Khan MH, Kunselman AR, Leuenberger UA,
Davidson WR Jr, Ray CA, Gray KS, Hogeman CS,
Sinoway LI.
Division of Cardiology,
Pennsylvania State University College of
Medicine, Milton S Hershey Medical Center,
Hershey,USA.
Abstract : Bed rest reduces
orthostatic tolerance. Despite decades of study,
the cause of this phenomenon remains unclear. In
this report we examined hemodynamic and
sympathetic nerve responses to graded lower body
negative pressure (LBNP) before and after 24 h
of bed rest. LBNP allows for baroreceptor
disengagement in a graded fashion. We measured
heart rate (HR), cardiac output (HR x stroke
volume obtained by echo Doppler), and muscle
sympathetic nerve activity (MSNA) during a
progressive and graded LBNP paradigm. Negative
pressure was increased by 10 mmHg every 3 min
until presyncope or completion of -60 mmHg.
After bed rest, LBNP tolerance was reduced in 11
of 13 subjects (P <.023), HR was greater (P
<.002), cardiac output was unchanged, and the
ability to augment MSNA at high levels of LBNP
was reduced (rate of rise for 30- to 60-mmHg
LBNP before bed rest 0.073 bursts x min(-1) x
mmHg(-1); after bed rest 0.035 bursts x min(-1)
x mmHg(-1); P < 0.OI6). These findings
suggest that 24 h of bed rest reduces
sympathetic nerve responses to LBNP.
When normal human subjects rise to the
standing position, gravitational forces lead to
pooling of blood in dependent areas. This leads
to a reduction in venous return. The normal
physiological responses to this stress are
increases in heart rate (HR) and peripheral
vascular resistance. These reflex responses act
to maintain blood pressure and preserve cerebral
and cardiac perfusion. When these responses are
impaired, the threshold for orthostatic
intolerance (OI) decreases.
Bed rest and spaceflight reduce the
threshold for OI. Despite decades of study,
debate continues as to whether this OI is
primarily due to an inability to maintain
cardiac output (CO) or to a reduced ability to
raise peripheral vascular resistance.
In this study, we performed 24-h bed rest
experiments to examine this issue. We selected
24 h of bed rest because it is sufficient to
impair orthostatic tolerance (OT) yet leads to a
relatively small reduction in plasma volume and
heart muscle mass compared with changes seen
with longer bed rest paradigms. Significant
changes in plasma volume have been shown to
contribute to OI. Therefore, we hypothesized
that if muscle sympathetic nerve activity (MSNA)
responses were impaired after 24 h of bed rest
it would strongly point to "peripheral" causes
of OI.
During the lower body negative pressure
(LBNP) tests we measured HR and blood pressure,
made peripheral sympathetic nerve recordings,
and calculated stroke volume (SV), peripheral
vascular resistance, and cardiac output. The
results of these experiments demonstrate that
bed rest reduces tolerance to graded LBNP. This
effect was associated with a reduced ability to
increase MSNA at higher levels of LBNP.
RESULTS
The most common symptoms during LBNP at the
end of the study before and after bed rest were
lightheadedness and dizziness followed by
yawning,
nausea, feeling of warmth, and abdominal
discomfort.
LBNP tolerance. Before bed rest five
subjects completed the entire paradigm, whereas
after bed rest only two did so. Before bed rest
the LBNP test was stopped because of hypotension
in seven subjects and because of nausea in one
subject. After bed rest the test was
discontinued because of hypotension in nine
subjects, because of nausea in one subject, and
because of cold sweats in one subject. The
modified cumulative stress index was lower after
bed rest (P < 0.023), with 11 of the 13
subjects being less tolerant to the paradigm
after bed rest.
Cardiovascular responses. The cardiovascular
responses to LBNP before and after bed rest are
shown as a change from baseline Æ in Fig. 2. The
number of subjects at each level of LBNP for
each variable is shown in Table 1. During the
LBNP paradigm, ZHR rose to a greater degree
after bed rest (bed rest effect P < 0.0OI8).
After bed rest ASV values were generally lower
than the values noted at the same level of LBNP
before bed rest, but no statistical effect of
bed rest was noted. CO, the product of HR and
SV, fell with LBNP but was unaffected by bed
rest (not significant). LSVR and mean arterial
pressure (MAP) with LBNP were also unaffected by
bed rest. Because we used the blood pressure
values at the earliest signs of LBNP
intolerance, we did not observe a lower BP at
the highest level of tolerable LBNP after bed
rest.
To examine the effects of bed rest on MSNA,
the rate of change measured as z bursts and z
bursts/100 heartbeats was calculated for "low
levels" (baseline to -30mmHg) and "high levels"
(-30 mmllg to end LBNP) of LBNP. This analysis
demonstrated that the rate of increase in MSNA
at low levels of LBNP was similar before and
after bed rest. However, the rate of increase in
MSNA for high levels of LBNP was lower after bed
rest (Fig. 3). This was noted despite the fact
that MAP values tended to be lower. MSNA values
before and after LBNP are shown in Table 2.
DISCUSSION
The main findings of this study were that 1)
after bed rest subjects were less tolerant of
LBNP than before, 2) the ÆCO response to LBNP
was not altered by bed rest, and 3) the rate of
increase of LMSNA during high levels of LBNP was
lower after bed rest than before. This latter
effect was seen despite the fact that absolute
blood pressure at each level of LBNP tended to
be lower after bed rest than before. This
suggests that the reduced MSNA response to LBNP
after bed rest was not due to a smaller
hypotensive stimulus. Thus 24 h of bed rest is a
sufficient stimulus to alter the MSNA-Æ blood
pressure stimulus-response relationship.
The potential causes for this decline in
orthostatic tolerance after bed rest (or
spaceflight) can be grouped into those that may
accentuate the fall in CO and those that lead to
an impairment in the vasoconstrictor response
seen with orthostatic stress. It is clear that
bed rest or spaceflight leads to reductions in
plasma volume, which can reduce ventricular
filling and in the process lead to an
accentuated reduction in CO with standing.
However, the incidence of OI after headdown bed
rest (HDBR) or spaceflight is not well
correlated with reductions in plasma volume, and
restoring plasma volume (and central venous
pressure) to before bed rest levels does not
restore OT. In the present report we limited the
period of bed rest to 24 h because this time
period does not allow the full expression of the
fall in plasma volume seen with bed rest.
Several investigators have suggested that
increased lower limb venous compliance after bed
rest or spaceflight may contribute to OI.
However, orthostatic hypotension has been
observed within 4 h of head-down tilt, before
any changes in peripheral venous compliance
could occur.
Work by Levine et al. suggested that the
inability of volume replacement to normalize OT
may be due to cardiac atrophy. We doubt that
cardiac atrophy contributed to the OI observed
in the present study because LBNP intolerance
was observed after only 24 h of bed rest. The
main stimulus for cardiac protein synthesis is
the rate-pressure product. We are not aware of
any data to suggest that the ratepressure
product falls after bed rest. Moreover, even if
it did decline, it is doubtful that 24 h of a
reduced rate-pressure product would be
sufficient stimulus to reduce protein synthesis
and cause cardiac atrophy, and therefore this
response is not likely to explain the present
findings.
The autonomic regulatory systems controlling
blood pressure responses to postural stress
include the cardiopulmonary, aortic, and carotid
baroreflexes and yestibular inputs. Hypotension
evokes an increase in efferent sympathetic
vasoconstrictor activity as well as
parasympathetic withdrawal that leads to an
increase in HR. With HDBR, the sensitivities of
the arterial and cardiopulmonary baroreflexes
appear to be reduced. Furthermore, the greatest
reduction in barorefiex gain is found in
subjects demonstrating the greatest OI after bed
rest. This impairment appears to be specific for
the vasoconstrictor arm of this reflex because
HR responses are not impaired. The mechanism for
the reduced ability to raise sympathetic nerve
activity after immobilization is unclear. Recent
work by Moffitt et al. in a rat model suggests
that the baroreflex impairment after hindlimb
unweighting is due to altered central processing
of baroreceptor input.
Recently, it was suggested that myogenic
responses are impaired after bed rest. Reduced
myogenic responses could contribute to impaired
vasoconstriction with postural stress seen after
bed rest. However, this would not explain the
reduced MSNA responses after bed rest.
Nevertheless, the present report does not allow
us to exclude an effect of bed rest on myogenic
activity.
As mentioned above, 24 h of bed rest does
not lead to large changes in plasma volume
and/or cardiac atrophy. Therefore, the results
of the present study may not explain OI seen
after longer periods of bed rest.
In this study, subjects underwent a graded
LBNP paradigm until presyncope or -60 mmHg
level. Thus presyncope was not observed in 5 of
13 subjects before and 2 of 13 subjects after
bed rest. This limits our ability to precisely
quantify the magnitude of OT in this study.
Nonetheless, 11 of 13 subjects had a reduction
in the cumulative LBNP index used. Thus we
believe our contention that LBNP tolerance was
reduced after HDBR is valid.
In conclusion, after 24 h of bed rest, LBNP
tolerance was reduced, HR was greater, CO was
unchanged, and the ability to augment MSNA at
high levels of LBNP was reduced. These findings
suggest that 24 h of bed rest is sufficient to
interfere with the ability to raise MSNA
normally with LBNP.
