Measurement of Vasomotor Reserve in the Transcranial
Doppler-CO2 Test Using an Ultrasound
Contrast Agent (Levovist)
Matthias Rohrberg, MD; Rudolf Brodhun, MD
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Background and Purpose—Determination of vasomotor reserve (VMR) with the transcranial Doppler-CO2 (TCD-CO2)
test is used to assess the risk of impending cerebral ischemia in patients with high-grade stenosis or occlusion of the
internal carotid artery. In patients with a poor temporal window, however, this examination is limited. The aim of this
study therefore was to examine whether the use of an ultrasound contrast agent (USCA) influences the results of the
TCD-CO2 test.
Methods—In the first part of the study, 6 control subjects and 20 patients were examined with the TCD-CO2 test. The VMR
was determined first without the application of a contrast agent and then with continuous infusion of an USCA
(Levovist, 300 mg/mL, 1 mL/min). In the second part of the study, 2 tests without USCA were performed in each of
13 patients and 2 tests with USCA infusion were performed in each of 12 patients. Statistical analysis included
differences between the VMR determined with the 2 comparative measurements (⌬VMR), the mean (M⌬VMR), and SD.
Results—Based on the mean difference, the TCD-CO2 test produced the same results with and without USCA (M⌬VMR
1.8%), although the differences showed a wide distribution (2 SDs, ⫾20.7%). Similar spreads were seen in repeated
determinations of VMR in the same patient without USCA (2 SDs, ⫾20.0%), whereas the distribution under continuous
USCA infusion was considerably smaller (2 SDs, ⫾8.2%).
Conclusions—The TCD-CO2 test can be performed with continuous infusion of an USCA without influencing the results.
Even with a good temporal window, the results of the TCD-CO2 test show better reproducibility and thus better
reliability if an USCA is used. (Stroke. 2001;32:1298-1303.)
Key Words: carotid artery disease 䡲 cerebral blood flow 䡲 cerebral ischemia 䡲 contrast media
䡲 ultrasonography, Doppler, transcranial
D
etermination of the vasomotor reserve (VMR) is a useful
method for risk assessment of cerebral ischemia in
patients with high-grade stenosis or occlusion of the internal
carotid artery (ICA). Patients with steno-occlusive disease in
whom cerebrovascular reactivity is impaired are at high risk
to suffer cerebral ischemia.1,2 The VMR is based on the
dilatative capacity of the intracerebral arterioles.3 The residual dilatative capacity of the cerebral arterioles can be
measured quantitatively with the transcranial Doppler-CO2
(TCD-CO2) test. Arterial hypercapnia leads to dilatation of
the arterioles with a resultant increase in the mean flow rate
(VMean) in the basal intracranial arteries, eg, in the middle
cerebral artery (MCA). The alteration in the cerebral blood
flow in response to the CO2 stimulus is dependent on the
cerebral perfusion pressure4 (Figure 1). With decreasing
perfusion pressure, eg, in the case of a preceding obstruction
in the arteries supplying the brain, there is an increasing
leftward shift in the S-shaped curve, ie, toward smaller
changes in cerebral blood flow with increasing PCO2. If, in
hypercapnia, an increase in the PCO2 by 1% by volume leads
to a flow increase of ⬍10% in the MCA, the VMR is
considered to be diminished. If, in hypocapnia, the flow also
does not decrease by ⬎10% when there is a decrease in the
PCO2 by 1% by volume, the VMR is by definition “exhausted”
(the so-called 2-sided method).3
Because the TCD-CO2 test requires transtemporal examination of the MCA, an inadequate ultrasonic window is a
common problem, particularly in elderly female patients.
Even in younger patients, ⬍50 years old, an inadequate
temporal window can be expected in 5% to 10%; in women
⬎75 years old, the proportion can be as high as 50%.3
Reliable determination of VMean is not possible given a weak
signal in the MCA, and assessment of the VMR therefore is
either not possible or very unreliable. Intravenous injection of
an ultrasound contrast agent (USCA) that is not eliminated
via the lungs (eg, Levovist) considerably improves the quality
of the Doppler signal even if penetration of the temporal bone
is poor.5–10 Therefore, it seemed to be logical to perform the
Received October 10, 2000; final revision received January 12, 2001; accepted February 12, 2001.
From the Department of Neurology and Neuropsychiatry, Asklepios Kliniken Schildautal, Seesen, Germany.
Correspondence to Dr Matthias Rohrberg, Department of Neurology and Neuropsychiatry, Asklepios Kliniken Schildautal, Karl-Herold-Str 1, D-38723
Seesen, Germany. E-mail [email protected]
© 2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1298
Rohrberg and Brodhun
Transcranial Doppler-CO2 Test and Levovist
1299
Figure 1. Changes in cerebral blood
flow as a function of arterial PCO2 at different perfusion pressures (modified
according to Widder3).
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TCD-CO2 test with such an agent. The effect of a single-bolus
injection is only of short duration. Immediately after the
injection, the rapid increase in the concentration leads to
excessive enhancement of the ultrasound signal (so-called
blooming effect), which then gradually weakens with declining concentrations.11 Evaluation of the TCD-CO2 test requires
determination of the flow signal in the MCA for 10 to 15
minutes and thus a constant concentration and effect of the
USCA over this period of time. This can be achieved through
a continuous injection with an infusion pump.6,12
However, the question of whether the use of echoenhancing contrast agents leads to an increase in the velocity
determined by Doppler ultrasound is controversial in the
literature. Although Melany et al13 came to the conclusion
that USCAs do not significantly influence the measured
velocity, Forsberg et al14 and Fürst et al15 described an
increase of 20% to 45% in the maximum Doppler shift. These
possible differences of the measured VMean could influence the
results of the TCD-CO2 test. However, there are, to our
knowledge, no data available that address this question, and
the validity of the TCD-CO2 test with an USCA remains to be
established. In the present study, we therefore compared
calculation of the VMR with and without the use of an
USCA. Because this meant that the test had to be repeated in
the same patient, in a second part, we examined the influence
of Levovist on the reproducibility of the TCD-CO2 test.
The TCD was performed with a Neuroguard Doppler system with
integrated software for the CO2 test and the possibility of simultaneous monitoring of both MCAs. Two Doppler probes were fastened
to the patient’s head over the temporal window using a special
fixation device that permitted stable fixation of the probes. If
possible, both MCAs were examined simultaneously at a depth of
between 50 and 60 mm, and the intensity-weighted VMean was
recorded continuously. Because a stable Doppler signal without the
use of the contrast medium was necessary for comparison of the
results with and without an USCA, subjects with a bilateral poor
temporal window were withdrawn from the study and subjects with
a good temporal window only on 1 side were examined unilaterally.
When the VMean was stable for ⱖ5 minutes, the patients were given
pure carbogen via a mask with a valve and reservoir bag. After
stabilization of the new VMean for a few minutes (Figure 2), the test
was terminated. If there was little or no change in VMean in
hypercapnia, the test was not terminated before 10 minutes had
elapsed. The integrated software was used to determine the VMean in
normocapnia (VNormo) and the VMean in hypercapnia (VHyper), and the
VMR was calculated with the formula shown in Figure 2. The test
Subjects and Methods
The MCA was insonated transtemporally by means of 2-MHz
pulse-wave Doppler probes affixed to the patient’s head, and the
VMean was continuously recorded. Pure carbogen (5% CO2 and 95%
O2) was delivered via face mask; this produced the required increase
in the arterial PCO2 of 1% by volume. The change in the VMean in the
MCA in hypercapnia was measured, and the VMR was calculated as
the relative percent increase in VMean (Figure 2). For further evaluation of pathological results (increase in VMean ⬍10%), in accordance
with the “2-sided” method, the flow change in the MCA in
hypocapnia (hyperventilation) was also measured. To observe a
uniform examination protocol for all measurements, these results
were not, however, included in the study.
Figure 2. Determination of VMR in the TCD-CO2 test.
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TABLE 1. Participants in Part 1: Comparison of Repeated
Measurements With and Without Levovist
Participants, n
Subjects, 6
Patients, 20
Sex, n
TABLE 3.
Age, y
Diagnosis
M, 4
24–31
䡠䡠䡠
F, 2
Mean 28.0
M, 14
53–72
䡠䡠䡠
Unilateral ICA occlusion (n⫽13)
M⌬VMR
F, 6
Mean 64.0
Unilateral ICA stenosis* (n⫽4)
Bilateral ICA stenosis* (n⫽3)
2 SD⌬VMR
Differences in the VMR Among Study Groups
Comparison With and
Without Levovist
(n⫽50), %
Repeatability
Without
Levovist
(n⫽22), %
Repeatability
With Levovist
(n⫽21), %
1.8
4.8
2.2
P⫽0.228*
P⫽0.034*
P⫽0.025*
⫾20.7
⫾20.0
⫾8.2
P⫽0.0002†
*Stenosis of ⬎70%.
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was repeated in the same patient or subject after an interval of 15
minutes during which the flow in the MCA had returned to normal
again. The position of the Doppler probes was not changed between
the tests.
Levovist was infused with an IVAC Medical Systems P 4000
infusion pump specially configured for the administration of high
flow rates and with Medrad connecting tubes. For each test, 4 g
Levovist (Schering) was injected into a cubital vein in a concentration of 300 mg/mL with a flow rate of 1 mL/min (60 mL/h) via an
indwelling cannula. If it was necessary to prolong the examination
time, Levovist was administered again continuously in a concentration of 300 mg/mL up to the end of the examination.
The examinations were performed between July 1 and December
31, 1999, in the Department of Neurology and Neuropsychiatry of
the Asklepios Kliniken Schildautal, Seesen, Germany.
Part 1
In the first part of the study, the results of the TCD-CO2 test with and
without Levovist were compared in the same subject or patient.
For this portion of the study, we examined 6 healthy volunteers
and 20 patients with carotid stenosis or occlusion in whom performance of the TCD-CO2 test was indicated (Table 1). The patients
gave informed consent to participate in the study. Inclusion criteria
were high-grade stenosis (⬎70%) or occlusion of the extracranial or
intracranial ICA, the common carotid artery, or the brachiocephalic
trunk as confirmed with Doppler and duplex ultrasound studies as
well as a good temporal ultrasonic window, so that a stable envelope
curve was obtainable over the Doppler frequency spectrum of the
MCA when the examination was performed without contrast enhancement. The examination was not carried out in the first 6 weeks
after acute cerebral ischemia. The exclusion criteria were obstructive
lung disease, angina pectoris, myocardial infarction in the past 6
months, intracerebral hemorrhage in the past 3 months, and cerebral
infarction in the past 6 weeks. Lack of cooperation or failure to give
informed consent were further exclusion criteria.
In 1 patient and 1 control subject, the MCA was examined only
unilaterally, so that a total of 50 comparative measurements were
performed.
Part 2
The second part of the study was further divided into 2 sections. The
inclusion and exclusion criteria were the same as for the first part. In
*t test for paired observations.
†F test.
section A, we compared the repeated measures of VMR in 13
patients in whom the test was performed twice without Levovist
(Table 2). The MCA was examined only unilaterally in 4 patients, so
that 22 comparative measurements were performed.
In section B, twin measurements with infusion of Levovist were
carried out in 12 patients. In 3 patients, the MCA was examined only
unilaterally, so that a total of 21 comparative measurements were
obtained (Table 3).
Statistical Methods
Comparison of the 2 test results in the respective parts of the study
was performed according to the method of Bland and Altman.16 In
this method, the difference between the 2 test results
(⌬VMR⫽VMR2⫺VMR1) is plotted against their mean (MVMR) and
the mean difference (M⌬VMR), and the interval of 2 SDs from the
mean is calculated as a measure of the agreement between the results
(M⌬VMR⫾2 SD⌬VMR). Because evaluation of the data using the
Kolmogorov-Smirnov test showed a normal distribution of the data
(P⬎0.66), the VMR of the repeated measurements for each study
group was tested by using the t test for paired observations. In the
second part of the study, the F test was performed to compare the
variance of ⌬VMR in sections A and B.
Results
The results of the individual subgroups are summarized in
Table 3 and presented graphically in Figures 3 to 5. In the
first part, we compared the results of the TCD-CO2 test
obtained in the same patient or subject with and without the
infusion of Levovist. The mean difference between the VMR
values obtained with the 2 procedures was 1.8% (ie, when the
measurement was performed with Levovist, the VMR was on
average 1.8% higher, but this difference was not significant in
the t test; P⫽0.228). In general, it can be assumed that 95%
of the differences in the VMR are within the range of
⫾20.7% of this mean (2 SDs).
TABLE 2. Patients in Part 2: Repeatability of the TCD-CO2 Test With and
Without Levovist
Section
Sex, n
Age, y
Diagnosis
A: Repeated Measurements
M, 9
39–80
Unilateral ICA occlusion (n⫽4)
Without Levovist, 13
F, 4
Mean 64.8
Bilateral ICA occlusion (n⫽1)
Unilateral ICA stenosis* (n⫽6)
Bilateral ICA stenosis* (n⫽1)
Trunk stenosis* (n⫽1)
M, 10
42–75
Unilateral ICA occlusion (n⫽9)
F, 2
Mean 61.1
Unilateral ICA stenosis* (n⫽1)
Bilateral ICA stenosis* (n⫽2)
B: Repeated Measurements
With Levovist, 12
*Stenosis of ⬎70%.
Rohrberg and Brodhun
Transcranial Doppler-CO2 Test and Levovist
1301
Figure 3. Comparison of the TCD-CO2 test with
and without Levovist.
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In the second part of the study, the agreement was
examined between repeated measurements (repeatability)
with the TCD-CO2 test in the same patient. In section A, the
mean difference in the VMR on repeated measurements
without Levovist was 4.8% (P⫽0.034, t test), indicating that
the second measurement tend to be of a higher value. The
distribution of the differences was ⫾20.0% (2 SDs) and
therefore was within the same range as in the first part. After
the infusion of Levovist in section B, the mean difference
between the repeated measurements was 2.2% (P⫽0.025, t
test), and the distribution was ⫾8.2% (2 SDs). The t test for
paired observations showed in both sections a remarkable
difference for repeated measurements with a tendency for
higher second measurements. However, the level of significance was low (P⫽0.034 and P⫽0.025). The differences in
the variation of ⌬VMR in the 2 sections were highly
significant as demonstrated by the F test (P⫽0.0002).
Discussion
Various procedures are used to determine the VMR. A
reliable method of determining the cerebrovascular reserve
capacity and the least invasive method for the patient are
Doppler ultrasound procedures such as the TCD-CO2 or
acetazolamide test. In contrast to the TCD-CO2 test, in the
acetazolamide test there may be nonresponders or compensatory hyperventilation by the patient. Widder3 therefore
recommends performance of the TCD-CO2 test for clarification of pathological findings.
We were able to show that in patients with a sufficient
temporal bone window, the TCD-CO2 test can be performed
under a continuous infusion of Levovist. In the statistical
mean, there was no significant difference between VMR
measurements with and without USCA, and the comparative
measurements showed a good mean agreement. However,
there were occasional considerable individual differences.
The variation in ⌬VMR (2 SDs) was ⫾20.7%. There are 2
possible explanations for this: on the one hand, the differences might be due to the USCA, but on the other hand, these
differences may reflect errors caused by poor repeatability
(reliability) inherent in the TCD-CO2 test.
In a second part of the study, we therefore examined the
repeatability of the TCD-CO2 test. Here we found that on
repeated measurements in the same patient and probe position
without the use of an USCA, the differences showed a
Figure 4. Repeatability of the TCD-CO2 test
without Levovist.
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Figure 5. Repeatability of the TCD-CO2 test with
Levovist.
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similarly wide distribution (2 SDs, ⫾20.0%). We thus were
able to show that the TCD-CO2 test without an USCA has a
relatively poor reproducibility, thus explaining the wide
spread of the differences in the comparison between the tests
with and without the contrast medium. However, variation
fell significantly after an infusion of Levovist (2 SDs,
⫾8.2%), thus indicating a better reproducibility of the test
results. In our opinion, even with an apparently good temporal window, the use of an USCA produces a more stable
Doppler signal and improves the reproducibility of the
measurements.
In the second part of our study, there was a slight but
significant difference in the repeated measurements, indicating a systematic error. This may in part be explained by the
short interval of 15 minutes between the 2 measurements. If
the second TCD-CO2 test is repeated too quickly, the flow of
the MCA may in some cases not have returned to normal. We
therefore recommend choosing an interval of ⱖ15 minutes
before repeating the TCD-CO2 test twice in the same patient.
Our results show that the use of an USCA in the TCD-CO2
test does not produce substantial systematic differences compared with examination without an echo-enhancing contrast
agent. Because the performance of the test without the
contrast medium does not provide reliable results in subjects
with poor penetration of the temporal bone window, a
corresponding comparison of the tests is not possible in such
subjects. Nevertheless, it can be assumed that in patients with
an inadequate temporal window, the VMR can be determined
more reliably using a contrast agent. Alternative and more
invasive methods, such as xenon-enhanced computed tomography or positron emission tomography,17–19 are not
necessary.
However, the results also show that even with an apparently good temporal window, the repeatability, and thus the
diagnostic reliability, of the TCD-CO2 test is significantly
improved when the test is performed with the continuous
administration of an USCA. We therefore recommend, particularly in cases of pathological or borderline findings,
repeating the test with an USCA to be able to make an
unambiguous and reliable diagnostic statement.
The TCD-CO2 test provides important information about
patients with steno-occlusive disease of the cerebral arteries,
although the studies to date that have investigated impaired
VMR as an indication for cerebrovascular surgery have not
been able to provide definitive results as to the indication for
surgery. After the EC-IC Bypass Study in 1985,20 the use of
extracranial-intracranial bypass surgery for occlusion of the
ICA has been highly controversial.21,22 A number of studies
have shown that patients with an exhausted VMR are at an
increased risk of cerebral ischemia.23–26 After extracranialintracranial bypass surgery, the previously impaired cerebrovascular and oxygen metabolic reserve is normalized.27,28
Thus, determination of the VMR may help in identifying
those patients most likely to profit from extracranialintracranial bypass surgery.29,30 In patients with asymptomatic stenosis of the ICA, Gur et al31 were able to show that an
impaired VMR is associated with a high risk of cerebral
ischemia. Nevertheless, the use of VMR in the selection of
patients for carotid endarterectomy needs to be studied.
The results of our study show that the TCD-CO2 test can be
improved by the use of an USCA. This provides a more
objective test method for risk assessment in patients with
steno-occlusive disease of the ICA, especially in patients with
poor penetration of the temporal bone window.
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Measurement of Vasomotor Reserve in the Transcranial Doppler-CO2 Test Using an
Ultrasound Contrast Agent (Levovist)
Matthias Rohrberg and Rudolf Brodhun
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Stroke. 2001;32:1298-1303
doi: 10.1161/01.STR.32.6.1298
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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