. Data were analyzed using nonparametric tests because of the number of subjects. Comparisons between the Ex-Lb, Con, and Nut groups, and between F and NF subjects, were made using the Mann-Whitney test for unpaired variables. Two periods within the same group were compared using the Wilcoxon test for paired data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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There was no significant change in the CSA of the Tib and Gast veins at rest on HDBR day 55 compared with pre-HDBR in any of Ex-Lb, Con, and Nut (Fig. 2). Only when considering the NF group was there a significant decrease in resting CSA [Tib: from 0.33 ± 0.07 to 0.28 ± 0.06 cm2 (P < 0.05), Gast: from 0.083 ± 0.021 to 0.066 ± 0.018 (P < 0.05)]. The number of subjects within each group that decreased the resting Tib CSA on HDBR day 55 relative to pre-HDBR was three, four, and five for the Ex-Lb, Con, and Nut groups (38, 50, and 63%), respectively. For the 11 F subjects, only 3 had a decrease in resting CSA (27%), whereas for the 13 NF subjects, 9 had a decrease in CSA (69%). The proportion of subjects that reduced their Gast vein CSA at rest, was 13, 86, and 57% for Ex-Lb, Co, and Nut, respectively, and it was 36 and 70% and for F and NF, respectively.
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As a consequence of the smaller starting Tib or Gast CSA at rest for some individuals on the HDBR day 55 testing, or the higher maximal CSA reached at –45 mmHg, the percent increase from rest to –45 mmHg LBNP was significantly greater at HDBR day 55 for the Con and Nut groups as well as for the NF group (Fig. 3). The proportion of subjects within each group that showed a greater CSA percent increase at HDBR day 55 for the Tib vein was 50% Ex-Lb, 75% Con, and 88% Nut, and for the Gast vein the proportion was 25% Ex-Lb and 86% Con and Nut. Of the 13 NF subjects, 11 (85%) had a greater percentage increase in Tib CSA after HDBR, whereas only 5 of the 11 F subjects (45%) had a greater percent increase. Also 70% of the NF subjects and 55% of the F had a greater percent increase in Gast vein CSA after HDBR.
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Between the pre-HDBR to HDBR day 55 session the absolute STth at rest did not differ for any group, whereas the maximal thickness at –45 mmHg LBNP was significantly higher in the Con and Nut groups (P < 0.05), and it approached significance in the NF group (P = 0.07) (Fig. 4). However, the percent increase in STth on going from rest to –45 mmHg LBNP was significantly greater on HDBR day 55 compared with pre-HDBR in the Con and Nut groups as well as in the NF group (Fig. 5).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Previously, Convertino et al. (10) concluded that the increased leg compliance after HDBR contributed to orthostatic intolerance. On the other hand, Melchior and Fortney (29) reported no relationship between leg vein compliance and orthostatic tolerance. Subsequently, Fu et al. (15) observed that those most likely to faint after HDBR had increased leg vein compliance in pre-HDBR testing but that the increase in compliance with HDBR was not related to a change in tolerance. More recently and contrary to most published studies, Bleeker et al. (7) reported a reduction in leg vein compliance and an increase in leg vein resistance after HDBR but the change in orthostatic tolerance was not related to leg vascular conductance. Xiao et al. (34) also reported findings that conflicted with previous studies as their subjects with higher values of leg vein compliance in the pre-HDBR testing were more, not less, tolerant in the orthostatic position after HDBR. Conversely the echographic direct measurement of the calf vein CSA demonstrated a higher capacity of the vein to expand at the end of the bed rest in the nontolerant subjects, which is not in agreement with many (7, 15, 29, 34) but not all (10) of the plethysmographic results which did not see any difference between tolerant and nontolerant subjects.
The plethysmographic method measures the whole calf CSA change, but it never measures vein CSA. We have demonstrated that the higher capacity for the vein to expand its CSA is related to the fact that the calf vein CSA at rest decreased or that the maximal CSA at LBNP –45 mmHg became higher at the end of the bed rest. Moreover, plethysmography was used to measure the calf compliance in response to a gradual pressure-controlled occlusion of the whole venous network. Conversely, the echography was used to measure the vein CSA changes for evaluating the capacity of the vein to stow blood volume under a passive fluid shift. During a previous 90-day HDBR, the calf volume filling measured by plethysmography during a stand test tended to increase in the NF subjects, whereas the percent increase in calf vein CSA (capacitance) was significantly higher in NF (5). The 90-day HDBR study during which we performed at the same time both the echographic and plethysmographic measurements confirmed that these two methods do not measure the same thing and that plethysmography provides a very indirect approach of what happens at the vein and tissue levels.
Tib and Gast Vein CSA at Rest
At HDBR day 55, the Tib and Gast vein CSA at rest were significantly reduced compared with pre-HDBR in 70% of the NF subjects, suggesting that the vein size at rest is one the major parameters for evaluating the vein deconditioning.
Several factors could have contributed to the reduction of resting vein CSA. A reduction in venous flow might be anticipated with the inactivity of bed rest and the absence of increased cardiac output and sympathetic stimulation in relation with exercise or postural change. Previous studies focused on the flow changes in the lower limbs in relation to the antiorthostatic position have proposed that reductions in perfusion pressure and in demand for blood flow with reduced activity could result in structural and functional changes in the vasculature. Hindlimb suspension in the rat caused changes in vessel wall dimensions, reduced capillary density, reduced sympathetic perivascular nervous fiber density, and functional changes in rat limb arterial vessels (11, 12, 26, 35). In support of this, other authors have reported that 1) reduction in flow contributed to reduce arterial CSA and that such response was endothelium dependent (22), 2) reduction in CSA in the soleus muscle was associated with decrement in muscle perfusion (27), and 3) imbalance between sympathetic vasoconstrictor traffic and nitric oxide release might contribute to increased vascular resistance and reduced flow (20). Although the structure of the vein is not similar to that of the arteries, we may suggest that a similar disadaptative process could result in structural alterations of the veins with the chronic changes in distending pressure and flow stimulus while in the head-down position. These structural and functional changes could contribute to increase the relative stowage of blood in the veins after HDBR, reducing venous return, and increase the risk of orthostatic intolerance.
Nevertheless the HDBR position and Ex-Lb countermeasure had a more limited impact on the vein size than expected because only 50–75% of the non-Ex-Lb subjects reduced their calf vein CSA and 13–38% of the Ex-Lb subjects still reduced it.
Maximal Tib and Gast Vein CSA at – 45 mmHg LBNP
The maximal CSA of both the Tib and Gast veins reached at LBNP 45 mmHg, was not significantly affected by HDBR or by the exercise + LBNP and nutrition countermeasures because only 50–63% of the non-Ex-Lb subjects increased maximal CSA, whereas 25% of the Ex-Lb subjects increased maximal CSA. Moreover the maximal CSA was not significantly different for the Tib (nonintramuscular) and the Gast (muscular) vein whether the subject experienced or not leg muscle atrophy as measured by MRI (33). Thus the maximal calf vein CSA did not depend on the muscle environment.
Future studies focused on the effect of the bed rest on the vein wall structure and capacity to respond to vasoactive drugs and flow pressure might be necessary to better understand the changes in vessel area and capacitance and the possible role of the sympathetic nervous system on the vein response to fluid shift. Purdy et al. (30) reported no significant effect of rat hindlimb suspension on maximal vein response to norepinephrine (jugular and femoral). Moreover, Halliwill et al. (16) specifically studied calf veins and demonstrated no effects of sympathetic activation on calf venous compliance in humans. This observation is in agreement with the fact that the maximal expansion of the vein (at LBNP –45 mmHg) does not change significantly, whereas the arterial vasoconstriction is significantly reduced by bed rest (2, 4, 18, 31, 32). This should be in relation with the fact that the vein wall is anatomically much less complex and respond much more like a passive system compared with the artery that is directly and strongly regulated by the sympathetic system.
Tib and Gast CSA Relative Change From 0 to – 45 mmHg (Vein Capacitance)
The proportion of subjects reducing their CSA at rest or increasing their maximal vein CSA at LBNP –45 mmHg at HDBR day 55 was found to be higher inside the Con and Nut and NF groups compared with the Ex-Lb or F groups. This may explain why the relative change in CSA from 0 to –45 mmHg LBNP (vein capacitance) was higher in these three groups, whereas no significant change in the minimal vein CSA or maximal CSA average value was evidenced between these groups.
Finally the combined Ex-Lb countermeasure that prevented cardiac volume decrease was found to prevent CSA reduction and make smaller the relative change in CSA during LBNP, while probably keeping unchanged the flow volume into the leg veins at rest.
Calf STth Change From 0 to – 45 mmHg LBNP (Tissue Capacitance)
The absolute values of STth measured at rest were not significantly different from pre-HDBR to day 55 of HDBR for any group. With application of –45 mmHg LBNP, there was a small increase in STth after HDBR, but the difference was not significant, probably due to the relatively small sample size in each group. These results were not similar to those obtained in a 7-day HDBR on men on which a significant decrease in STth was found (
3–6%) (13) and with spaceflight data (21). Methodological differences between studies might have accounted for the contrasting findings because the previous studies examined the anterior part of the Tib bone were the skin thickness is regular but very thin, whereas we did our measurements on the posterior part of the calf were the skin thickness is higher but less regular. There was however, a significant increase in relative change in STth (from 0 to –45 mmHg LBNP) after HDBR that reflected a greater fluid stowage in this tissue in the Con, Nut and NF groups, but not in the Ex-Lb and F groups. The proportion of subjects with a higher increase in STth at HDBR day 55 was more important in Con and Nut compared with Ex-Lb (63, 75, vs. 25%, respectively) and in NF compared with F (92 vs. 9%, respectively). Thus HDBR contributed to increase the superficial tissue capacity to stow liquid, whereas the Ex-Lb countermeasure efficiently prevented such disadaptation. On the other hand, the higher amount of liquid stowed into the superficial tissue areas as observed in almost all the NF subjects might have contributed to the reduction in orthostatic tolerance in this group.
Other studies also using the ultrasound method reported an increase in superficial tissue thickness of comparable range. The superficial tissue was found to increase by 11.6% when a subject moves from supine to 30° head-up tilt (14). On patients during hemodialysis echographic skin measurements showed a decrease in tibial tissue thickness of 12.8% in men and 23.9% in women (19). This confirmed the huge capacity of the skin compartment to stow liquid and suggested that this response to fluid shift could be of different amplitude in men and women.
Increased capillary permeability, caused by leg dehydration, extravascular pressure and loss of muscle mass, has been reported during previous bed rest periods or at the end of spaceflight (8). These modifications in capillary permeability may explain the greater calf volume filling measured by plethysmography and the higher superficial tissue capacitance observed in intolerant subjects by echography in the present study. It is nevertheless difficult to evaluate the relative contribution of tissue filtration and secondary vein filling to the changes in calf volume, because the vein CSA is small compared with the calf CSA and the identification of the distal vein network problematic.
Conclusion
The higher amount of liquid stowed both into the main veins and into the superficial tissue areas as observed in the NF group during LBNP, probably contributed to the reduction in orthostatic tolerance. The exercise countermeasure (aerobic exercise in LBNP + resistive) had a protective effect against vein and skin tissue increased stowage and contributed to reduce the disadaptation of these targets and to maintain the adequate level of orthostatic tolerance while the nutrition countermeasure had no effect.
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GRANTS |
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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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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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  P. Arbeille, P. Kerbeci, L. Mattar, J. K. Shoemaker, and R. Hughson Insufficient flow reduction during LBNP in both splanchnic and lower limb areas is associated with orthostatic intolerance after bedrest Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1846 - H1854. [Abstract] [Full Text] [PDF]
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