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(Stroke. 2000;31:1608.)
© 2000 American Heart Association, Inc.
Original Contributions |
From the Department of Internal Medicine, Academic Medical Center Amsterdam (M.P.M.H., W.W., J.J. van L.); Cardiovascular Research Institute, Amsterdam (M.P.M.H., W.W., J.J. van L.); Departments of Physiology (W.N.J.M.C.) and Internal Medicine (J.W.M.L.), University Hospital Nijmegen; and Department of Anesthesia, Copenhagen Muscle Research Center, Rigshospitalet, Copenhagen (N.H.S.), Denmark.
Correspondence to J.J. van Lieshout, Department of Internal Medicine, Room F4-264, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail j.j.vanlieshout{at}amc.uva.nl
| Abstract |
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MethodsThis study addressed the relationship between orthostatic tolerance, mean cerebral artery blood velocity (Vmean, determined by transcranial Doppler ultrasonography), oxygenation (oxyhemoglobin [O2Hb], determined by near-infrared spectroscopy), and mean arterial pressure at brain level (MAPMCA, determined by finger arterial pressure monitoring [Finapres]) in 9 patients (aged 37 to 70 years; 4 women) and their age- and sex-matched controls during 5 minutes of standing.
ResultsSupine MAPMCA (108±14 versus 86±14 mm Hg) and Vmean (84±21 versus 62±13 cm · s-1) were higher in the patients. After 5 minutes of standing, MAPMCA was lower in the patients (31±14 versus 72±14 mm Hg), as was Vmean (51±8 versus 59±9 cm · s-1), with a larger reduction in O2Hb (-11.6±4 versus -6.7±4.5 µmol · L-1). Four patients terminated standing after 1 to 3.5 minutes. In these symptomatic patients, the orthostatic fall in Vmean was greater (45±6 versus 64±10 cm · s-1), and the orthostatic decrease in O2Hb (-12.0±3.3 versus -7.6±3.9 µmol · L-1) tended to be larger. The reduction in MAPMCA was larger after 10 seconds of standing, and MAPMCA was lower after 1 minute (25±8 versus 40±6 mm Hg).
ConclusionsIn patients with sympathetic failure, the orthostatic reduction in cerebral blood velocity and oxygenation is larger. Patients who become symptomatic within 5 minutes of standing are characterized by a pronounced orthostatic fall in blood pressure, cerebral blood velocity, and oxygenation manifest within the first 10 seconds of standing.
Key Words: cardiac output hypotension, orthostatic posture ultrasonography, Doppler, transcranial
| Introduction |
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We hypothesized that in patients with sympathetic failure, orthostatic symptoms reflect a reduced cerebral perfusion with an insufficiency of cerebral oxygen supply. Changes in cerebral tissue oxygenation can be assessed continuously and noninvasively by near-infrared spectroscopy (NIRS).8 9 10 This study addressed the relationship between orthostatic tolerance and estimates of cerebral perfusion in patients with sympathetic failure and healthy controls during orthostatic stress. The effect of standing on cerebral perfusion was evaluated by transcranial Doppler ultrasound (TCD)determined middle cerebral artery (MCA) mean blood velocity (Vmean) and by NIRS-determined cerebral oxygenation. Arterial pressure, central blood volume, and beat-to-beat cardiac output (CO) were measured to follow systemic circulatory responses.
| Subjects and Methods |
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Protocol
At least 2 hours after a light breakfast without
caffeine-containing beverages, the subjects were instrumented at 9
AM in a room with an ambient temperature of 22°C. A test
run was performed to familiarize the subjects with the protocol. After
10 minutes of supine rest, the subjects were asked to stand in a
relaxed position for 5 minutes. Standing was terminated if the subject
developed symptoms of orthostatic intolerance such as
blurred vision, dizziness, or nonresponsiveness.
Measurements
Cerebral oxygenation was monitored with NIRS.
NIRS is based on the transparency of tissue to light in the
near-infrared region and the O2 statusdependent
changes in absorption in cerebral tissue caused by chromophores, ie,
mainly oxyhemoglobin and deoxyhemoglobin (O2Hb
and HHb, respectively).12 13 With the use of a modified
Lambert-Beer law, changes in light absorption at different wavelengths
are measured, and tissue oxygenation is
monitored.14 To estimate the concentration changes in
O2Hb and HHb, a differential path length factor
of 6.0 was applied to account for the scattering of light in the
tissue.15 16 A continuous-wave NIRS instrument
(Oxymon) with 3 wavelengths (901, 848, and 770 nm) and 10-Hz
sampling time was used. The NIRS optodes were attached on the right
side of the forehead, with the transmitting and receiving optodes
placed 5.5 cm apart. Since there is no standard for cerebral oximetry,
calibration is not possible. However, NIRS determined
oxygenation changes in parallel with cerebral blood
flow as determined by 133Xe
clearance,17 and estimated cerebral
O2 saturation in humans during carotid clamping
and declamping compares satisfactorily with jugular bulb venous
O2 saturation.18 We therefore
describe changes in O2Hb and HHb concentration
(micromoles per liter), with supine control values as reference set at
0 µmol ·
L-1.
Right MCA Vmean was measured (Multidop X2, DWL) through the posterior temporal "window."19 Once the optimal signal-to-noise ratio was obtained, the probe was covered with an adhesive ultrasonic gel (Tensive, Parker Laboratories Inc) and secured with a head band. The Vmean was obtained from the maximal TCD frequency shifts over 1 beat divided by the corresponding beat interval. As a reflection of PaCO2, end-tidal CO2 (PETCO2)20 was measured by an infrared CO2 analyzer (Hewlett Packard 78345A).
Arterial pressure was measured from the middle finger of the nondominant arm with a Finapres model 5 (Netherlands Organization for Applied Scientific Research, TNO-Biomedical Instrumentation). Finapres is based on the volume clamp method of Peñáz and the Physiocal criteria of Wesseling et al21 and reflects blood pressure changes under conditions of orthostatic stress and arterial hypotension.22 23 24 The cuffed finger was fixed in the anterior axillary line at heart level, maintaining a fixed distance to the TCD probe.
Beat-to-beat changes in stroke volume were estimated by modeling flow from arterial pressure (Modelflow, TNO-Biomedical Instrumentation). This method computes an aortic flow waveform from a peripheral arterial pressure signal using a nonlinear 3-element model of the aortic input impedance. Peripheral arterial pressure appears sufficiently close to the aortic pressure to be applied in the model and to allow for reliable estimations of stroke volume (SV) from an arterial pressure signal.25 26 Thus, SV is tracked from peripheral arterial pressure in patients with cardiovascular disease,25 with septic shock,26 and under conditions of orthostatic stress with a limited offset of 3±9 mL in comparison to a thermodilution-based estimate.27 28
As an index of the central blood volume, thoracic electric impedance (TI)29 was measured by an impedance cardiograph (Kardio-Dynagraph, Diefenbach GmbH). An event marker identified changes in posture.
Data Acquisition and Analysis
The signals of arterial pressure, the spectral
envelope of MCA velocity, TI, PETCO2,
and marker were analog/digital converted at 100 Hz and stored on hard
disk for off-line analysis. NIRS data were sampled at 10 Hz.
Signals were routed through an interface providing electric isolation
with offset and sensitivity adjustments when appropriate. Variables
were also recorded on a polygraph on a thermo-writer (Graphtec
WR7700, Western Graphtec Inc) for on-line inspection.
The Vmean was computed as the integral of the maximal frequency shifts over 1 beat divided by the corresponding beat interval. Mean arterial pressure (MAP) was the true integral of the arterial pressure wave over 1 beat divided by the beat interval. MAP at the MCA level (MAPMCA) was calculated from MAP measured at heart level and the vertical finger-to-TCD probe distance.30 Heart rate (HR) was computed as the inverse of the interbeat pressure interval and expressed in beats per minute. CO was the product of SV and HR, and total peripheral resistance (TPR) was MAP at heart level divided by CO. To allow for comparisons, beat-to-beat data were transformed to equidistantly resampled data at 2 Hz by polynomial interpolation.31 Blood pressures, HR, Vmean, PETCO2, and TI are expressed in absolute values. Resting supine values for SV, CO, and TPR were set at 100% (control), and changes were expressed in percentages from control. Control values were the average of 60-second supine rest before standing. In the standing position, 20-second averages were calculated.
Variables were tested for normality and are expressed as mean and SD or median with range. Responses to standing were examined by Friedmans repeated-measures ANOVA on ranks. Significant F ratios were subjected to Dunns test to locate significant differences. Differences between patients and controls and between symptomatic and asymptomatic patients were analyzed by parametric or nonparametric tests where appropriate. A P value <0.05 was considered to indicate a statistically significant difference.
| Results |
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In the patients the correlation coefficient for MAPMCA and MCA Vmean was 0.68 and for CO and MCA Vmean was 0.48 (P<0.05). The correlation coefficient for MAPMCA and O2Hb was 0.41 and for CO and O2Hb was 0.36 (P<0.05). In the control subjects these values for MAPMCA and MCA Vmean were 0.18, for CO and MCA Vmean 0.25, for MAPMCA and O2Hb 0.06, and for CO and HbO2 0.39.
Asymptomatic Versus Symptomatic Patients
In symptomatic patients supine blood pressure was
higher, but Vmean did not differ. In
symptomatic patients the reduction in
MAPMCA was greater after 10 and 30 seconds of
standing. After 1 minute of standing the reduction in
MAPMCA was 94±14 versus 59±15 mm Hg in
asymptomatic patients, and it was accompanied by a slightly
lower CO. In the symptomatic patients the
orthostatic fall in Vmean was larger,
with a tendency for a larger postural reduction in
O2Hb and a lower
PETCO2. There was a tendency toward a
larger TI in symptomatic patients (Figure 3
, Tables 3
and 4
). Figure 4
shows representative
examples of the reduction in Vmean and
O2Hb during standing in a control subject and in
an asymptomatic versus a symptomatic
patient.
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| Discussion |
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This report quantifies the postural changes in cerebral artery blood
velocity and oxygenation, as measured by TCD and NIRS,
in patients with sympathetic failure. TCD is used to evaluate
cerebrovascular dynamics, including its
autoregulation,32 33 in patients with sympathetic failure
as well.34 35 The diameter of the MCA remains constant
over an
30 mm Hg range of blood pressure, with
Vmean reflecting changes in cerebral blood
flow.36 This requirement is considered to be fulfilled in
upright healthy subjects given the relatively small changes in
arterial pressure at brain level. It is, however, uncertain
whether the MCA diameter remains stable at the low blood pressure
levels developed in patients with sympathetic failure. Cerebral
perfusion pressure decreases from the supine to the upright
position.37 In this study the reduction in cerebral blood
velocity was accompanied by a fall in cerebral
oxygenation under circumstances of considerable
orthostatic hypotension. We consider that the fall in
cerebral blood velocity and oxygenation was accompanied
by complaints of cerebral hypoperfusion in the symptomatic
patients at a reduced arterial pressure and CO. We may
speculate that under those circumstances the excessive fall in blood
pressure might reduce the diameter of the MCA cerebral velocity and
overestimate cerebral blood flow,38 but the data regard
changes in blood velocity, not flow, and cannot be said to reflect a
decrease in flow, however suggestive.
Given a constant arterial O2 content,
the cerebral tissue O2 supply is predominantly a
function of cerebral arterial blood flow. NIRS follows
changes in cerebral oxygenation in parallel with
cerebral blood flow as determined by 133Xe
clearance,17 and estimated cerebral
O2 saturation in humans during carotid clamping
and declamping compares satisfactorily with jugular bulb venous
O2 saturation.18 The determination
of cerebral tissue oxygenation by NIRS reflects the
locally monitored cerebral cortex. Within the sampled volume,
hemoglobin is contained in arterioles, capillaries, and venules, and
the relative position of pigments determined by NIRS is unknown. From
anatomic studies of brains, the ratio of venule to total vessel volume
ranges from 2/3 to 4/5.39 Only
5% of the blood is
situated in the capillaries and
20% in the arterioles, and it may
be argued that NIRS determines local SvO2
rather than tissue O2 content. Yet, resting
values of O2Hb are higher than internal jugular
SvO2.13 Thus, the
O2Hb of the cerebral tissue measured by NIRS is not
necessarily equal to the region perfused by the MCA, and it may be
questioned whether the fall in the NIRS O2Hb
signal can be taken to reflect a fall in MCA territory perfusion. In
this study the reduction in MCA blood velocity was accompanied by a
fall in cerebral oxygenation under circumstances of
considerable orthostatic hypotension. We consider that
during head-up tilt in healthy subjects, even when the reduction in MAP
is limited, cerebrovascular oxygenation is related to
cerebral perfusion, as determined by TCD,13 40 and that
NIRS properly reflects the reduction in O2Hb
associated with fainting.12 Comparable results have been
obtained during lower body negative pressure41 42 and
centrifuge studies.43
At rest, blood pressure was elevated in the patients but fell
considerably on standing because of a large reduction in SV and CO
unopposed by an increase in TPR (Table 2
and Figure 1
).
The large reduction in Vmean and
O2Hb indicates that with a fall in
arterial pressure of this magnitude, autoregulatory
mechanisms are not capable of preventing a symptomatic
decrease in cerebral perfusion, as reflected by TCD and NIRS. Apart
from the considerable fall in blood pressure and CO (Figure 2
),
the reduction in PETCO2 may also have
contributed to the reduction in MCA
Vmean.44 On standing, in healthy
subjects a slight decrease in PETCO2
is common45 and can be explained by an increase in
breathing rate in the upright position and changes of the
ventilation-perfusion relationship.46
In subjects with orthostatic hypotension due to sympathetic
failure, orthostatic tolerance varies considerably, but the
underlying mechanism is not well understood.47 In
symptomatic recumbent patients, blood pressure but not MCA
Vmean was higher, suggesting a shift in the
relationship between cerebral perfusion pressure and blood velocity
comparable to that in chronic hypertensive patients.48 The
differences in MCA Vmean between
symptomatic and asymptomatic patients were
relatively small (Table 3
), but the effects on
orthostatic tolerance were dramatic. We believe that when
these patients are upright, cerebral blood flow is close to the
critical lower level of cerebral perfusion, and an additional small
reduction elicits symptoms of cerebral hypoperfusion. This is supported
by a recognizably larger fall to lower values in blood pressure and MCA
Vmean in symptomatic patients, with
cerebral oxygenation following this pattern. In
patients with sympathetic failure, the postural fall in
arterial pressure is amplified by the larger
orthostatic fall in CO (Figure 1
and Table 2
)
because of enhanced venous pooling of blood, with an excessive
reduction of venous return.49 50 This is compatible with
the tendency for higher values for thoracic electric impedance in
symptomatic patients, suggesting a smaller central blood
volume (Table 3
).29 In addition, the decrease in
PETCO2 on standing may have
contributed to the cerebral hypoperfusion in the
symptomatic patients. The fall in blood pressure, cerebral
blood velocity, and oxygenation in the
symptomatic patients was larger in the first 10 seconds of
standing (Table 4
and Figures 3
and 4
), suggesting
that the rapidity of the reduction also contributes to trigger
orthostatic symptoms.
The anomaly in dynamic plasma volume regulation in patients with autonomic failure is as yet not well understood.51 52 The level of upright arterial pressure is closely related to the magnitude of the blood volume,53 presumably because in this group of patients CO has become strictly dependent on venous return and the effective blood volume.49 54 There is no specific treatment for sympathetic vasomotor failure, and therapy should be focused on alleviating the patients orthostatic tolerance and reducing the orthostatic fall in CO by increasing the circulating volume.50 55
| Acknowledgments |
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Received January 31, 2000; revision received April 3, 2000; accepted April 12, 2000.
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