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Eur J Appl Physiol (2014) 114:597–608DOI 10.1007/s00421-013-2787-4

ORIGINAL ARTICLE

Gradient compression garments protect against orthostatic intolerance during recovery from bed rest

Michael B. Stenger · Stuart M. C. Lee · L. Christine Ribeiro · Tiffany R. Phillips · Robert J. Ploutz‑Snyder · Michael C. Willig · Christian M. Westby · Steven H. Platts

Received: 2 July 2013 / Accepted: 29 November 2013 / Published online: 14 December 2013 © Springer-Verlag Berlin Heidelberg (outside the USA) 2013

the tilt-induced increase in heart rate (ΔHR, 17 ± 2 bpm) and decrease in stroke volume (ΔSV, −28 ± 3 ml) on BR+0 were less than on BR-5 (24 ± 2 bpm, −43 ± 4 ml). On BR+1 ΔHR in the control group (33 ± 4 bpm) was higher than in the treatment group (23 ± 2 bpm) but there were no group differences on BR+3.Conclusions Wearing the GCG prevented the orthostatic intolerance that is normally present after BR. Thigh-high garments provided protection after BR, and wearing these garments did not impair recovery.

Keywords Spaceflight · Countermeasure · Anti-gravity suit · Tilt test · Presyncope

Introduction

Orthostatic intolerance is a well-recognized consequence of space flight. Despite the use of countermeasures (e.g., in-flight exercise, end-of-mission fluid loading, liquid cool-ing during re-entry), the rate of presyncope among Space Shuttle astronauts during post-flight orthostasis in the hours after landing when compression garments are removed is approximately 20 % (Fritsch-Yelle et al. 1996; Lee et al. 1999; Meck et al. 2004), with a higher incidence among women (Waters et al. 2002). The rate of presyncope after long-duration space flight is significantly greater—5 of the 6 NASA astronauts who participated in Mir Space Station missions were unable to complete the 10-min tilt test on landing day (Meck et al. 2001).

During re-entry and landing, astronauts and cosmo-nauts use lower body compression garments to prevent the lower body blood pooling (Perez et al. 2003; Vil-Viliams et al. 1998) that is a key contributor to post-flight ortho-static intolerance (Hoffler and Johnson 1975). Astronauts

Abstract Introduction Abdomen-high, lower body graded com-pression garments (GCGs) may represent the next-genera-tion of orthostatic intolerance protection with applications for exploration missions and commercial space flight.Purpose To evaluate the efficacy of the GCG to prevent orthostatic intolerance after a 14-day 6° head-down tilt bed rest (BR) and to determine whether wearing thigh-high compression garments impairs recovery from BR.Methods Sixteen (12 M, 4 F) subjects participated in a 15-min 80° head-up tilt test 5 day before BR (BR-5), on the last morning of BR (BR+0), and on day 1 (BR+1) and 3 after BR (BR+3). No subjects wore the GCG on BR-5, and all subjects wore the GCG during testing on BR+0. Con-trol subjects (n = 8) wore the GCG only through testing on BR+0. Treatment subjects (n = 8) wore the GCG on BR+0 and thigh-high garments on BR+1 and BR+2.Results No subjects were presyncopal during tilt on BR+0 while wearing the GCG. Despite lower plasma vol-ume index (BR-5: 1.52 ± 0.06, BR+0: 1.32 ± 0.05 l/m2),

Communicated by Dag Linnarsson.

M. B. Stenger (*) · S. M. C. Lee · L. C. Ribeiro · T. R. Phillips Wyle Science, Technology and Engineering Group, 1290 Hercules Ave, Houston, TX 77058, USAe-mail: michael.b.stenger@nasa.gov

R. J. Ploutz-Snyder · C. M. Westby Universities Space Research Association, Houston, TX, USA

M. C. Willig JES Tech, Houston, TX, USA

S. H. Platts Biomedical Research and Environmental Sciences Division, NASA Johnson Space Center, Houston, TX, USA

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during the Space Shuttle era used inflatable anti-gravity suits (AGS), and astronauts and cosmonauts returning to Earth via a Soyuz capsule wear an elastic compression gar-ment (Kentavr). These garments are effective in preventing orthostatic intolerance in hypovolemic subjects during tilt tests (Platts et al. 2009b) and were shown to support arterial blood pressures during vehicle re-entry (Perez et al. 2003). However, neither has been tested after head-down tilt bed rest, and each garment has limitations that might impact on compliance and efficacy (Platts et al. 2009b). For example, the inflatable AGS requires a compressed air source that was not available upon exiting the Space Shuttle, gradually deflates when disconnected from the air source (Lee et al. 2011), and may impair egress ability due to its bulky design (Bishop et al. 1999). The elastic Kentavr used during Soyuz landings can be worn and is effective after egressing the vehicle, but the feet, knees and groin are not covered by the garment, and consequently these areas are subject to uncomfortable swelling during extended use (Platts et al. 2009b). Additionally, both the AGS and Kentavr may pro-mote venous stasis because the same pressure is applied across the entire length of the lower body. In contrast, gra-dient compression, which provides high pressures at the feet and ankles with decreasing compression higher in the leg and over the abdomen, enhances venous return and may be a superior method of protection against orthostatic intol-erance (Shibao et al. 2013).

In the development of a garment for exploration class space missions that improves upon the beneficial features of the AGS and Kentavr, our laboratory has been evaluat-ing different configurations of elastic, gradient compres-sion garments that provide a continuous counterpressure along the area of coverage. The intent of these efforts is to develop a garment that could be used during re-entry and landing and worn comfortably in the hours and days after landing during recovery to the pre-flight condition. In response to anecdotal reports from the astronauts that included comments that high abdominal compression can be uncomfortable, particularly after end-of-mission oral fluid loading, we initially tested a thigh-high only gradi-ent compression garment that provided 55 mmHg at the ankle, decreasing linearly to 18 mmHg at the knee and 6 mmHg at the top of the leg. The maximum compres-sion provided by this garment was higher than that pro-vided by the Kentavr (~30 mmHg) (Platts et al. 2009b), but the average compression across the leg was lower. These thigh-high garments were effective in preventing some signs and symptoms of orthostatic intolerance in 5 astronauts after a 13-day Space Shuttle mission (Stenger et al. 2010), but the lack of abdominal compression may have limited their efficacy. Previous studies show that abdomen-only compression can be superior to leg-only compression, although compression of both the legs and

the abdomen may be the ideal configuration (Denq et al. 1997; Smit et al. 2004).

Therefore, we worked closely with an established pro-vider of medical compression garments (BSN-medical, Inc., Rutherford College, NC, USA) to develop a new elastic, gradient compression garment (GCG) that pro-vided increased leg compression compared to the previous thigh-high garments and added a pair of biker-style shorts to apply abdominal compression. The GCG provides a continuous, gradient compression from the feet to the bot-tom of the rib cage, covering the same areas as the inflat-able AGS and the Kentavr. However, unlike both of these suits, the GCG provides a gradient compression, decreasing from a high of 55 mmHg at the ankle to 35 mmHg at the knee and 18 mmHg at the top of the leg and ~16 mmHg of compression over the abdomen. The GCG provides a higher compression than the Kentavr (~30 mmHg), without leaving areas uncompressed, and without requiring a com-pressed air source like the inflatable AGS suit. In a recent evaluation of the GCG following short duration (~2 weeks) Space Shuttle missions, the GCG prevented the tachycardia and drop in stroke volume during orthostasis normally seen after space flight and was comfortable to wear (Stenger et al. 2013).

The beneficial effects of wearing the GCG after space-flight were observed during a short duration stand test within a few hours of landing. However, it is not clear if wearing an anti-orthostatic countermeasure garment like the GCG impedes the re-adaptation to Earth gravity and thereby prolongs the recovery process. For example, the prolonged use of high compression garments could par-tially prevent the fluid shifts during standing in normal gravity (Lateef and Kelvin 2008) to the extent that the nor-mal post-flight plasma volume recovery would be impaired or delayed. Russian flight surgeons and medical special-ists gradually loosen a series of lacings in the Kentavr over the calves, thighs and abdomen over the first few days after landing such that the Kentavr provides progressively less protection over time as cosmonauts recover from the effects of space flight (Garshnek 1989). No similar proto-col exists in the NASA Medical Operations plan, and to our knowledge these effects have not been systematically tested. Therefore, there were two main purposes of the cur-rent study. First, we sought to confirm the positive benefits of wearing the GCG during an 80° head-up tilt test after 2 weeks of simulated microgravity exposure (bed rest). Results from our previous Space Shuttle study were lim-ited by the short duration of the stand test (3.5 min) which may not have been as sensitive as longer tests previously employed by our and other laboratories. Second, we sought to determine whether there were any negative effects of a gradual reduction in cardiovascular support that would pro-long the recovery time reported in previous studies (~3 days

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following a short duration Shuttle mission) (Waters et al. 2002). We hypothesized that reducing the compression applied by gradient compression garments over the first 3 days of post-bed rest recovery would provide protection against orthostatic intolerance without delaying the recov-ery of orthostatic responses and plasma volume compared to a control group that did not wear compression garments past the immediate post-bed rest period.

Methods

Overall protocol

Sixteen healthy, normotensive, non-smokers of nor-mal body weight volunteered to participate in this study. Eight control [6 men, 2 women; age 37 ± 3 years; height 177.1 ± 3.0 cm; weight 75.4 ± 4.0 kg; BMI 24 ± 1.1 kg/m2; peak oxygen consumption (VO2pk) 37.3 ± 3.1 ml/kg/min; mean ± SE] and 8 treatment (6 men, 2 women; age 39 ± 3 years; height 172.3 ± 3.0 cm; weight 75.7 ± 3.5 kg; BMI 25.5 ± 0.8 kg/m2; VO2pk 37.8 ± 4.6 ml/kg/min] sub-jects participated in a 14-day 6° head-down bed rest at the General Clinical Research Center (GCRC) Satellite Flight Analogs Research Unit at the University of Texas Medical Branch (UTMB) in Galveston, TX, USA. Order of presen-tation for participation in the study was not controlled, and subjects were assigned to the two groups in balanced man-ner based on gender and pre-bed rest VO2pk. All protocols were reviewed and approved by the NASA Johnson Space Center Committee for the Protection of Human Subjects,

UTMB Institutional Review Board and UTMB GCRC Advisory Committee. Subjects received verbal and written descriptions of all study protocols and procedures before providing written informed consent.

Test subjects were admitted to the bed rest facility 13 days before the start of the head-down bed rest. Dur-ing the head-down tilt portion of the study, subjects were 6° head-down for 24 h/day for 14 days, and standard con-ditions (diet, wake/sleep time, time allowed in sunlight) were maintained across all subjects throughout the study (Meck et al. 2009). Five days prior to head-down bed rest (BR-5), hematocrit, hemoglobin, and plasma volume were measured, an echocardiogram was performed, and cardio-vascular responses to a 15-min 80° head-up tilt test were assessed. These tests were repeated immediately follow-ing the conclusion of bed rest (BR+0), 1 day after bed rest (BR+1), and 3 days after bed rest (BR+3). Hemato-crit, hemoglobin, and plasma volume also were measured 2 days after bed rest (BR+2). Additionally, circumference of the abdomen, thigh, calf, and ankle was measured during each testing session to track changes in body segments that might affect garment fit. The testing schedule is shown in Fig. 1.

For the duration of the bed rest study, subjects con-sumed an isocaloric diet that included 2 mmol/kg/day sodium, 1.3 mmol/kg/day potassium, 1,000 mg/day cal-cium, 1,400 mg/day phosphorous, 800 IU/day of vitamin D3 (2,000 IU/day during pre-bed rest phase if warranted by pre-screening) and fluid intake of at least 28.5 ml/kg/day. Prior to all test sessions, subjects were only allowed to consume a light snack of complex carbohydrates within 2 h

Fig. 1 Diagram of the testing schedule across days

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of testing. Subjects also abstained from caffeine, nicotine, and alcohol within the preceding 12 h and medication and maximal exercise within the preceding 24 h.

Compression garments

The control subjects donned the custom-fitted GCG upon awaking on BR+0 at 06:00 and removed the GCG follow-ing our testing on BR+0 (~11:00). The schedule for don-ning and doffing the GCG in the control subjects was meant to simulate the timeline previously used by Shuttle astro-nauts who donned the AGS before re-entry and removed it soon after landing. The treatment subjects donned the GCG upon waking on BR+0 but wore this garment through bedtime (~22:00) on BR+0. Treatment subjects also wore thigh-high compression garments from waking until bed time on BR+1 and BR+2. The plan for wearing compres-sion garments in the treatment group was meant to simulate a prescription for an astronaut who might be particularly susceptible to post-space flight orthostatic intolerance and require support over several days after landing. This plan also mirrors that employed by Russian medical personnel to protect cosmonauts returning from long-duration space flight missions (Garshnek 1989).

The specific configuration of the GCG tested on R + 0 consisted of a combination of a custom-fitted thigh-high stockings with custom-fitted “biker-style” shorts that pro-vide a continuous gradient compression from the foot to the abdomen (Stenger et al. 2013). Individualized construc-tion of the GCG was based on detailed measurements made of each subject 8 days prior to head-down bed rest when the subject had acclimated to the diet and bed rest facil-ity. Trained personnel measured the circumference of each subject’s legs every 3.8 cm (1.5 in.) from the base of the toes to the top of the thigh. Additional measurements were taken along the torso ending just below the breast-line. The manufacturer (BSN-medical Inc, Rutherford College, NC, USA) used these detailed measurements to construct an individualized GCG for each subject designed to produce a pressure of 55 mmHg at the ankle, decreasing to approxi-mately 35 mmHg at the knee and 18 mmHg at the thigh. The pressure in the abdominal region was ~16 mmHg. The compression provided from these elastic garments is directly related to the tension in the circumferential fibers (Law of LaPlace); this tension is based on the length of the fibers and was verified by a HATRA test instrument that is identified in the British Standard for testing compression in elastic stockings. Furthermore, the validation of this line of garments was reviewed and approved by the FDA.

On days BR+1 and BR+2, subjects in the treatment group wore commercial, off-the-shelf thigh-high stockings, extending from the base of the toes to the top of the thighs, from the time of waking in the morning until retiring in the

evening (06:00–22:00). On BR+1, the thigh-high garment provided 30–40 mmHg of compression at the ankle and decreased up the leg to 10 mmHg at the top of the thigh. On BR+2, the thigh-high garment provided 10–20 mmHg of compression at the ankle and decreased up the leg to 5 mmHg at the top of the thigh. Compression profiles, based on information from the manufacturer, are shown for all three garments in Fig. 2.

Questionnaire

Test operators queried treatment subjects regarding gar-ment comfort and fit on BR+0 through BR+2. Subjects scored fit and comfort of the shorts and thigh stockings separately on a scale of 1–5, with 1 being “very comfort-able” and 5 being “very uncomfortable”. A score of 3 was considered to be “neutral”. Reports were given separately for the shorts and the thigh-high portions of the garment to identify any specific areas of concern. Subjects were queried every 2 h from 08:00 (1 h after donning) to doffing (~22:00). Instructions regarding the scale were provided prior to scoring at each time point. A similar scoring of comfort was employed in our previous study of the GCG worn by Space Shuttle astronauts (Stenger et al. 2013). To evaluate the difference between recovery leg pain and gar-ment comfort, control subjects also were queried about leg comfort from BR+0 through BR+2, even when they were not wearing the garment.

Tilt test

After a 5-min baseline period, subjects were tilted to 80° head-up for 15 min or until presyncopal symptoms inter-vened (e.g., systolic blood pressure of <70 mmHg, light-headedness, nausea) or if subject requested that test be terminated. The baseline data collection period was con-ducted supine on BR-5, BR+1 and BR+3. Baseline data

Fig. 2 Compression profile for the three different gradient compres-sion garments used in this study

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on BR+0 were collected with the tilt table set at −6° head-down, representing the condition of simulated spaceflight (Platts et al. 2009a). Subjects were instrumented to meas-ure brachial blood pressure at 1-min intervals (Dinamap, GE, Milwaukee, WI, USA), beat-to-beat blood pressure (sampling rate of 100 Hz) in the finger (Finometer, Finap-res Medical Systems, The Netherlands), and ECG (MDE Escort II, Arleta, CA, USA). Ascending aorta blood veloc-ity was measured from three beats per minute using pulsed Doppler (Biosound MyLabs, Indianapolis, IN, USA) at the suprasternal notch. The timing of these measures cor-responded to the brachial artery blood pressure measure-ments. Left ventricular outflow tract (LVOT) diameter was measured during supine rest using two-dimensional (2D) echocardiography with a 2–4 MHz phase array probe at the cusp insertion point of the aortic valve (iE33, Philips Ultra-sound, Bothell, WA, USA). All Doppler images were saved for subsequent off-line analysis. Ultrasound measures were stored digitally and independently analyzed by 2 sonogra-phers using customized MATLAB® programs (MathWorks, Natick, MA, USA). For all ultrasound measurements, a dif-ference in analysis of greater than 10 % between sonogra-phers was flagged for re-analysis by a third sonographer. LVOT cross-sectional area (CSA = π·d2/4), stroke volume (LVOT CSA × aortic blood velocity time integral), cardiac output (stroke volume × heart rate), and total peripheral resistance (mean arterial pressure/cardiac output) were calculated.

Plasma volume determination

Plasma volume and blood volume were determined using a carbon monoxide rebreathing procedure (Burge and Skin-ner 1995) with modifications. After a 10-min supine rest period, the subject breathed 100 % oxygen for 2 min in a closed breathing circuit. Twenty-eight millilitres of car-bon monoxide was added to the breathing circuit, and this mixture (carbon monoxide and oxygen) was rebreathed for 10 min. A baseline 3-ml blood sample was collected. While still breathing through the closed circuit, an additional 32 ml of carbon monoxide was added into the system. This mixture was rebreathed for 10 min followed by a second 3-ml blood draw. Blood samples were analyzed by the JSC Clinical Laboratory (College of American Pathologists accredited) for hematocrit, hemoglobin, and carboxyhemo-globin. Hemoglobin and hematocrit determination was measured using the Coulter LH750 (Beckman Coulter, Inc., Brea, CA, USA). Carboxyhemoglobin was analyzed using the IL 682 co-oximeter (Instrumentation Laboratory Com-pany, Bedford, MA, USA). From these values, red blood cell volume, total blood volume and plasma volume were calculated. To account for subjects of different body masses and plasma volumes, plasma volume was normalized by

body surface area and is represented as plasma volume index (PVI).

Cardiac function

Two-dimensional and 3-dimensional (3D) echocardiograms (iE33, Philips Ultrasound, Bothell, WA, USA) were per-formed by registered sonographers following the American Society of Echocardiography standards and guidelines with subjects in the left lateral decubitus position while subjects were either supine (BR-5, BR+1, and BR+3) or −6° head-down (BR+0). 2D, 3D and Doppler images were collected for at least 3 cardiac cycles to determine systolic and dias-tolic function, and evaluate chamber size and flows through cardiac valves. Images were stored digitally for off-line analysis. Analyses of 2D and tissue Doppler images were performed using ProSolv (ProSolv Cardiovascular, Indi-anapolis, IN, USA) and analyses of 3D images were per-formed using QLab (Philips, Bothell, WA, USA).

Analysis and statistics

All statistical analyses were performed using Stata, IC soft-ware (v12.1, StataCorp LP, College Station, TX, USA) and setting 2-tailed alpha to reject the null hypothesis at 0.05. As described earlier in “Methods”, our dependent variables were assessed once before bed rest (BR-5) and 3 (hemody-namic measurements; BR+0, BR+1, BR+3) or 4 (plasma volume measured at BR+0, BR+1, BR+2, BR+3 and echocardiography measures at BR+0, BR+4 h, BR+1, BR+3) times post-bed rest. Separate mixed-effects lin-ear regression models were used to evaluate the effects of wearing the experimental garment (treatment versus con-trol) and bed rest (multiple observations pre- and post-bed rest) on our continuously scaled-dependent variables.

Separate mixed-effects, fully factorialized linear regres-sion models were fit to each primary outcome in order to test the hypotheses that the effects of bed rest are attenu-ated by the garments. Specifically, our initial statistical model included dummy-coded beta coefficients comparing pre- (BR-5) to post-bed rest (BR+0), treatment vs. control, and the treatment by day interaction term enabling us to determine whether there were any pre- to post-bed rest dif-ferences in the treatment group relative to controls. Then to better understand recovery from bed rest, we ran a sub-sequent model focusing only on the recovery time points, with dummy-coded beta coefficients comparing the BR+0 observation to each of the subsequent post-bed rest recov-ery observations, the treatment main effect, and important treatment by day (relative to BR+0) interaction effect terms. This model included a priori contrasts comparing the treatment group versus controls at each recovery time period. As is typical with mixed-effects modeling, these

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models included a random intercept to accommodate the longitudinal design of the experiment, allowing each par-ticipant to have their own off-set. All data are represented as mean ± SEM.

Results

Pre- to immediate post-bed rest

Three subjects became presyncopal during BR-5 testing. In the control group, one test was terminated after 14 min of tilt. In the treatment group, one subject became presyn-copal after 12 min of tilt, and another became presyncopal after 14 min of tilt. No subjects were presyncopal on BR+0 while wearing the GCG.

Analysis of bed rest effects (BR-5 vs. BR+0) by group (Treatment, Control) revealed no significant group effects or interactions. Therefore, the data presented in Table 1 are the means of both groups of subjects combined. Although

PVI was significantly lower (P < 0.001) after bed rest, tilt tolerance was not reduced after bed rest when sub-jects were wearing the GCG. The tilt-induced increase in heart rate (ΔHR) was lower on BR+0 compared to BR-5 (P = 0.002), and the tilt-induced decrease in stroke volume (ΔSV) was significantly smaller (P < 0.001).

Left ventricular mass (LVM, P < 0.001) and end-systolic left ventricular volume (LVVS, P = 0.001) from 3D meas-ures were reduced after bed rest. End-diastolic left ventric-ular volume (LVVD) also tended to be lower (P = 0.06). Similarly, end-diastolic left ventricular diameter (LVDD, P = 0.04) and mitral E-wave (ME, P < 0.001) from 2D measures were significantly reduced after bed rest.

Post-bed rest recovery

No control subjects were presyncopal during BR+1 tilt testing, but one treatment subject became presyncopal after 12 min of tilt. This subject was not presyncopal during tilt on any other test days. On BR+3, one control

Table 1 Pre- to post-bed rest hemodynamic, cardiac function, and anthropometric measures

Day effect for PVI, echocardiographic, and anthropometric measures refers to pre- to post-bed rest comparison. Day effect for hemodynamic variables refers to comparison of the tilt response (tilt-rest) from pre- to post-bed rest

BR-5 BR+0 Day effect

Baseline

Plasma volume index (L/m2) 1.5 ± 0.1 1.3 ± 0.0 <0.001

Heart rate (bpm) 59 ± 2 63 ± 2

Systolic blood pressure (mmHg) 114 ± 2 123 ± 2

Diastolic blood pressure (mmHg) 69 ± 1 77 ± 2

Stroke volume (ml) 80 ± 6 68 ± 5

Cardiac output (l/min) 4.8 ± 0.4 4.5 ± 0.4

Total peripheral resistance 19 ± 1 22 ± 2

80° head-up tilt

Heart rate (bpm) 83 ± 4 81 ± 4 0.002

Systolic blood pressure (mmHg) 120 ± 4 128 ± 2

Diastolic blood pressure (mmHg) 75 ± 1 80 ± 2 0.002

Stroke volume (ml) 37 ± 3 40 ± 3 0.001

Cardiac output (l/min) 3.1 ± 03 3.3 ± 0.3

Total peripheral resistance 29 ± 4 32 ± 3

Echocardiography

Left ventricular mass (g) 141 ± 6 132 ± 5 <0.001

Left ventricular diastolic volume (ml) 130 ± 5 119 ± 5 0.061

Left ventricular systolic volume (ml) 46 ± 2 41 ± 1 0.001

Left ventricular diastolic diameter (cm) 5.0 ± 0.1 4.8 ± 0.1 0.039

Left ventricular systolic diameter (cm) 3.1 ± 0.1 3.0 ± 0.1 0.067

Mitral E-wave velocity (cm/s) 73 ± 4 62 ± 3 <0.001

Mitral A-wave velocity (cm/s) 41 ± 3 41 ± 2

Anthropometrics

Body mass (kg) 76 ± 3 74 ± 3 <0.001

Waist circumference (cm) 81 ± 2 80 ± 1 <0.001

Thigh circumference (cm) 49 ± 1 48 ± 1 <0.001

Calf circumference (cm) 35 ± 1 34 ± 1 <0.001

Ankle circumference (cm) 22 ± 0 22 ± 0

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subject became presyncopal during head-up tilt at approx-imately the same time (14 min) that testing was termi-nated for this subject on BR-5. Also, one treatment sub-ject became presyncopal after 8 min of tilt test on BR+3. This subject also became presyncopal on BR-5 at 12 min of tilt.

Plasma volume index was higher on BR+1 (P = 0.056), BR+2 (P < 0.001) and BR+3 (P = 0.006) than BR+0 with no group effect (Table 2). However, ΔHR was greater on BR+1 (p < 0.001) and BR+3 (P = 0.031) than on BR+0. Pairwise contrasts comparing groups within time periods showed that ΔHR was higher in the control group than

the treatment group only on BR+1 (P = 0.05). The ΔSV was more negative on both BR+1 (P < 0.001) and BR+3 (P = 0.02) than BR+0 for the combined groups, with no differences between groups.

Left ventricular mass was greater on BR+1 (P = 0.007) and BR+3 (P = 0.001) compared to BR+0. LVDV and LVSV also were greater on BR+1 (P ≤ 0.001) and BR+3 (P < 0.001) compared to BR+0. There were no effects of group on these 3D echocardiographic measures of ven-tricular size and volume. LVDD and ME from 2D echocar-diography also were greater on BR+3 than on BR+0 for the combined groups (P = 0.024 and 0.003, respectively).

Table 2 Post-bed rest recovery of hemodynamic and cardiac function parameters between control and treatment groups

Day effect references changes compared to BR+0. Day Effect for PVI, echocardiographic, and anthropometric measures refers to pre- to post-bed rest comparison. Day Effect for hemodynamic variables refers to comparison of the tilt response (tilt-rest) from pre- to post-bed resta Group Effect on BR-1b Group by Day Interaction on BR-1

Control Treatment Day effect

BR+0 BR+1 BR+2 BR+3 BR+0 BR+1 BR+2 BR+3

Baseline

Plasma volume index (l/m2) 1.3 ± 0.1 1.5 ± 0.1 1.6 ± 0.1 1.5 ± 0.1 1.4 ± 0.1 1.4 ± 0.1 1.5 ± 0.1 1.5 ± 0.1 1, 2, 3

Heart rate (bpm) 65 ± 4 64 ± 4 65 ± 4 61 ± 3 64 ± 3 61 ± 3

Systolic blood pressure (mmHg) 125 ± 3 115 ± 2 118 ± 4 120 ± 2 117 ± 3 117 ± 3

Diastolic blood pressure (mmHg) ± 3 70 ± 2 71 ± 2 77 ± 2 74 ± 2 75 ± 2

Stroke volume (ml) 66 ± 7 70 ± 9 69 ± 8 70 ± 8 74 ± 8 72 ± 9

Cardiac output (l/min) 4.5 ± 0.4 4.5 ± 0.4 4.6 ± 0.4 4.5 ± 0.6 4.7 ± 0.5 4.5 ± 0.6

Total peripheral resistance 21 ± 2 20 ± 2 20 ± 2 23 ± 3 20 ± 2 23 ± 3

80° head-up tilt

Heart rate (bpm)a 84 ± 6 97 ± 7 90 ± 6 77 ± 4 87 ± 5 87 ± 4 1, 3

Systolic blood pressure (mmHg) 130 ± 3 119 ± 2 121 ± 4 127 ± 3 117 ± 4 120 ± 5

Diastolic blood pressure (mmHg) 79 ± 3 75 ± 2 74 ± 1 82 ± 2 76 ± 2 80 ± 4

Stroke volume (ml) 39 ± 4 30 ± 3 33 ± 3 41 ± 5 31 ± 2 33 ± 4 1, 3

Cardiac output (l/min) 3.4 ± 0.3 3.0 ± 03 3.1 ± 0.3 3.2 ± 0.5 2.7 ± 0.3 29 ± 0.4

Total peripheral resistance 30 ± 3 31 ± 3 30 ± 3 34 ± 5 35 ± 3 36 ± 4

BR+0 BR+4 h BR+1 BR+3 BR+0 BR+4 h BR+1 BR+3 Day effect

Echocardiography

Left ventricular mass (g) 130 ± 6 133 ± 7 137 ± 6 139 ± 6 134 ± 8 134 ± 6 140 ± 9 140 ± 7 1, 3

Left ventricular diastolic volume (ml) 117 ± 5 124 ± 6 132 ± 5 131 ± 5 120 ± 8 123 ± 6 129 ± 9 132 ± 7 1, 3

Left ventricular systolic volume (ml) 39 ± 2 43 ± 2 45 ± 2 47 ± 2 42 ± 2 42 ± 2 45 ± 3 46 ± 3 4 h, 1, 3

Left ventricular diastolic diameter (cm) 4.7 ± 0.1 4.9 ± 0.2 5.0 ± 0.2 5.1 ± 0.2 4.9 ± 0.2 4.9 ± 0.1 5.0 ± 0.2 5.1 ± 0.2 3

Left ventricular systolic diameter (cm) 2.8 ± 0.1 2.9 ± 0.1 3.0 ± 0.1 3.0 ± 0.1 3.2 ± 02 3.2 ± 0.2 3.2 ± 0.1 3.1 ± 0.2

Mitral E-wave velocity (cm/s)a,b 59 ± 3 61 ± 4 60 ± 3 71 ± 5 64 ± 6 61 ± 6 77 ± 4 73 ± 7 3

Mitral A-wave velocity (cm/s) 42 ± 3 45 ± 3 41 ± 3 42 ± 2 41 ± 4 41 ± 3 46 ± 5 44 ± 4

BR+0 BR+1 BR+2 BR+3 BR+0 BR+1 BR+2 BR+3 Day effect

Anthropometrics

Body mass (kg) 74 ± 4 75 ± 4 75 ± 4 75 ± 4 74 ± 4 75 ± 3 75 ± 4 75 ± 4

Waist circumference (cm) 78 ± 3 79 ± 3 80 ± 3 80 ± 3 81 ± 3 82 ± 3 82 ± 3 82 ± 3

Thigh circumference (cm) 47 ± 1 48 ± 2 49 ± 2 47 ± 1 48 ± 1 49 ± 1 49 ± 1 49 ± 1

Calf circumference (cm) 33 ± 1 34 ± 1 34 ± 1 34 ± 1 34 ± 1 34 ± 1 34 ± 1 34 ± 1

Ankle circumference (cm) 21 ± 0 21 ± 0 21 ± 0 21 ± 0 22 ± 0 22 ± 1 22 ± 0 22 ± 0

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While there were no group differences in LVDD, we found a significant group by BR+1 (relative to BR+0) interaction effect (P = 0.02) suggesting greater increase in the treat-ment group relative to controls with contrasts comparing groups on BR+1 revealing significant increasing value in the treatment group.

Anthropometrics and garment comfort

Calf and thigh circumference decreased (P < 0.001) by an average of 1.2 ± 0.1 and 1.6 ± 0.2 cm, respectively, from pre- to post-bed rest (BR+0; Table 1). However, there was no change in ankle circumference and waist circumference only tended to be less (P = 0.06) after bed rest. Body mass decreased (P < 0.001) by −1.4 ± 0.3 kg from BR-5 to BR+0. During recovery from bed rest, all anthropometric measures were significantly different than BR+0 by BR+1 (P < 0.05) indicating rapid recovery towards pre-bed rest levels, and there was no effect of treatment (Figs. 3, 4).

No subjects in the control group, who wore the garments only through the end of the tilt test on BR+0, reported comfort ratings greater than “2” for the shorts. Similar lev-els of comfort were reported for the thigh-high portion of the garments in the control group. As expected, scores were consistently 1 in the control subjects after the garments were doffed, suggesting no lingering effects of wearing the GCG. In the treatment group who wore the GCG all day on BR+0, one subject reported scores of “3” during the first 4 h of wearing the shorts, but thereafter that subjects scores were consistently “2” until doffing the GCG at the end of the day. This same subject reported scores of “3” for the thigh-highs in the mornings, with scores decreasing to “2” thereafter. Only one other treatment subject reported a score as high as “3” for the shorts on BR+0, and this was reported at the end of day. This treatment subject also reported a score of “3” at the end of the day while wearing thigh-highs.

Discussion

This study has resulted in two significant findings. First, the GCG is an effective countermeasure to signs and symp-toms of post-bed rest orthostatic intolerance. While three subjects could not complete the 80° head-up tilt test before bed rest when not wearing the GCG, no subjects became presyncopal on BR+0 after 2 weeks of 6° head-down tilt bed rest-induced deconditioning. In fact, ΔHR and ΔSV were smaller on BR+0 when subjects were wearing the GCG, which could be interpreted as an improved response to 80° head-up tilt compared to BR-5. Second, although subjects received protection against orthostatic intolerance while wearing the thigh-high only garments on BR+1 and BR+2, there was no effect of the garments (control vs. treatment) on responses to orthostatic testing on BR+3 without garments. Also, PVI recovered to pre-bed rest levels in both groups by BR+3. Thus, at least after short duration missions, astronauts and cosmonauts who wear the GCG immediately post-flight should be protected from

Fig. 3 Change in heart rate and stroke volume from rest to upright tilt in all subjects (n = 16) before bed rest (BR-5) and at the end of bed rest (BR+0). No subjects wore compression garments on BR-5, and all subjects wore the GCG on BR+0. Asterisks significantly dif-ferent than pre-bed rest

Fig. 4 Change in heart rate from rest to upright tilt in control (open bars) and treatment (solid bars) before bed rest (BR-5), at the end of bed rest (BR+0), after 1 day of recovery (BR+1), and after 3 days of recovery (BR+3). No tilt testing was performed on BR+2. No subjects wore the GCG on BR-5, but all subjects wore the GCG on BR+0. Control subjects did not wear garments on BR+1 or BR+3. Treatment subjects wore thigh-high compression garments on BR+1 but no compression garments on BR+3. Asterisk significantly differ-ent than GCG and BR+0

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orthostatic intolerance, and wearing thigh-high compres-sion garments with gradually decreasing levels of compres-sion over the first few days post-landing should not impair recovery from space flight.

Pre- to immediate post-bed rest

The positive effect of the GCG on orthostatic tolerance during tilt can be inferred when comparing our results to findings from testing after space flight and bed rest when no compression garment is worn. Many previous studies have demonstrated orthostatic intolerance (presenting as tachycardia and reduced stroke volume and leading to pre-syncope or syncope in some subjects) as a common result after space flight and bed rest exposures of similar duration to the present study. After Space Shuttle missions lasting 1–2 weeks, Fritsch-Yelle et al. (1996) found that 8 of 29 astronauts (28 %) could not complete a 10-min stand test, and heart rate was elevated and stoke volume was reduced in both presyncopal and non-presyncopal astronauts on landing day. An even higher incidence of presyncope (9 of 14 astronauts, 64 %) was reported by Buckey et al. (1996) after missions of similar durations. Head-down tilt bed rest studies, a well-accepted analog of the space flight-induced cardiovascular deconditioning, with similar durations to ours also have consistently reported decreased orthostatic intolerance when no countermeasures were applied. Sch-neider et al. (2002) found decreased tolerance to lower body negative pressure (LBNP), along with elevated heart rate, after 15 days of 6° head-down tilt bed rest, and Waters et al. (2005) showed elevated heart rate and decreased stroke volume during multiple head-up tilt angles, despite plasma volume restoration with salt tablets and water, after 12 days of head-down tilt bed rest. In contrast, all 16 sub-jects (100 %) in the current study were able to complete the 15-min, 80° head-up tilt test after 14 days of 6° head-down tilt bed rest without any signs or symptoms of orthostatic intolerance while wearing the GCG. Further, the smaller heart rate and stroke volume responses to head-up tilt, despite a lower plasma volume after bed rest, suggest that the post-bed rest tilt while wearing the GCG represented a smaller cardiovascular stressor than head-up tilt before bed rest without the GCG. Importantly, the GCG appears to provide adequate protection against post-bed rest ortho-static intolerance in women, as female astronauts have a high rate of post-spaceflight presyncope on landing day (Fritsch-Yelle et al. 1996; Waters et al. 2002). None of the four women in this bed rest study became presyncopal dur-ing the post-bed rest tilt test while wearing the GCG, even though the duration of head-up tilt was longer than post-landing tilt tests in astronauts.

Reduced plasma volume, stroke volume, and echocar-diographic measures of left ventricular size and diastolic

function are common adaptations to bed rest that might contribute to orthostatic intolerance after bed rest (Levine et al. 1997; Schneider et al. 2002; Waters et al. 2005). We also observed these changes in our subjects before they became ambulatory on BR+0 even though the subjects already had been wearing the compression garments for several hours. The GCG had no influence on cardiac func-tion obtained on BR+0 when subjects were in the 6° head-down tilt posture; the veins in the lower body already were emptied in this posture, and the compression provided by the GCG did not induce additional fluid shifts to increase venous return and stroke volume. However, the benefits of wearing the GCG became apparent when the subjects were tilted head-up. Orthostatic tolerance was maintained and the tilt-induced elevation in heart rate and reduction in stroke volume that are normally exacerbated by bed rest were prevented while wearing the GCG. It is likely that the GCG prevented venous pooling in the legs and abdomen and improved cardiac filling during the upright posture, factors which appear to be associated with orthostatic intol-erance after bed rest and space flight (Arbeille et al. 2008; Buckey et al. 1996; Levine et al. 1997).

Recovery from bed rest

The second purpose of this study was to evaluate the impact on the compression garments worn during the first 3 days post-bed rest on the recovery from bed rest-induced deconditioning. Specifically, we sought to determine whether wearing compression garments, with decreasing levels of compression each day, would inhibit the restora-tion of plasma volume and cardiovascular responses to tilt by BR+3. Although we observed some between-group differences on BR+1 when only the treatment group was wearing thigh-high compression garments, plasma volume, cardiac function, and orthostatic responses were not dif-ferent between groups on BR+3 when neither group was wearing garments.

On BR+1, both treatment and control groups exhibited symptoms of bed rest deconditioning during 80° head-up tilt that were not present during the BR+0 test day. ΔHR was greater and ΔSV was more negative in both groups on BR+1 despite recovery of PVI, but ΔHR was not as large in the treatment subjects. It is clear from these results that orthostatic responses are not completely recovered after just 1 day of reambulation in subjects not wearing garments and that the thigh-high garments worn by the treatment group on BR+1 were not as effective as the GCG worn on BR+0. A portion of the lower ΔHR in the treatment group, compared to the control group on BR+1, might be explained by an improved diastolic function compared to BR+0 which was not observed in the control group; per-haps the increased early filling of the left ventricle resulted

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from improved venous return consequent to the recovery of plasma volume in conjunction with the compression gar-ments. Unfortunately with the limited data available in this area, it is difficult to ascribe with certainty what reduced the effectiveness of the compression garments on BR+1. Abdominal compression appears to be play a dominant role in the effectiveness of compression garments (Denq et al. 1997), but the decreased effectiveness of the BR+1 gar-ments also might be ascribed to the decreased leg compres-sion compared to the BR+0 garments.

Although testing was not performed on BR+2, we sus-pect that the BR+2 garments may have provided an appro-priate level of support for ambulatory subjects recovering from bed rest. Others have reported that higher levels of compression produce measurable effects during orthos-tatic stress in normal subjects. Smit et al. (2004) report that 40 mmHg of leg compression can improve blood pressure, but 20 mmHg is less effective. Watanuki and Murata (1994) estimated that a minimum of 17 mmHg in the lower leg and 15 mmHg in the thigh is required in the leg to improve venous return. While both of these reports suggest a higher level than the average compression provided by the BR+2 garments (~9 mmHg), the thigh-high garments used on BR+2 provided 20 mmHg of compression at the ankle, decreasing to ~10 mmHg at the knee. Thus, although the level of compression decreased further in the thigh, the highest compression levels were provided in the lower leg where hydrostatic pressures would be greatest. The overall reduced compression compared to BR+0 and BR+1 may have been appropriate, as a significant countermeasure may not have been necessary at this point in the recovery after bed rest. However, the time course of the recovery of ortho-static tolerance has not been well described, particularly after long duration space flight and bed rest. Orthostatic tolerance appears to be recovered in astronauts by 3 days after Space Shuttle landings (Waters et al. 2002), but we anticipate that some level of orthostatic intolerance will persist for a longer time after long-duration space flight missions (Baevsky et al. 2007; Johnson et al. 1977).

Garment fit and comfort

An important contributor to garment efficacy is the proper fitting of the garment, which can change during the course of a space flight mission due to cephalad shifts (Thornton et al. 1976, 1987) and loss of plasma volume (Fritsch-Yelle et al. 1996; Waters et al. 2002) as well as decreased muscle mass (LeBlanc et al. 2000). Similar to our previous Space Shuttle study, bed rest subjects experienced a decrease in calf, thigh, and waist circumference from pre- to post-bed rest (Stenger et al. 2013). If these changes, particu-larly muscle atrophy, had been more extreme, as might be expected for long-duration missions, then it is possible that

the efficacy of the thigh-high garments would have been impacted. However, loss of volume in these areas, as deter-mined by the circumference measures, was not outside the acceptable range for the material properties of the GCG. The GCG is constructed such that they take advantage of a relatively flat portion of the material’s length-tension curve and changes in body circumference of less than 3.8 cm (1.5 in.) do not result in an appreciable change in compression (Personal Communication, Kevin Tucker, BSN-medical, Inc.).

Similar to our previous experience with the GCG in Space Shuttle astronauts (Stenger et al. 2013), the com-fort ratings for the garments were generally favorable. The weakness of the previous scoring provided by the Space Shuttle astronauts, however, was that they wore the gar-ments for only a short period of time. Some astronauts donned the GCG soon after landing, wearing them dur-ing the walk-around, but most doffed the garments after the stand test was completed in the laboratory. Subjects in the control group for this bed rest study wore the garments for a longer period of time (~4–5 h) to simulate the period of time that an astronaut might wear the garments prior to re-entry and landing; astronauts and cosmonauts would have to don the GCG while in orbit, before donning the re-entry suit (Russian Sokol suit or the NASA Advanced Crew Escape Suit) and continuing to wear the garments at least through the time that the space craft landing sup-port personnel arrived. The control subjects in the current study never rated the comfort of either the shorts or the thigh-highs as worse than a “3”, neutral. The limitation of this reporting, however, is that for the hours before the tilt test the subjects were in bed and not in the same posture as astronauts and cosmonauts would be in the spacecraft. Anecdotal reports from astronauts wearing the Kentavr and from subjects in our laboratory wearing the GCG show that bending of the hip, knee, and ankle joints causes both com-pression garments to press into the body sometimes at more uncomfortable levels. This is one area of potential improve-ment for future garments.

Earth benefits

Findings from this study have the potential to affect the practice of prescribing compression garments for the treat-ment of patients who are hypotensive and/or suffer from episodes of orthostatic intolerance (Lanier et al. 2011). Commercially available knee-high and thigh-high compres-sion garments, while easy to don and convenient to wear, had limited effectiveness when tested in our laboratory. In contrast, the commercially available breast-high garment, while an effective protection against orthostatic intolerance, can be difficult to don, uncomfortable, and/or inconvenient to remove to urinate or defecate (Shibao et al. 2013). The

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three-piece garment developed for this project provides the same amount of coverage as and greater levels of compres-sion than the commercially available breast-high garment. The GCG is an effective countermeasure to orthostatic intolerance, is easy to don and doff, and can be adjusted for comfort without much difficulty. The improvements to the wear and comfort realized in the development of the three-piece garments should enhance compliance with long-term use of compression garments, reduce the likelihood of hypotensive episodes, and improve the lifestyle of patients with orthostatic intolerance.

Limitations

There were several limitations to this study design that might affect its interpretation and the extension of these findings. First, the cost associated with performing a bed rest study precluded us from studying more than 16 sub-jects. Therefore, we were unable to directly compare the results from a true control group that did not wear any gar-ments on BR+0 to subjects wearing the GCG. However, this represents the conditions to which astronauts and cosmonauts are exposed; all returning crewmembers are required to wear compression garments during re-entry and landing. Although we cannot say with absolute cer-tainty that the GCG was completely effective compared to no-garment at all, the preponderance of literature supports that an increased level of orthostatic intolerance, higher heart rates, lower stroke volumes, and lower blood pres-sures are expected findings after 2 weeks of head-down tilt bed rest. Our subjects did not exhibit these responses on BR+0 despite the reduced PVI. Second, with the cur-rent study design we could not describe the effects of only lowering compression in these garments across the days of recovery; from BR+0 to BR+1 and BR+2, we reduced both the compression and the amount of coverage. This design was chosen based on anecdotal reports from astro-nauts that during recovery from long-duration space flight the gaiters (lower leg garments) from the Kentavr are worn for a longer period of time than the shorts to control lower leg and ankle swelling. Third, the GCG was designed and implemented based on the best state of knowledge at the time, combining the experiences in previous testing from the JSC Cardiovascular Laboratory and the manufacturer. Unfortunately, there has not been a systematic evaluation of garment pressures and areas of coverage to define the opti-mal configuration for different orthostatic intolerance con-ditions. Finally, these garments have not been tested dur-ing gravity re-entry and landing profiles similar to Soyuz, Shuttle, or commercial space flight so their effectiveness cannot be guaranteed without additional testing, particu-larly after longer duration exposures to real or simulated microgravity.

Conclusions

The three-piece, abdomen-high compression garments are comfortable to wear and effectively prevent the signs and symptoms of orthostatic intolerance that are normally seen after 2 weeks of head-down tilt bed rest. Additionally, wearing garments that each day decrease in compression level during recovery from bed rest does not prevent the restoration of plasma volume and cardiovascular responses to head-up tilt by BR+3 relative to subjects who wear no compression garments. Wearing these garments during re-adaptation to Earth gravity may benefit astronauts who participate in short duration space flight (such as commer-cial space flyers) and potentially those who participate on exploration class missions to the Moon, near Earth aster-oids, and Mars. Compression garments of a similar design also may be beneficial to patients who regularly experience orthostatic hypotension.

Acknowledgments The authors would like to thank the subjects who participated in this study; Kevin Tucker and Mary Ann Hettich of BSN-medical, Inc. who collaborated in the design and constructed the GCG for this and our previous Space Shuttle study; the JSC Car-diovascular Laboratory personnel who were responsible for collecting and analyzing the cardiovascular data; the JSC Clinical Laboratory for analyzing the blood samples; the staff at the Flight Analogs Research Unit at UTMB-Galveston who supported the bed rest subjects and coordinated their efforts with ours for a successful project; and Jamie Guined and Jackie Reeves who provided editorial comments to this manuscript. This work was funded by the NASA Human Research Project and supported in part by grant 1UL1RR029876-01 from the National Center for Advancing Translational Sciences, National Insti-tutes of Health.

Conflict of interest The authors declare that the experiment described complies with the current laws of the United States of America and that the authors have no conflict of interest.

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