Contrast Transcranial Doppler Ultrasound in the Detection
of Right-to-Left Shunts
Comparison of Different Procedures and Different Contrast Agents
Dirk W. Droste, MD; Jens-Uwe Kriete; Jörg Stypmann, MD; Marco Castrucci, MD;
Thomas Wichter, MD; Ralf Tietje; Birgitta Weltermann, MD;
Peter Young, MD; E. Bernd Ringelstein, MD
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Background and Purpose—Cardiac right-to-left shunts can be identified by transesophageal echocardiography (TEE) and
by transcranial Doppler ultrasound (TCD) with the use of different contrast agents and different provocation procedures.
Currently, data on an appropriate time window for the appearance of contrast bubbles in the TCD recording after the
injection of the contrast medium and the comparison of different provocation maneuvers to increase right-to-left
shunting are insufficient.
Methods—Forty-six patients were investigated by both TEE and bilateral TCD of the middle cerebral artery. The following
protocol with 6 injection modes was applied in a randomized way: (1) injection of 10 mL of agitated saline without
Valsalva maneuver, (2) injection of 10 mL of agitated saline with Valsalva maneuver, (3) injection of 10 mL of a
commercial galactose-based contrast agent (Echovist) without Valsalva maneuver, (4) injection of 10 mL of Echovist
with Valsalva maneuver, (5) injection of 10 mL of Echovist with standardized Valsalva maneuver, and (6) injection of
10 mL of Echovist with coughing.
Results—In 20 patients, a right-to-left shunt was demonstrated by TEE and contrast TCD (shunt-positive). Sixteen patients
were negative in both investigations, no patient was positive on TEE and negative on TCD, and 10 patients were only
positive on at least 1 TCD investigation but negative during TEE. The amount of microbubbles detected in the various
tests decreased in the following order: Echovist and Valsalva maneuver, Echovist with coughing, Echovist and
standardized Valsalva maneuver, saline with Valsalva maneuver, Echovist, and saline. With a time window of 20 to 25
seconds for the bubbles to appear in the TCD recording and with a sequence of first Echovist and Valsalva maneuver
and then Echovist with coughing, all shunts were reliably identified with a specificity of 65% compared with TEE as
the traditional gold standard. The time of first microbubble appearance was not helpful to distinguish between shunts
detected on TEE and other shunts.
Conclusions—TCD performed twice with 2 provocation maneuvers using Echovist is a sensitive method to identify cardiac
right-to-left shunts also identified by TEE. (Stroke. 1999;30:1827-1832.)
Key Words: cerebrovascular disorders n cerebral embolism n foramen ovale, patent n ultrasonography
P
contrast agent within intracranial arteries, eg, the middle
cerebral arteries (MCAs). The echo-contrast agents used for
this test are unable to pass the pulmonary capillary bed. In
case of an RLS, the contrast agent enters the arterial circulation and produces microembolic signals (MES) during the
TCD recording, thus mimicking the pathway of paradoxical
cerebral emboli.9,10
Two main contrast agents are in use: agitated saline
containing tiny air bubbles and a galactose-based agent
(Echovist-300, Schering AG), which is a suspension of
galactose microparticles in an aqueous 20% galactose solution with adherent tiny microbubbles smaller than human
aradoxical thrombotic embolism via a cardiac right-toleft shunt (RLS) is a well-recognized cause of stroke,
especially in younger patients.1 Transesophageal echocardiography (TEE) enhanced by echo-contrast agents is considered the “gold standard” for the detection of cardiac RLS.2– 6
The Valsalva maneuver increases right atrial pressure, thus
facilitating or demasking intermittent right-to-left shunting of
contrast medium via an atrial septal defect or a patent
foramen ovale.3,7,8
Cardiac RLS can also be identified by the use of contrastenhanced transcranial Doppler sonography (TCD). The technique is based on the detection of an intravenously injected
Received May 6, 1999; final revision received May 31, 1999; accepted May 31, 1999.
From the Department of Neurology (D.W.D., J-U.K., R.T., B.W., P.Y., E.B.R.) and the Department of Cardiology and Angiology and Institute for
Arteriosclerosis Research (J.S., M.C., T.W.), University of Münster (Germany).
Reprint requests to Dr Dirk W. Droste, Klinik und Poliklinik für Neurologie der WWU Münster, Albert-Schweitzer-Str 33, D-48129 Münster,
Germany.
© 1999 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1827
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Stroke
September 1999
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erythrocytes. Several procedural questions of contrastenhanced TCD are unsolved. (1) Several authors hypothesized that MES passing pulmonary shunts appear later in the
cerebral circulation than those passing cardiac shunts and that
the choice of an appropriate diagnostic time window may
increase the specificity of the test.11–13 Time windows proposed between the intravenous injection of the contrast
medium and its appearance in the MCAs are 6 heart beats12
and 10,14 15,15 20,13 22,16 and 25 seconds.11,17 (2) Different
procedures to enhance right-to-left shunting have been proposed in the literature: a nonstandardized Valsalva maneuver,
a standardized Valsalva maneuver, and coughing.16,18,19
(3) Only 1 direct comparison of saline and Echovist injections
has been published thus far, but with different doses of these
agents.17 In the present study, we (1) investigated the effect of
different diagnostic time windows on the sensitivity and
specificity of the test, (2) systematically compared different
provocation maneuvers, and (3) compared identical doses of
the 2 contrast agents with respect to sensitivity and
specificity.
Subjects and Methods
Patients
Forty-six subjects (20 men, 26 women) aged 24 to 77 years (mean
age, 47 years) were included in the study. All patients had suffered
cerebral or retinal ischemic events. Eight patients had had recurrent
events. There were 25 strokes, 16 transient ischemic attacks, 11
attacks of amaurosis fugax, and 1 central retinal artery occlusion.
Eighteen subjects were cigarette smokers, 5 were diabetics, 20 had
arterial hypertension, and 26 suffered from hyperlipidemia. No
patient had a mechanical prosthetic cardiac valve.
In all 46 patients, TEE was performed to detect or rule out an
intracardiac shunt. Apart from these 46 patients, 23 additional
patients had been screened but had been excluded from the study for
the following reasons: in 18 of them no TEE could be obtained, and
in 5 patients there was no bilateral temporal window suitable
for TCD.
Echocardiography
All patients underwent TEE, which was performed by trained
echocardiographers from the Department of Cardiology of our
hospital. The investigators used a Hewlett Packard Sonos 2500 or
5500 imaging system and a 4- to 7-MHz multiplane probe. After
informed consent had been obtained, patients were examined in the
fasting state and received local pharyngeal anesthesia with 10%
topical lidocaine. Additional intravenous sedation (midazolam) was
given if the probe was not well tolerated. For the diagnosis of an
interatrial shunt, 10 mL of contrast agent (Echovist) was injected as
a bolus into a large antecubital vein during 2-dimensional TEE. The
presence of an interatrial shunt was assumed when microbubble
transit from the right to the left atrium occurred spontaneously or
during subsequent Valsalva maneuver. The patients were trained
regarding the Valsalva maneuver before the procedure. The effectiveness of the Valsalva maneuver was verified by a reduction in
ventricular and atrial size and by bulging of the interatrial septum
into the left atrium. Intrapulmonary shunts were not systematically
investigated in this study.
Ultrasound Investigations
All subjects underwent a full color duplex investigation of their neck
arteries (Sonos 2500, Hewlett Packard) and a continuous-wave
Doppler investigation of the periorbital arteries. Subjects were also
examined by TCD, including the intracranial segments of the internal
carotid arteries, the MCAs, and the anterior and posterior cerebral
arteries. One patient had a high-grade extracranial internal carotid
artery occlusion, and 2 patients had a high-grade extracranial internal
carotid artery stenosis.
For TCD embolus detection, the MCA was insonated bilaterally
through the temporal bone windows. Two 2-MHz transducers were
mounted on the temporal planes and secured with a head ribbon. A
small sample volume of 8 mm in length and a low gain provided a
setting optimal for embolus discrimination from the background
spectrum. The bigate technique was used, with 2 sample volumes
placed at a distance of 1 cm into each MCA main stem. Power was
22 mW/cm2. The patients were lying comfortably on a stretcher. The
investigations were well tolerated by the subjects without major side
effects.
The same transcranial pulsed Doppler ultrasound device (TC4040,
EME/Nicolet, software version 2.30) was used for all studies. The
machine employed a 128-point fast Fourier transform analysis and
used a graded color scale to display the intensity of the Doppler
signals received. In addition to online recording onto the hard disk,
the Doppler audio signal was recorded by an 8-channel digital audio
tape deck recorder (TA-88, TEAC Corporation) with normal speed.
An experienced observer’s analysis of MES comprised listening to
each of the software-recorded signals, watching each signal on the
screen, and evaluating the tapes. The following definition for MES
was used: typical visible and audible (click, chirp, whistle) shortduration, high-intensity signal within the Doppler flow spectrum
with a time delay in the 2 channels of each side.10 Single MES within
clusters were discriminated by reducing the amplification during
offline analysis.
The following 6 different procedures were performed in a randomized fashion: injection of (1) Echovist without Valsalva strain, (2) saline
without Valsalva strain, (3) Echovist with nonstandardized Valsalva
strain, (4) saline with nonstandardized Valsalva strain, (5) Echovist with
standardized Valsalva maneuver, and (6) Echovist with coughing. Each
of the these comprised at least 2 minutes, with bolus injection of the
contrast agent starting at 0 seconds, Valsalva strain for 5 seconds starting
at 5 seconds, bolus rinsing with nonagitated saline starting at 40 seconds,
and resting phase until 120 seconds. Microcavitation saline contrast was
generated by agitating a mixture of 10 mL of normal saline and 1 mL of
air between two 12-mL syringes connected by a 3-way stopcock. Once
the contrast was prepared, 10 mL was immediately injected as a bolus
into a right cubital vein, which had previously been cannulated with a
21-gauge indwelling intravenous catheter. Echovist was prepared following the instructions of the manufacturer, and 10 mL was injected.
The Valsalva maneuver started 5 seconds after the beginning of the
injection with deep inspiration, followed by pressing against the closed
glottis and expiration 10 seconds after the beginning of the injection.
The standardized Valsalva maneuver was performed in like manner but
with a manometer connected to a tube with a mouthpiece. The patients
were trained before the procedure to achieve and to maintain a pressure
of 40 mm Hg lasting 5 seconds. The patients could see the manometer
during the test for pressure control. For the coughing test, patients were
instructed to cough 3 times in between seconds 5 and 10 after injection
of the contrast agent.
In single cases, MES could still be detected 80 to 120 seconds
after the injection. In these cases, the resting time preceding the next
test was prolonged until an MES-free period of at least 40 seconds’
duration was documented. In each test, only the first 40 seconds after
injection were used for MES analysis. Data from the right and left
MCA were pooled.
Statistical Analysis
With TEE used as the gold standard, the sensitivity and specificity of
TCD were calculated as follows. Sensitivity was calculated as the
percentage of true-positives (RLS confirmed by both methods) in
comparison to true-positives plus false-negatives (TCD-negatives
and TEE-positives). Specificity was determined as the percentage of
true-positives compared with true-positives plus false-positives
(TCD-positives and TEE-negatives). For statistical analysis, the
numbers of MES seen during the 6 procedures were compared with
the nonparametric Friedman 2-way ANOVA. Furthermore, the
numbers of MES and the times of the first appearance of MES were
compared for the patients with an RLS on TEE and those with an
Droste et al
Contrast TCD and TEE in the Detection of Right-to-Left Shunts
1829
RLS only in the TCD investigation (nonparametric Mann-Whitney U
tests). For these tests, the mean values of each patient were
calculated and compared to avoid repeated measures. Statistical
significance was determined at the 0.05 level.
Results
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Sixteen patients had no RLS on TEE and did not show MES in
any of the tests within 40 seconds after the beginning of the
injection. Nineteen patients had an RLS on both tests: the TEE
and within 40 seconds after the beginning of the injection in at
least 1 TCD procedure. In 17 of these patients a patent foramen
ovale was found, and in the remaining 2 patients an atrial septal
defect was found. Eleven patients had MES in at least 1 TCD
investigation but no RLS on TEE. Four of these patients
underwent a second TEE, which demonstrated a patent foramen
ovale in 1 patient. No patient had an RLS on TEE but failed to
have one in the TCD investigation.
The subgroup of 20 patients with concordant identification
of RLS by TEE and TCD and the 10 patients with a shunt
only in the TCD investigation were studied in more detail to
detect possible differences in the streaming characteristics of
contrast material via the atrial RLS versus a presumed
pulmonary shunt. As an example, the top sections of both
panels in the Figure illustrate the appearance and amount of
all MES seen in the TCD recordings of 2 of the tests, whereas
the bottom sections depict the time of first MES appearance.
The distributions of MES occurrence in the other 4 tests
were similar, with MES occurring up to 40 seconds after the
injection and first appearances of MES up to 26 and even 30
seconds after the injection of the contrast agent. The 2 patient
groups with concordant shunt identification in both investigations (n520) and with shunt demonstration only in the
TCD investigation (n510) were compared concerning the
time of first MES appearance in the TCD recording. For these
comparisons, the mean times of first appearance of all 6 tests
(only the positive tests) were calculated for each single
patient. The mean time of first MES appearance in the first
group was 12.0 seconds (range, 7.5 to 16.0 seconds) and in
the second group was 14.6 (range, 6.5 to 30 seconds). There
was no difference in the time of first MES appearance
between the 2 patient groups (P50.37, Mann-Whitney U
test). These 2 groups were also compared concerning the
mean numbers of MES in all 6 tests of each patient (positive
and negative tests). There was a significant difference indicating more MES in the group of 20 patients with concordant
shunt identification (P50.006). The mean number was 20.09
(range, 0.33 to 103.83) in the group of 20 patients with
concordant shunt identification and 2.77 (range, 0.17 to 3.84)
in the 10 patients with a shunt only during TCD. Although in
general there were fewer MES in the patient group with a
shunt only in the TCD investigation compared with the group
with concordant shunt identification, introducing a threshold
in number of MES could not reliably discriminate the 2
groups. As an example, in the test with Echovist and the
nonstandardized Valsalva maneuver, the total numbers of
MES in the individual patients within 40 seconds after the
injection were 0, 0, 0, 0, 0, 1, 1, 4, 12, and 25 (shunt only in
the TCD recording) and 0, 0, 2, 2, 3, 9, 11, 12, 15, 15, 19, 23,
Top sections of both panels show all MES detected in the
patients with RLS identified on contrast TCD plus contrast TEE
(dark gray columns) and in the patients with a shunt only in the
contrast TCD investigation (light gray columns). The dark columns are shown on top of the light columns. Bottom sections of
both panels show the corresponding values for the frequency of
first MES appearance.
32, 38, 60, 69, 81, 88, 100, and 107 (concordant shunt
identification).
In the 30 patients with a positive TCD test, the total
number of MES recorded in all tests within 40 seconds was
729 for Echovist with nonstandardized Valsalva maneuver
(mean rank in a Friedman 2-way ANOVA, 4.14), 664 for
Echovist with coughing (mean rank, 4.00), 553 for Echovist
with standardized Valsalva maneuver (mean rank, 3.99), 335
for saline with nonstandardized Valsalva maneuver (mean
rank, 3.32), 223 for Echovist without Valsalva maneuver
(mean rank, 3.00), and 73 for saline without Valsalva maneuver (mean rank, 2.55; P,0.0001). The number of MES in
the single tests varied from 0 to 109 in patients with a
TEE-proven shunt and from 0 to 25 in patients with a shunt
only seen during contrast TCD.
With TEE used as the traditional gold standard, sensitivity
and specificity of each injection mode were calculated on the
basis of a variety of proposed time windows (Table 1).
1830
Stroke
September 1999
TABLE 1. Sensitivity and Specificity of Different Contrast TCD Procedures Using Different
Time Windows of First MES Appearance in the Detection of Interatrial RLS Demonstrated
on TEE
Diagnostic Window, s
#40
#25
#22
#20
#15
#10
Sensitivity
60
60
55
50
30
20
0
Specificity
85
88
88
88
88
96
100
Sensitivity
40
40
40
40
35
20
0
Specificity
92
92
92
92
96
96
100
Sensitivity
90
90
90
90
80
45
15
Specificity
81
81
85
85
92
96
100
Sensitivity
85
85
85
85
75
40
15
Specificity
81
81
81
81
81
88
96
Sensitivity
80
80
80
80
80
30
0
Specificity
73
73
73
73
77
88
96
Sensitivity
85
85
80
80
75
40
10
Specificity
69
73
73
73
73
88
96
Sensitivity
90
90
90
90
80
50
15
Specificity
81
81
81
81
85
92
100
Sensitivity
90
90
90
90
90
45
15
Specificity
81
81
81
81
81
88
96
Sensitivity
100
100
100
100
90
60
20
Specificity
65
69
69
69
73
88
96
Procedure
#6
Echovist
Saline
Echovist, Valsalva maneuver
Saline, Valsalva maneuver
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Echovist, standardized Valsalva maneuver
Echovist, coughing
Echovist, with and without Valsalva maneuver
Saline, with and without Valsalva maneuver
Echovist, Valsalva maneuver, and coughing
Values are percentages.
Besides the individual tests, the classic combinations of
Echovist without and with the nonstandardized Valsalva
maneuver, of saline without and with the nonstandardized
Valsalva maneuver, and the combination of the 2 most
sensitive TCD tests (Echovist with nonstandardized Valsalva
maneuver and Echovist with coughing) were also considered.
This latter combination reliably identified all TEE-proven
shunts.
Discussion
Our study demonstrates that contrast TCD detects TEEproven RLS with a sensitivity of 100% and a specificity of
65% when Echovist with Valsalva maneuver is combined
with Echovist with coughing and when a diagnostic window
of 20 to 25 seconds is chosen for the microbubbles to appear
within the MCAs. No single test had the desired sensitivity of
100%. The values for sensitivity and specificity of the present
study are in agreement with those reported in the literature
(Table 2).
It is a well-known phenomenon that more patients are
identified as having an RLS when investigated by contrast
TCD than with TEE (see the specificities in Table 2). In these
cases, the lungs are the most likely location of venous-arterial
shunts, allowing the contrast material to bypass the pulmonary capillaries and to slip into the cerebral arteries. As
another option, these shunts may correspond to very small
intracardiac shunts unnoted during TEE. In our study, smaller
amounts of bubbles could pass these shunts compared with
the shunts also demonstrated on TEE. Differences in the
performance of the Valsalva maneuver may also account for
these discrepancies. Despite training and control, the Valsalva maneuver may occasionally not have been as effective
during TEE compared with the TCD investigation because of
the TEE tube in the esophagus and sedation. Some authors
believe that those MES that occur late after contrast injection
may have passed these pulmonary shunts.11–13 However,
Horner et al27 reported that in pulmonary shunts, the transit
time is in a range comparable to that in cardiac shunts and that
this parameter does not allow reliable discrimination between
the 2 conditions. Microbubbles detected in the arterial circulation at any time must have passed a shunt. Our study proves
Droste et al
TABLE 2.
With TEE
Contrast TCD and TEE in the Detection of Right-to-Left Shunts
1831
Review of the Literature on Sensitivity and Specificity of Contrast TCD Compared
Author
Year
Contrast Agent
No. of
Patients
RLS on
TEE
Sensitivity
of Contrast
TCD, %
Specificity
of Contrast
TCD, %
100
Nemec et al
1991
Agitated saline
32
13
100
Chimowitz et al20
1991
Agitated saline
4
1
100
50
Karnik et al21
1992
Agitated gelatine
36
15
87
100
Venketasubramian et al22
1993
Agitated saline
49
12
100
100
Di Tullio et al
1993
Agitated gelatine
49
19
68
100
Job et al15
1994
Oxypoly-gelatine
137
64
89
92
Jauss et al11
1994
Echovist
40
15
93
100
Klötzsch et al12
1994
Echovist
111
50
91
94
Anzola et al
1995
Agitated saline
40
21
90
100
Schminke et al24
1995
Echovist
65
24
91
81
Zanette et al16
1996
Agitated saline
38
38
79
100
Horner et al25
1997
Echovist
45
35
97
70
Albert et al
1997
Oxypoly-gelatine
69
18
100
72
Stendel et al4
1998
Echovist
46
13
85
100
Droste et al17
1999
Agitated saline
54
19
95
75
Echovist
54
19
95
75
6
23
14
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26
Studies using only TTE were not included.
the overlapping time spans of the first appearance of MES in
the cerebral circulation of patients with and without an RLS
demonstrated by TEE and the inability to distinguish the 2
shunt entities by means of the TCD investigation. Similar to
intracardiac shunts, pulmonary shunts can also allow an early
transit of contrast bubbles. The clinical significance of
pulmonary shunts in stroke etiology, however, is completely
unknown thus far. TCD is more sensitive than TEE in the
detection of RLS. The therapeutic consequences to be drawn
in stroke patients with a shunt during TCD and not during
TEE warrant further research.
In 2 cases without shunt on TEE, the first MES during
TCD occurred beyond 25 seconds after the injection of the
contrast medium. Therefore, a time window of 20 to 25
seconds is recommended to achieve a higher specificity of the
TCD investigation. Time windows shorter than 20 seconds
decreased sensitivity and should not be used.
Interestingly, the standardized Valsalva maneuver did not
give better results than the “normal,” nonstandardized Valsalva maneuver, probably because of the fact that the patients
were trained beforehand and proper performance was ensured. The nonstandardized Valsalva maneuver is sufficient
for the TCD-based detection of RLS.
The tests using Echovist were better than the corresponding tests using agitated saline. A higher amount of bubbles
and greater bubble durability may account for this finding.
We recommend performance of TCD-based tests for RLS
with Echovist instead of agitated normal saline.
The sensitivity of contrast TCD depends on the amount of
bubbles injected, the number of occasions for bubbles to
trespass a possible shunt, and the sensitivity of the TCD
device to detect the microbubbles in the cerebral arteries. A
previous study had shown that sensitivity is increased with
the use of bilateral instead of unilateral TCD recordings and
repeated instead of single testings.17 This study corroborates
the necessity of repeated bilateral recordings, here once with
Valsalva maneuver and once with coughing to achieve high
sensitivity. Additionally, the present investigation demonstrated that the sensitivity is higher with the use of Echovist
than with the same quantity of saline.
In addition to the sole identification of an existing RLS, the
need for quantification of the RLS measured by the amount of
MES recorded has been postulated to possibly better quantify
stroke risk.28 Given the low reproducibility of these tests,
such quantifications are difficult to perform and obviously
warrant bilateral and repeated recordings, preferentially with
the use of Echovist.
In our study 1 RLS identified in the contrast TCD investigation, but first unnoted on TEE, could be identified as
persistent foramen ovale in a repeated TEE. Our study
emphasizes the value of a second TEE opinion in these
discordant cases. The combination of contrast TCD and TEE,
although associated with redundancy, increases the treating
physician’s confidence in the case of concordant findings and
enables the physician to take appropriate therapeutic
measures.
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Contrast Transcranial Doppler Ultrasound in the Detection of Right-to-Left Shunts:
Comparison of Different Procedures and Different Contrast Agents
Dirk W. Droste, Jens-Uwe Kriete, Jörg Stypmann, Marco Castrucci, Thomas Wichter, Ralf
Tietje, Birgitta Weltermann, Peter Young and E. Bernd Ringelstein
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Stroke. 1999;30:1827-1832
doi: 10.1161/01.STR.30.9.1827
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