J Appl Physiol 103: 1964–1972, 2007.
First published October 18, 2007; doi:10.1152/japplphysiol.00132.2007.
Lower body negative pressure exercise plus brief postexercise lower body
negative pressure improve post-bed rest orthostatic tolerance
Donald E. Watenpaugh,1 Deborah D. O’Leary,2 Suzanne M. Schneider,3 Stuart M. C. Lee,4
Brandon R. Macias,5 Kunihiko Tanaka,6 Richard L. Hughson,7 and Alan R. Hargens5
1
Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas; 2Department
of Community Health Sciences, Brock University, St. Catharines, Ontario, Canada; 3University of New Mexico, Albuquerque,
New Mexico; 4Wyle Laboratories, Houston, Texas; 5Department of Orthopaedic Surgery, University of California, San Diego,
California; 6Department of Physiology, Gifu University, Gifu, Japan; and 7University of Waterloo, Waterloo,
Ontario, Canada
Submitted 7 January 2007; accepted in final form 12 October 2007
(65) reduce orthostatic
tolerance. When spacecraft reenter Earth’s atmosphere and
land, vertical acceleration (⫹Gz) forces challenge cerebral
blood flow, such that compromised orthostatic tolerance endangers crew members. This cardiovascular deconditioning
also delays return to normal upright activities. For example,
after return from spaceflights lasting months, Russian astronauts wear anti-G garments for up to 4 days (25).
Hypovolemia constitutes the most established cause of postflight orthostatic intolerance (65). Some investigators postulate
that the chronic stroke volume (SV) reduction secondary to
hypovolemia causes cardiac remodeling and atrophy (65),
which in turn contributes to intolerance (40). The cardiac
baroreflex appears to function appropriately in response to
postflight hypovolemia because all astronauts exhibit accentuated postural tachycardia after flight (6, 39, 65). No increase
occurs in leg compliance after spaceflight (6, 62), but some
evidence suggests that problems with the vascular baroreflex
arm contribute to postflight orthostatic intolerance (23, 24, 66).
In weightlessness, gravitational pressure gradients never arise
in the circulation, so cerebral blood flow continues unchallenged, and baroreflexive vasoconstriction remains chronically
understimulated. Also, chronic lack of gravitational pressures
in the lower body circulation may compromise local arteriolar
structure and function (16, 65).
Most literature indicates that exercise training during bed
rest does not protect orthostatic tolerance (20, 27, 29). However, based on the mechanistic information above, our laboratory previously hypothesized that addition of a gravity-like
stress such as lower body negative pressure (LBNP) during
exercise would be effective (38, 64). Control subjects (no
exercise) were compared with subjects who performed daily
LBNP exercise during 5 days of bed rest. LBNP exercise
consisted of 30 min/day of supine interval treadmill exercise at
intensities up to 90% of maximum heart rate (HR), followed
immediately by 5 min of resting LBNP (i.e., ongoing LBNP
during recovery from the LBNP exercise) (38). We added the
5-min postexercise LBNP period as a pilot study of postexercise hypotension during bed rest; at the time of the study, it was
not intended as a formal part of the countermeasure (S. M. C.
Lee, unpublished observations).
Tilt tolerance time in control subjects decreased significantly
(18%), yet tolerance tended to increase in LBNP exercisers
(9%, not significant). Hematocrit increased in controls, indicating substantial hemoconcentration; hematocrit did not increase in the exercisers. The countermeasure was then evaluated during 15 days of bed rest (53, 59). For this study, LBNP
exercise was prolonged to 40 min, but the 5-min postexercise
LBNP period was deleted: we assumed such a short period of
LBNP did not contribute to the positive results from the 5-day
Address for reprint requests and other correspondence: D. E. Watenpaugh,
Sleep Consultants, Inc., 1521 Cooper St., Fort Worth, TX 76104 (e-mail:
[email protected]).
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.
human; microgravity; spaceflight; countermeasure; cerebral blood
flow
BOTH BED REST (20) AND WEIGHTLESSNESS
1964
8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society
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Watenpaugh DE, O’Leary DD, Schneider SM, Lee SM,
Macias BR, Tanaka K, Hughson RL, Hargens AR. Lower body
negative pressure exercise plus brief postexercise lower body
negative pressure improve post-bed rest orthostatic tolerance.
J Appl Physiol 103: 1964–1972, 2007. First published October 18,
2007; doi:10.1152/japplphysiol.00132.2007.—Orthostatic intolerance
follows actual weightlessness and weightlessness simulated by bed
rest. Orthostasis immediately after acute exercise imposes greater
cardiovascular stress than orthostasis without prior exercise. We
hypothesized that 5 min/day of simulated orthostasis [supine lower
body negative pressure (LBNP)] immediately following LBNP exercise maintains orthostatic tolerance during bed rest. Identical twins
(14 women, 16 men) underwent 30 days of 6° head-down tilt bed rest.
One of each pair was randomly selected as a control, and their sibling
performed 40 min/day of treadmill exercise while supine in 53 mmHg
(SD 4) [7.05 kPa (SD 0.50)] LBNP. LBNP continued for 5 min after
exercise stopped. Head-up tilt at 60° plus graded LBNP assessed
orthostatic tolerance before and after bed rest. Hemodynamic measurements accompanied these tests. Bed rest decreased orthostatic
tolerance time to a greater extent in control [34% (SD 10)] than in
countermeasure subjects [13% (SD 20); P ⬍ 0.004]. Controls exhibited cardiac stroke volume reduction and relative cardioacceleration
typically seen after bed rest, yet no such changes occurred in the
countermeasure group. These findings demonstrate that 40 min/day of
supine LBNP treadmill exercise followed immediately by 5 min of
resting LBNP attenuates, but does not fully prevent, the orthostatic
intolerance associated with 30 days of bed rest. We speculate that
longer postexercise LBNP may improve results. Together with our
earlier related studies, these ground-based results support spaceflight
evaluation of postexercise orthostatic stress as a time-efficient countermeasure against postflight orthostatic intolerance.
POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
METHODS
Subjects. University of California, San Diego (UCSD), University
of North Texas Health Science Center, and National Aeronautics and
Space Administration Institutional Review Boards approved this
study. Fifteen pairs of healthy identical twins (14 women and 16 men)
participated after providing informed, written consent. We employed
identical twins, with one sibling as the control subject and the other as
the countermeasure subject, to minimize genetic variability between
control and countermeasure groups and thus strengthen our ability to
ascribe intergroup differences to the countermeasure (5). Age ranged
from 21 to 36 yr, weight from 43.7 to 84.1 kg, and height from 152
to 191 cm. Subjects provided their medical history and underwent
physical examination and an exercise stress test to establish their
healthy status.
Experimental design and conditions. The UCSD Hillcrest Hospital
General Clinical Research Center housed, fed, and cared for subjects
throughout their participation. The study occupied 6 days of familiarization and baseline data collection, 30 days of bed rest, and 3 days of
post-bed rest testing and recovery. Siblings shared rooms and received
diets containing 180 mmol Na/day. Water intake was ad libitum.
Subjects abstained from caffeine and alcohol throughout the study. No
subject used tobacco. Nonprescription medications such as analgesics
and stool softeners were given as needed. Some female subjects used
oral contraceptives. Menstrual cycle phase was not controlled or
accounted for except that female subjects were at approximately the
same phase of their cycle during pre- and post-bed rest testing because
of the 30-day bed rest period.
Before baseline (pre-bed rest) data collection, subjects experienced
all testing procedures to become fully familiarized with the study. All
tests took place at the same time of day pre- vs. post-bed rest for a
given subject, and all were at least 2-h postprandial. After completion
of baseline data collection, twin siblings were randomly assigned to
control or countermeasure groups. Group assignment after baseline
data collection eliminated any possibility of group assignment influencing pre-bed rest results. Body weight did not vary significantly
between groups or across bed rest. During the entire bed rest period,
subjects remained at 6° head-down tilt except during periods for
showers and training (0.5–1.5 h/day), when they were horizontal (0°).
No training occurred on the day before end-bed rest orthostatic
tolerance testing. All training and testing sessions occurred at room
temperature (21–23°C).
LBNP exercise and orthostatic training. The LBNP exercise device
consists of a vacuum control system connected to a rectangular
chamber containing a vertically oriented treadmill. Earlier reports
detail chamber construction and operation (21, 38, 59), and Fig. 1
further illustrates waist seal hardware and integration. Waist seal area
was set to equal approximately twice a given subject’s waist crosssectional area, such that the negative pressure necessary to produce
one body weight equals ⬃50 – 60 mmHg (6.65–7.98 kPa). This larger
waist seal reduces orthostatic stress and risks of LBNP (petechiae,
hernia, syncope) by decreasing the LBNP necessary to generate a
given level of footward force (58). Subjects wore inelastic shorts
during countermeasure sessions to prevent abnormal LBNP-induced
lower abdominal distension (4, 38, 59). The shorts held a 12 ⫻ 30-cm
air bladder in place over the lower abdomen. A tube from the air
bladder passed through the LBNP waist seal to outside the chamber.
Therefore, the bladder automatically inflated to compress the lower
abdomen in direct proportion to the magnitude of LBNP.
Countermeasure sessions consisted of 40 min of supine running
exercise per day at 1.0 –1.2 body weight of footward force, as
Fig. 1. Schematic illustration of lower body negative pressure
(LBNP) exercise chamber waist seal components. The subject
dons the waist seal, the seal plates are juxtaposed in place on
the chamber and clamped, and the waist seal is then affixed to
the seal plate flange with an integral bungee cord. Multiple
waist seals and paired waist seal plates produce a range of
elliptical chamber orifices to accommodate different-sized subjects and tune the LBNP-to-footward force ratio. The waist belt
and shoulder straps on the waist seal itself are not shown for
simplicity.
J Appl Physiol • VOL
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bed rest study. Supine LBNP assessed orthostatic tolerance.
Surprisingly, orthostatic tolerance decreased identically (24%)
after bed rest alone and bed rest with LBNP exercise, despite
some protection of subtolerance HR and blood pressure responses by LBNP exercise (53). As in the 5-day study, the
countermeasure maintained blood volume.
We confronted the possibility that a short resting LBNP
period immediately following LBNP exercise may challenge
orthostatic blood pressure control mechanisms enough to maintain tolerance during bed rest. For a variety of reasons, orthostasis immediately after acute exercise imposes greater cardiovascular stress than orthostasis without prior exercise (11, 15,
22, 30, 31, 52). For example, Bjurstedt and coworkers (3)
reported that five of six subjects experienced presyncope during 6 min of 70° head-up tilt (HUT) after exhausting exercise,
whereas all six tolerated the test in preexercise conditions.
Also, people sometimes faint when standing still after strenuous exercise when they otherwise have no such trouble (68).
These findings imply that orthostatic stimulation imposed immediately following exercise may more efficiently train orthostatic cardiovascular control mechanisms than stimulation
without prior exercise, because of the greater cardiovascular
stress. Given the collective observations above, we hypothesized that daily exposure to short periods of simulated orthostatic stress immediately following vigorous dynamic exercise
maintains orthostatic tolerance during bed rest. The countermeasure protocol again included 5 min of resting LBNP
immediately following supine LBNP treadmill exercise.
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POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
Fig. 2. LBNP exercise protocol target workloads and actual heart rate and
rating of perceived exertion responses (means ⫾ SD; n ⫽ 15). Heart rate and
rating of perceived exertion at the end of LBNP exercise training sessions
exceeded mean values after warm-up by 20%, despite identical treadmill
speed. Heart rate declined during postexercise LBNP, but it did not approach
resting levels before LBNP stopped. V̇O2pk, peak oxygen consumption.
J Appl Physiol • VOL
measured each minute. At any sign of presyncope, subjects were
encouraged to move and stretch their legs, drink water, and wipe their
face with a wet towel. In the rare cases where presyncopal signs
continued after these measures, LBNP was stopped until all symptoms
abated. LBNP was then restarted at the prescribed level and continued
to completion of the session. Countermeasure subjects underwent the
exercise and orthostatic training protocol 6 days/wk.
Orthostatic tolerance testing. Orthostatic tolerance tests consisted
of combined HUT and LBNP (17). A semicylindrical Plexiglas LBNP
chamber was attached to a tilt table. Subjects underwent three tests:
familiarization, pre-bed rest baseline data collection, and post-bed rest
data collection. After instrumentation for the orthostatic tolerance test,
5 min of supine resting cardiovascular data were collected. HUT to
60° (⫹0.87 Gz) then began and continued for 5 min. Thereafter,
LBNP ensued at 10 mmHg (1.33 kPa) for 3 min, followed by stepwise
10-mmHg decrements for 3 min each until presyncope. We defined
presyncope as drop of systolic pressure below 70 mmHg; sudden and
progressive blood pressure reduction; sudden, obvious, and sustained
drop in HR; sudden appearance or rapid worsening of presyncopal
signs and symptoms (nausea, dizziness, tingling, clamminess, sweating, ashen face, weak legs, anxiety, unresponsiveness); or any combination of the above. Subjects stood on a footplate inside the LBNP
chamber during HUT, and they were instructed and reminded as
necessary to remain quiet, still, and relaxed throughout the test.
Orthostatic tolerance time equaled the time from onset of HUT to
presyncope. The same medical monitor judged presyncopal symptoms
and called test endpoints pre- and post-bed rest. Baseline (pre-bed
rest) data from this test were previously employed to investigate
heritability of orthostatic cardiovascular function (46).
Orthostatic tolerance test instrumentation. Electrocardiography allowed determination of HR and monitoring for dysrhythmias. Doppler
ultrasound from the suprasternal notch yielded beat-by-beat aortic
outflow tract blood flow velocity (2-MHz probe, CFM750, GE/
Vingmed, Horten, Norway), such that the integral of this signal
provided cardiac SV. Aortic flow (cardiac output) was then calculated
using outflow tract diameter as determined with standard echocardiography (Hewlett Packard, Palo Alto, CA) (47). We measured finger
arterial blood pressure continuously with a Finapres device (Ohmeda
2300, Englewood, CO) on the right hand, and left arm blood pressure
was measured each minute with manual sphygmomanometric auscultation. The Finapres was adjusted before testing such that finger
diastolic pressure was within 5 mmHg of arm diastolic pressure.
Transcranial Doppler ultrasound permitted measurement of middle
cerebral arterial blood flow velocity from a temporal cranial window
(Transpect TCD, Medasonics, Mountain View, CA) (37, 47). Because
of its influence on cerebral hemodynamics, end-tidal carbon dioxide
was monitored (Ohmeda 5200, Englewood, CO) via nasal cannulas.
Total peripheral resistance was calculated as mean arterial pressure
divided by cardiac output. SV and cardiac output were converted to
indexes by dividing by calculated body surface area. We calculated
cerebral vascular resistance (CVR) as mean arterial pressure at eye
level divided by cerebral blood flow velocity. This approach assumes
minimal change in middle cerebral arterial diameter occurred such
that velocity provided a reliable quantitative indicator of blood
flow (47).
Statistical analyses. Multifactor repeated-measures ANOVA assessed independent and interactive effects of bed rest and the countermeasure for orthostatic tolerance test time. For physiological variables during the test, an additional factor (time) was included to
analyze data from the three levels of orthostatic stress that all subjects
achieved both pre- and post-bed rest: supine rest, HUT, and presyncope.
Dependent variables were averaged over the fifth minute of supine
rest, the fifth minute of HUT, and the minute before presyncope.
Technical problems with aortic Doppler in specific subjects and
during HUT plus LBNP led to significant loss of SV and thus blood
flow and TPR data, so n ⫽ 10 for these variables (5 per sex), and they
are not represented at presyncope. The sample size for sex compari-
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previously described (9, 59). We determined the negative pressures
necessary to produce this force range for each subject at supine rest in
the chamber. Individualized treadmill speeds elicited oxygen consumption estimated at 40 – 80% of peak levels, as determined from
pre-bed rest peak upright treadmill exercise tests, as follows: 40% for
7 min (warm-up), 60% for 3 min, 40% for 2 min, 70% for 3 min, 50%
for 2 min, 80% for 3 min, 60% for 2 min, 80% for 3 min, 50% for 2
min, 70% for 3 min, 40% for 2 min, 60% for 3 min, and 40% for 5 min
(cooldown; Fig. 2). HR and rating of perceived exertion (RPE) were
recorded at the end of each training interval. If RPE ever reached 19
(near-maximal exertion), treadmill speed was immediately reduced to
the lowest workload for that subject (40% peak O2 consumption), and
workload remained there until the next scheduled interval. Subsequent
workloads during that session were adjusted as necessary to avoid
near-maximal RPE. As bed rest progressed and subjects acclimated to
LBNP exercise, they were challenged to exercise at ⬎1.0 body
weight.
Orthostatic training consisted of 5 min of resting LBNP immediately following each exercise session (Fig. 1). During this time,
subjects remained still and relaxed, but they were allowed to drink
water and wipe their face with a towel. HR and blood pressure were
POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
sons was marginal, and they were deemed beyond the scope of this
work. Tukey’s honestly significant difference post hoc tests determined which specific mean values differed from others for each
variable. We accepted a finding as significant if P ⬍ 0.05. SAS
software performed all statistical analyses (SAS Institute, Cary, NC).
Values are expressed as means (SD) unless noted otherwise.
symptoms resolved, after which they continued the protocol to
completion.
Orthostatic tolerance time. For this and other dependent
variables, no significant control vs. countermeasure group
differences existed prior to bed rest (F ⬍ 2.39; P ⬎ 0.132).
Bed rest reduced orthostatic tolerance time in both groups (F ⫽
64.84; P ⬍ 0.001; Fig. 3). However, countermeasure use
attenuated loss of orthostatic tolerance during bed rest: the 13%
(20) reduction of tolerance time seen in countermeasure subjects was significantly less than the 34% (10) reduction exhibited by control subjects (F ⬎ 10.20; P ⬍ 0.004). Figure 4
illustrates individual orthostatic tolerance data.
Cardiovascular responses to orthostatic stress. In control
subjects, 30 days of bed rest reduced SV index by 13% (21) in
supine posture and 28% (33) in HUT relative to pre-bed rest
conditions (F ⫽ 5.5; P ⫽ 0.025; Fig. 5). Countermeasure
subject SV index remained unchanged pre- vs. post-bed rest in
both postures (F ⫽ 0.05; P ⫽ 0.822). HUT decreased SV index
both pre- and post-bed rest, and it did so to a similar degree
in both groups (F ⬎ 47.8; P ⬍ 0.001). After bed rest, control
subjects exhibited higher HR than pre-bed rest in supine, HUT,
and presyncopal conditions (F ⫽ 8.87; P ⫽ 0.004; Fig. 5).
Post-bed rest control subject HR also exceeded post-bed rest
countermeasure subject HR in all conditions, including at
presyncope [control: 132 beats/min (31); countermeasure: 120
RESULTS
LBNP exercise and orthostatic training sessions. LBNP
during training sessions averaged 53 mmHg (4) [7.05 kPa
(0.50)]. All subjects progressively increased their footward
force (LBNP) levels to at least 1.05 body weight, and as much
as 1.2, as the 30-day study progressed. Mean treadmill speeds
ranged from 5.5 km/h (0.8) 9.2 km/h (1.5), and distance
covered during a session averaged 4.6 km (0.8). Peak HR at the
highest workload averaged 171 beats/min (15), which equaled
86% of subjects’ maximal HR as determined during pre-bed
rest maximal upright treadmill exercise sessions (Fig. 2). RPE
averaged 10 (4) after the 7-min warm-up, and the mean
increased to as high as 17 (4) at the end of the second 3-min
80% interval (Fig. 2). HR increased 24 beats/min (20%) on
average between the warm-up and end of LBNP exercise, yet
treadmill speed was the same. Mean RPE of 12 (4) after the
5-min cooldown was also 20% greater than that after the 7-min
warm-up. Mean HR decreased from 145 to 124 beats/min
during 5 min of postexercise LBNP, such that resting HR was
not reestablished before LBNP cessation.
Subjects tolerated LBNP exercise very well after resolution
of any initial comfort problems (e.g., ankle and leg chafing
from suspension system, waist chafing from seal, waist seal
sizing, shoulder strap vs. waist seal pressure distribution, etc.).
Less-fit subjects tended to spend the first few exercise sessions
acclimating to regular vigorous activity. LBNP was stopped
occasionally during postexercise LBNP periods because of
presyncopal symptoms. This occurred more for women than
for men, and more toward the beginning of the bed rest period
than toward the end. At these stoppages, subjects enacted the
remedies described above (see METHODS) until presyncopal
J Appl Physiol • VOL
Fig. 4. Individual orthostatic tolerance time data subdivided by group and sex
(‚, men; F, women). Pre, before bed rest; Post, after bed rest. All control
subjects exhibited reduced orthostatic tolerance after 30 days of bed rest.
Tolerance increased post-bed rest in 4 of the 15 countermeasure subjects.
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Fig. 3. Orthostatic tolerance time before (black bars) vs. after (gray bars) bed
rest in control (CON) and countermeasure (CM) groups. Values are means ⫾
SD. Horizontal bars designate significant differences (P ⬍ 0.004). Bed rest
reduced tolerance time in both groups, but CM subjects exhibited less loss of
tolerance than CON (n ⫽ 15 per group).
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POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
P ⬎ 0.23). End-tidal CO2 systematically declined with HUT
and declined further at presyncope (F ⬎ 12.19; P ⬍ 0.001), but
these responses also did not vary across group or bed rest (F ⬍
2.41; P ⬎ 0.11).
DISCUSSION
Fig. 5. Stroke volume index, heart rate, and cardiac index responses to
orthostatic tolerance testing. Supine, supine baseline; HUT, during the fifth
minute of 60° head-up tilt; PS, during the minute prior to presyncope. F,
control (CON) group; ƒ, countermeasure (CM) group. Values are means ⫾
SD; n ⫽ 15 except for stroke volume and cardiac indexes, where n ⫽ 10, and
no data appear at PS because of technical problems. *Control group exhibited
reduced stroke volume and elevated heart rate after bed rest relative to pre-bed
rest (P ⬍ 0.03); no such changes occurred in the countermeasure group (P ⬎
0.82). #After bed rest, control group heart rate exceeded countermeasure group
heart rate (P ⬍ 0.005).
beats/min (27); F ⫽ 9.06; P ⫽ 0.004]. No significant pre- vs.
post-bed rest difference appeared in countermeasure group HR
(F ⫽ 0.03; P ⫽ 0.866).
HUT routinely decreased cardiac index (F ⬎ 19.06; P ⬍
0.001), but no other main effects nor interactions emerged (Fig.
3). TPR increased during HUT (F ⬎ 11.3; P ⬍ 0.003; Fig. 6),
but this increase did not vary with group or bed rest (F ⬍ 2.66;
P ⬎ 0.108). Mean arterial pressure decreased at presyncope
(F ⬎ 26.9; P ⬍ 0.001), but no other factor significantly
affected this reduction (Fig. 6). CVR decreased with HUT and
decreased still further at presyncope (F ⬎ 19.52; P ⬍ 0.001),
and a trend emerged for CVR to decrease post-bed rest relative
to pre-bed rest in the countermeasure group but not in controls
(F ⫽ 3.69; P ⫽ 0.059; Fig. 6). Orthostatic tolerance testing to
presyncope consistently decreased mean cerebral artery flow
velocity (F ⬎ 30.0; P ⬍ 0.001) with no variation of this
response between groups or pre- vs. post-bed rest (F ⬍ 1.53;
J Appl Physiol • VOL
Fig. 6. Total peripheral resistance, mean arterial pressure, and cerebral vascular resistance responses to orthostatic tolerance testing. Supine, supine
baseline; HUT, during the fifth minute of 60° head-up tilt; PS, during the
minute before presyncope. F, control (CON) group; ƒ, countermeasure (CM)
group. Values are means ⫾ SD; n ⫽ 15 except for total peripheral resistance
index, where n ⫽ 10, and no data appear at PS because of technical problems.
No significant pre- vs. post-bed rest nor control vs. countermeasure group
differences emerged (P ⬎ 0.13).
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Postexercise resting LBNP only partially preserved orthostatic function. These findings support, but do not fully confirm, our hypothesis: 5 min/day of resting LBNP immediately
following 40 min of supine LBNP treadmill exercise attenuates
the orthostatic intolerance associated with 30 days of bed rest.
The countermeasure as is does not fully prevent loss of tolerance. However, compared with the negative orthostatic tolerance results from the 15-day bed rest evaluation of LBNP
exercise, in which we used no postexercise LBNP (53), the
present results are salient because benefits from only 5 min/day
of orthostatic stress emerged despite doubling bed rest time
from 15 to 30 days. There were no changes to the countermea-
POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
J Appl Physiol • VOL
lems limited sample size for these data. The countermeasure
group exhibited an interesting trend toward reduced CVR after
bed rest relative to pre-bed rest and control group values,
including at presyncope (Fig. 6). Some evidence suggests that
bed rest and spaceflight affect the cerebral circulation in ways
that compromise brain blood flow during orthostasis, perhaps
secondary to chronic elevation of cerebral circulatory and/or
intracranial pressures (37, 65, 67, 71, 72). If so, the brief but
strong stimulus offered by postexercise LBNP during bed rest
may have reduced perfusion pressure and challenged autoregulation enough to help prevent maladaptive cerebral circulatory
changes.
The present orthostatic tolerance results confirm and extend
findings from our laboratory’s previous 5-day bed-rest study
(38, 64). In that work, 5 min of postexercise LBNP applied
daily appeared to fully preserve orthostatic tolerance during the
relatively short bed rest period. Although the 5-min stimulus
did not prevent degradation of orthostatic tolerance fully during 30 days of bed rest, it roughly halved the magnitude of
degradation. We speculate that increasing postexercise LBNP
duration may fully protect orthostatic tolerance during prolonged bed rest.
Alternatively, more accurate simulation of gravity may be
necessary for full protection of tolerance. LBNP does not
create a gradient of pressure in the circulation as does gravity,
nor does it apply static ⫹Gz vestibular stimulation (61, 65).
Full preservation of orthostatic function may somehow depend
on reproducing the gravitational pressure gradient between the
cerebral circulation, carotid, and aortic baroreceptors. A literature search yielded no investigations of this idea. Vestibulovascular control mechanisms provide a more studied example
of how gravity affects the circulation in ways tht LBNP cannot
duplicate. Many works suggest vestibular inputs to circulatory
control may importantly influence orthostatic cardiovascular
function (36, 43, 51, 70), whereas other findings question this
contention (63). If future work confirms need for ⫹Gz vestibular stimulation to protect orthostatic tolerance during bed rest,
such results would suggest superiority of long-arm centrifugation over LBNP as a countermeasure.
Comparison to other countermeasures. Most current countermeasures against orthostatic intolerance either prove inadequate or take too much crew time. Toward the end of flights
lasting months, astronauts on Mir spent 2–3 h/day exercising,
yet they wore anti-G suits for up to 4 days postflight (26, 65).
Vernikos and coworkers (57) reported that standing 4 h/day
completely prevented, and 2 h/day partially prevented, reduction of orthostatic tolerance after 4 days of bed rest. Hyatt and
West (33) found that 4 h of 30 mmHg (3.99 kPa) LBNP plus
ingestion of 1 liter of isotonic beverage at the end of 7 days of
bed rest restored LBNP responses to pre-bed rest levels.
Vernikos and coworkers (57) also reported that walking 2 or
4 h/day did not alleviate orthostatic intolerance. This and
multiple other studies (20, 27, 29, 39), along with our laboratory’s results (53), document that exercise by itself offers little
or no protection against loss of orthostatic tolerance during bed
rest. Cerebral blood flow continues uncompromised or increases during even intense upright dynamic exercise (49),
because of blood pressure elevation from sympathoexcitation
and the skeletal muscle and respiratory pumps. Therefore,
dynamic exercise by itself does little or nothing to train resting
blood pressure control mechanisms for their task of maintain-
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sure protocol between the 15- and 30-day studies besides the
addition of 5 min of postexercise LBNP.
Acute responses to training sessions. Previous work discusses responses to LBNP exercise per se (4, 59, 60). The
present data confirm that the exercise portion of the protocol
provides a vigorous workout (Fig. 2): peak HR averaged 86%
of maximal levels. HR at a given treadmill speed and LBNP
level at the end of an exercise session exceeded by 20% HR at
the same speed and LBNP near the start of the session (after the
7-min warm-up). As discussed previously (59), multiple factors explain this cardiovascular drift, including 1) incomplete
recovery from prior exercise at higher workloads, 2) fluid
losses via respiration and sweat, 3) progressive LBNP-induced
blood and extravascular fluid accumulation in the lower body
(2, 60, 69), 4) cutaneous vasodilation from metabolic and
LBNP chamber heat accumulation (59), and 5) synergistic
interactions between the above factors. These acute responses
to LBNP exercise set-up conditions for exaggeration of subsequent orthostatic stress.
Mechanisms of current observations. We sought to exploit
postexercise hemodynamic conditions to train orthostatic
blood pressure control mechanisms efficiently. Static upright
posture immediately after strenuous exercise provides a substantially greater cardiovascular stress than orthostasis without
prior exercise (68). Factors contributing to this observation
include exercise-induced blood and extracellular fluid volume
reduction (31), cessation of skeletal muscle pumping (10, 11),
reduction of respiratory pumping (52), postexercise reduction
of vasoconstrictive sympathetic nerve activity (15, 30), ongoing skeletal muscle vasodilation to meet metabolic demands of
exercise recovery (52), and cutaneous vasodilation to dissipate
residual heat from exercise (22).
Bjurstedt and colleagues (3) blamed low systemic resistance
for postexercise orthostatic intolerance, because central venous
pressure and thus cardiac filling remained at preexercise values
during postexercise HUT. Indeed, Halliwill and coworkers (30)
noted reduced sensitivity of both the arterial-sympathovascular
baroreflex and the vasoconstrictive transduction of sympathetic
activity following dynamic exercise. Therefore, ongoing vasodilation during recovery from dynamic exercise accentuates the
cardiovascular challenge imposed by orthostatic stress. In some
ways, the postexercise condition mimics the hypovolemia and
limited ability to vasoconstrict seen after spaceflight.
Plasma and blood volume results from the present study are
presented elsewhere, and they agree with earlier evaluations
(38, 64): LBNP treadmill exercise prevents intravascular fluid
volume loss during bed rest. This in turn helps normalize
cardiac filling pressure during orthostasis and thus facilitates
maintenance of orthostatic tolerance (13, 20, 48, 65). However,
as noted above, maintenance of blood volume with LBNP
exercise alone failed to prevent bed rest-induced loss of tolerance (53). The clearest physiological difference between the
present control and countermeasure groups is the post-bed rest
SV reduction and HR elevation in controls. This did not occur
in countermeasure subjects. This maintenance of SV during
bed rest suggests that the countermeasure prevented any cardiac remodeling that may contribute to loss of orthostatic
tolerance (48, 65).
We saw no significant control vs. countermeasure group
differences in TPR during HUT, but intersubject variability
seemed to increase post-bed rest (Fig. 6), and technical prob-
1969
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POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
J Appl Physiol • VOL
tional implementation, a more proactive approach may employ
brief scheduled applications of such stimuli. LBNP exercisers
may easily and instantly stop LBNP by disengaging the waist
skirt from the chamber, opening a vacuum release valve, or
turning off the vacuum source. System operation could depend
on physiologic feedback and/or active subject participation
(e.g., a handgrip switch). Finally, the large chamber orifice
over which the waist seal lies provides failsafe protection: a
user who faints or is otherwise incapacitated would be drawn
into the chamber, breaking the seal and thus stopping LBNP.
Although evidence suggests LBNP and centrifugation offer
similar effectiveness as countermeasures, practical considerations favor LBNP. A human centrifuge on a spacecraft or a
spinning spacecraft would be much larger, more complex, and
expensive. The forces created by periodic operation of a human
centrifuge would impose significant energy requirements and
challenges to a spacecraft’s orientation control systems. LBNP
exercise would require minimal purpose-built hardware and
control systems: the spacecraft airlock could serve as a LBNP
exercise chamber with existing pressure controls, vacuum
vented to the spacecraft cabin, a waist seal installation, and a
stowable treadmill inside (59).
We used treadmill exercise, as opposed to alternatives such
as cycling, for multiple reasons presented previously (59). The
present findings do not exclude other forms of exercise, and
orthostatic training after shorter bouts of exercise than 40 min
may also prove feasible. Concerning postexercise orthostatic
training, methods other than LBNP exist to impose such
stimulation in weightlessness, and our results do not exclude
these options. Such methods include centrifugation (1, 8, 12,
28, 61) and thigh venous occlusion (32, 41). Thigh venous
occlusion in particular offers the potential for immediate implementation: one simply applies venous occlusion pressure
cuffs to the upper thighs following in-flight aerobic leg exercise and then inflates the cuffs to subdiastolic pressure for the
prescribed time.
Limitations. In some subjects, signal quality problems prevented quantification of SV using aortic Doppler ultrasound. In
others, as LBNP increased during orthostatic tolerance tests,
insonation of the aortic outflow tract became unreliable. These
problems limited the number of data points for SV, blood flow,
and TPR data through HUT, and they disallowed inclusion of
SV, blood flow, and TPR data at presyncope. Therefore, our
ability to interpret and conclude from these data is restricted.
We employed identical twin subjects to minimize genetic
variability between control and countermeasure groups. Hypothetically, this experimental design maximized our ability to
detect and quantify effects of the countermeasure (5). However, despite their genetic identity, physiological and psychological differences between twin siblings occasionally emerged
during baseline testing (46). Therefore, it did not seem appropriate to treat each twin pair as a single “subject” for statistical
purposes, so we utilized the same statistical approach as one
would with unrelated subjects. In these respects, the degree to
which use of twins helped us test our hypotheses remains
unclear but may have been overestimated. Twin subjects bring
instant roommate rapport and an established support system to
challenging studies such as this, which offers an advantage
over use of unrelated strangers. In one case, the psychological
support provided by a twin probably kept their sibling from
dropping out of the study.
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ing cerebral blood flow during gravitational stress. These
collective observations suggest that protection of orthostatic
tolerance during bed rest requires stimulation of orthostatic
(resting) blood pressure control mechanisms. In this regard, our
laboratory’s prior 15-day bed rest results (53) effectively provide an exercise-only control condition for the present study,
because if LBNP exercise alone failed to protect orthostatic
tolerance during 15 days of bed rest, no basis exists to expect
it to protect tolerance during 30 days of bed rest.
A study by Engelke and colleagues (18) refutes the contention that exercise offers little benefit for orthostatic function.
Their subjects performed a single bout of supine maximal
cycling exercise after 15 days of bed rest. When LBNP tolerance was measured 24 h later (end of bed rest), subjects
experienced less loss of tolerance after they had exercised than
in control conditions. Although these findings are scientifically
interesting, it is probably unrealistic to expect all crew members on a given flight to perform maximal exercise within 24 h
before return from space, especially if return was unexpectedly
urgent. Also, it may be unreasonable to expect occasional
maximal exercise to counter the scope and degree of deconditioning seen after months in space (25, 45).
The simplicity of a pharmacological remedy for postflight
orthostatic intolerance offers obvious advantages. Isotonic beverages provide limited and inconsistent benefit (6, 7) except
when given in conjunction with prolonged LBNP (33). Fludrocortisone (55, 56) and midodrine (50) each proved effective for
restoring orthostatic tolerance when given alone before the end
of bed rest, but postflight results for fludrocortisone taken late
in-flight were less promising (54). Although medications may
perform well for orthostatic tolerance, they may not offer
similar benefit for other systems and functions degraded by bed
rest or spaceflight, and protected by LBNP exercise, such as
spinal biomechanics (9), anti-G muscle strength, and upright
exercise capacity (38, 59). Although a “drug cocktail” of
agents could conceivably protect against all debilitating effects
of spaceflight, no such combination of medications currently
exists. Moreover, a LBNP treadmill system integrated with
virtual environments offers recreation and other utility: such a
system could be programmed to simulate the gravitational
force and possibly even local terrain features of destinations
such as Earth’s moon or Mars (42, 65).
Similarly, adjustment of centrifugation rate allows simulation of variable gravity. Also, centrifugation applies ⫹Gz force
to the otoliths unless the head is at the center of rotation, and
centrifugation more accurately duplicates gravitational pressure gradients in the circulation than LBNP (61). Neurolab
shuttle flight results imply that even short-arm centrifugation
may impose sufficient vestibular stimulation to aid postflight
orthostatic function (44). Several interesting bed rest studies
from Japan demonstrate that cycling exercise during short-arm
centrifugation defends against cardiovascular deconditioning,
including orthostatic intolerance (34), with efficacy rivaling
LBNP exercise (1, 35). Also, Evans and colleagues (19)
demonstrated that centrifuge training increases orthostatic tolerance in ambulatory subjects. Other works review the promise
(8, 14) and recent progress (12, 14) of centrifugation as a
countermeasure.
Safety and operational considerations. The muscle pumping
and sympathoexcitatory stimuli practically always reversed the
rare presyncope seen during postexercise LBNP. For opera-
POSTEXERCISE LBNP, BED REST, AND ORTHOSTATIC TOLERANCE
ACKNOWLEDGMENTS
We thank Wanda Boda, Bob Eastlack, Eli Groppo, Yasuaki Kawai, Amy
Langemack, Scott Meyer, Alan Moore, Chris Rogers, Aimee Schimizzi, Kevin
Shoemaker, Greg Steinbach, Toshiaki Ueno, Rachel Vanderlinden, Michael
Zeigler, and the twins, for their respective contributions to this work. We
especially thank the professional and competent staff of the UCSD Hillcrest
General Clinical Research Center (GCRC) for their care of the subjects and
excellent technical support.
GRANTS
National Institutes of Health grant M01 RR-00827 funded the UCSD
GCRC. National Aeronautics and Space Administration Grants 199-26-12-34,
NAG 9-1425 (to A. R. Hargens), and 199-14-11-13 (to S. M. Schneider), and
a Canadian Space Agency grant (to R. L. Hughson), supported this research
through the data collection phase. The University of North Texas Health
Science Center also provided support.
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Our study design left out an LBNP-alone condition because
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