„Contrast Agents in Sonography“ by T - European-Hospital

T. Albrecht, J. Hohmann
Contrast agents
in Sonography

4
Physico-chemical
and pharmacological
properties
Ultrasound contrast agents (USCA) or
echo enhancers consist of minute gas containing
microbubbles that have a high reflectivity
when exposed to an ultrasound
field. The history of USCA started in the mid
of the 1960s. The cardiologist Joyner performed
echo cardiography during the injection
of saline solution into the aortic root
via a catheter. During the injection he observed
bright signals on M-mode imaging.
The first written publication of this phenomenon
was by Gramiak and Shah and
appeared in 1968 1 . Small highly reflective
air bubbles within the injected fluid where
recognized to be the reason for the observed
signals.
The reason for the high reflectivity of air
bubbles is as follows: The ultrasound image
consists of reflected echoes which occur
when an ultrasound pulse encounters interfaces
of different materials or tissues. The
larger the proportion of sound energy reflected
at the interface, the more intense
are the signals shown on the sonographic
image. Each material has a characteristic
acustic in impedance (Z). Z is defined as the
product of the speed of sound in a specific
material and its physical density. Table 1
shows the density, speed of sound and
acustic impedance of some typical substances
relevant to clinical sonography. The
degree of reflection at in interface and thus
the intensity of the echoes displayed in the
sonographic image depends on the difference
in impedance between the two adjacent
materials: The higher the difference in
impedance, the stronger the reflected
echoes. Conversely the amplitude of the
sound wave travelling beyond the interface
decreases with higher impedances. As
shown in table 1, the difference in acuostic
impedance between air (and other gases) on
the one hand and water or soft tissue on the
other hand is very high, this leads to high reflectivity
of gas in sonography. The reflectivity
of air is so high that minute amounts of
gas bubbles are sufficient to produce considerable
signal enhancement in the entire
blood pool (less than 1 ml of gas are injected
with a typical dose of USCA).
In the 1970s cardiologists started to
use agitated saline solutions as the first
contrast agents for echocardiography.
When injected intravenously small air bubbles
included in the fluid produced signal
enhancement in the right heart. These
bubbles where however not able to withstand
pulmonary passage so that there was
no signal enhancement in the left heart.
They were therefore used for detection of
right to left shunts by demonstration of micro
bubbles within the left heart. Due to
their lack of transpulmonary stability, such
agitated fluids could neither be used for
echocardiography of the left heart nor for
extra-cardiac applications.
Table 1: Acoustic Impedance (Z) of some
materials relevant to clinical US.
Material Density Speed of sound Acoustic Impedance
(kg/m3) (m/s) (kg/m 2 s)
Air 1,2 330 400
Water 1000 1480 1 488 000
Soft tissue 1100 1540 1 630 000
Bone 1900 4080 7 800 000

Contrast agents
in Sonography
Abstract
Ultrasound contrast agents
consist of tiny gas bubbles encapsulated
by a stabilising membrane
or shell. When combined
with recent contrast-specific ultrasound
techniques, they provide substantial enhancement
of vessels and solid organs.
The clinical use and the diagnostic value of
ultrasound contrast agents are in principle
comparable to contrast agents for CT and
MRI. They add an additional dimension of
information to sonography, which results
in considerable improvement of diagnostic
accuracy in many cases. They can also
be used for functional imaging studies of
Albrecht, T.
Hohmann, J.
haemodynamics. This paper
reviews the physico-chemical
properties of various
microbubble contrast agents,
discusses non-linear bubble behaviour
and contrast-specific imaging techniques.
An overview of the most important radiological
clinical applications in the liver,
kidney and spleen is given.
Key words
Contrast media – microbubbles - ultrasound,
technology – liver, US – spleen, US – functional
imaging
PD Dr. med. Thomas Albrecht
Klinik und Poliklinik für
Radiologie und Nuklearmedizin
Campus Benjamin Franklin
Charité – Universitätsmedizin Berlin
Hindenburgdamm 30
D-12200 Berlin
3

Since the mid 1990s
transpulmonary microbubble
contrast agents have become
available. They distribute
evenly throughout the
entire blood pool and can be
used for echocardiography of
the left heart as well as for extracardiac
ultrasound. Transpulmonary
stability is
achieved by the addition of a
shell surrounding and thus
stabilising the microbubble.
Different materials are used
for these shells: Soft shells
consists of thin membranes
or layers of phosphor lipids or
surfactants. Other agents employ harder
and more stable shells made of albumin or
polymers. The average diameter of the micro
bubbles of all dedicated USCA ranges
between approximately 2 and 7 µ, they are
thus smaller then red cells and there is
therefore no risk of capillary embolization.
Contrast agent microbubbles consist of
various types of gases. There are two main
groups: High solubility gas agents using air
(e.g. Levovist, Schering AG, Berlin, Germany)
and low solubility gas USCA using
more stable perfluor gases (e.g. SonoVue,
Bracco SPA, Milan, Italy). The much lower
solubility of perfluor gases in plasma leads
to a higher stability of these agents with
stronger and longer lasting signal enhancement.
Table 2 summarizes the most
important USCA currently licenced or in
clinical development.
USCA are blood pool agents, in contrast
to conventional agents for CT or MRI
they do not diffuse into the extra cellular
fluid compartment. Following intra venous
injection they remain in the blood pool for
several minutes. The gas is gradually elimination
from the blood by exhalation via the
lungs, the shells are metabolized. All licensed
USCA are well tolerated with few
adverse reactions reported 2 . They are not
nephrotoxic and allergic reactions are very
rare and considerably less frequent then
Figure 1: In vivo mincroscopie of a capillary
with fluorescend microbubbles
(bright green) und red cells (arrows).
Courtesy of Dr. Jonathan Lindner, University
of Virginia; from: Handbook of Contrast
Echocardiography, Becher H und Burns PN,
Springer, Berlin 2000.
with iodinated X-ray contrast agents. Two
USCM for radiological applications are currently
available for clinical use in the European
Union: Levovist (Schering AG, Berlin,
Germany) since 1995 and SonoVue (Bracco
SPA, Milan, Italy) since 2001. Levovist
consists of a galctose matrix, galactosaemia
is thus a contraindication.
Non-linear properties of microbubbles
and contrast-specific imaging techniques
USCA were originally developed to enhance
signals from flowing blood in technically
difficult spectral or colour Doppler
studies. Due the rapid improvements in
equipment technology and particularly in
Doppler sensitivity, this application has become
virtually obsolete.
Outside the heart the agents do not
provide sufficient signal enhancement on
conventional B-mode imaging. In order to
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6
achieve clinically useful and Doppler independent
extra-cardiac enhancement, contrast-specific
imaging techniques are required.
Several such techniques have been
developed in recent years. They all exploit
the so called non-linear acoustic properties
of microbubbles.
When exposed to ultrasound ultrasound
waves, microbubbles occilate. This
occurs even at very low amplitude (energy)
of the insonating pulse. The occilations of
the bubbles have a strong tendency to be
resonant. The resonance frequency of a
typical contrast agent microbubble measuring
3m in diameter is close to 3 Mhz and
this frequency happens to be well within
the typical frequency range used in abdominal
and some other medical ultrasound.
This “lucky coincidence” of insonating
and resonance frequency
provides for a strong harmonic response of
the microbubbles.
The resonant behaviour of microbubbles
is crucially dependent on the amplitude
or energy of the transmitted pulse
(transducer out-put). The standardised
measure of transmit energy, which is displayed
by modern ultrasound systems, is
the mechanical index (MI). It is defined as
the peak rarefactional pressure of an ultrasound
longitudinal wave propagating in a
uniform medium, divided by the square
root of the centre frequency of the transmitted
pulse. The MI is not measured dur-
Table 2: The most important ultrasound
contrast agents (as of July 2003)
Name Manufacturer Gas Shell State of Development
Bisphere Point Biomedical Air Polymer Clinical development
BY963 Byk-Gulden Air Lipid Clinical development
completed, no license
application intended
EchoGen Sonus Dodeca- Surfactatant Licensed in EU,
fluoropentan not marketed
Echovist* Schering Air No shell, Licensed for
galactose matrix echocardiography and
hysterosalpingography in a
few European countries
Definity Dupont Merck/ Schwefel- Liposoms Licensed for
ImaRx hexafluorid echocardiography in
North America
Imagent Alliance Perfluorohexan/ Surfactatant Clinical development
Air completed
Levovist Schering Air Palmitic acid Licensed in 70 European and
galactose matrix Asian countries, not in USA
Optison MBI/Amersham Pefluoropropan Albumin Licensed for echocardiography
Medical in EU and North America
Sonavist Schering Air Polymer Clinical development stopped
Sonazoid Amersham Medical Perfluorocarbon Lipid Clinical development in Japan
SonoVue Bracco/ALTANA Schwefel- Phospholipid Licensed in EU and several
hexafluorid Asian countries, not in Japan
and USA
*No transpulmonary stability

Resonance pressure changes
Low
amplitude
Diameter of the microbubbles
Linear
oscillation
Non-operative status
ing an examination but calculated based
on a number of assumptions. Since these
assumptions are not fully met by patients in
clinical practise (e.g. uniform sound absorbtion
throughout the entire image), MI
readings should be regarded as estimates.
The true energy deposited in tissue will vary
between different parts of the image and
between patients as well as between transducers
and manufacturers. Nevertheless,
the MI value displayed on the scanner has
proven to be a very useful albeit imprecise
indicator of the transmit energy used during
clinical contrast enhanced examinations.
Careful control of transmit energy is
paramount when using contrast agents
and transducer out-put is the most important
machine setting that the operator
must control carefully. MI settings in clinical
contrast-enhanced sonography range
between approx. 0.05 and 1.8 depending
mainly on the agent used.
At very low transmit energy (MI <
0.05), the oscillations of the microbubbles
are symmetrical or linear and the changes
of bubble radius are inversely proportional
to the pressure changes in tissue: during
the positive phase of the US pulse the bubble
is compressed and during the negative
phase it is expanded, both to the same degree.
As the amplitude of the insonnating
US pulse is increased, the bubble becomes
High
amplitude
Figure 2: Linear
und non-linear
(harmonic)
resonance of
microbubbles.
At low amplitude
the oscillations
of the
bubble match the pressure changes induced
by the sound wave. The reflected echo has
the same frequency as the insonating pulse
(linear behaviour). At higher amplitude, the
bubble shows stronger resistance to compression
than to expansion and the oscillations
become asymmetrical. The reflected echo
thus contains frequencies (harmonics) which
are different from that of the insonating pulse
(non-linear behaviour).
Non-linear
oscillation
relatively more resistant to compression
than to expansion which leads to assymetrical
or non-linear occilations (Fig. 2). These
non-linear oscillations contain not only the
insonnating “fundamental” frequency but
several other “harmonic” frequencies”.
These harmonic components become part
of the signal returned from the bubble to
the transducer (bubble response) and are
exploited by contrast-specific imaging
modes. Harmonic signals occur at multiples
(two, three and four times) of the insonating
frequency. The second harmonic (double
the insonating frequency) has the highest
amplitude among the harmonics (Fig.
3) and is therefore the most relevant for
contrast-specific imaging.
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At even higher amplitudes destruction
of microbubbles occurs. The threshold for
destruction is variable and depends on a
number of different factors such as the size,
shell material and gas of the bubble as well
as the attenuation by the overlaying tissue.
For Albunex (no longer commercially available),
the threshold MI for bubble destruction
in vitro is 0.3 3 . The process of microbubble
destruction is complex. Recent
video-microscopic studies with extremely
high temporal resolution have given some
insight into the physical phenomena involved.
The most important mechanism is
Figure 3: Frequency spectrum of Levovist
insonated at 3,75 MHz at intermediate
amplitude. The strongest signal reflected
is the fundamental which has the same
frequency as the insonating pulse. Another
strong peak occurs at the second harmonic,
which has twice the insonationg frequency.
Courtesy of Prof. Peter Burns, University
of Toronto; from: Handbook Handbook
of Contrast Echocardiography, Becher H
und Burns PN, Springer, Berlin 2000
bubble fragmentation which is preceded
by massive expansion of the bubble by a
factor of 10 of its original radius. During the
next compression, the bubble can no
longer withstand the changes in pressure
and size, which results in fragmentation into
several smaller bubbles (Fig. 4). This
process only lasts a few milliseconds after
the start of insonation. Another reason for
bubble disruption is deflation of the bubbles
by ultrasound-induced diffusion 4,5 .
Similar to breaking glass, an intense
and strongly non-linear signal is produced
by the process of bubble disruption. This
signal is very different from a signal returned
from an intact bubble (“decorrelation”)
and has been termed stimulated
acoustic emission (SAE) or transient scattering.
It produces very bright but highly
transient echoes in the US image.
Contrast-specific imaging techniques
such as Pulse Subtraction Imaging (PSI) or
Vascular recognition Imaging (VRI) (both
by Toshiba) exploit the non-linear bubble
response for a highly sensitive and specific
display of contrast agents. PSI is based on
modulation of the phase of two subsequent
pulses (for details see separate section on
page x). It is a grey-scale technique with
high spatial and temporal resolution.

Figure 4: Videomicroscopic study of
a SonoVue bubble exposed to a high
amplitude (0,6 MPa) US pulse over an
observation period of 5ms. Initial resonance
is followed by rapid fragmentationv of the
bubble. The graph shows the non-linear
changes of radius over time.
Courtesy of: Dr. Nico de Jong, Thoraxcenter,
Rotterdam.
VRI is a single pulse colour Doppler
technique displaying the contrast agent information
as a colour overlay superimposed
on the conventional B-mode image.
Its advantage is the combination of tissue
and contrast information which can be displayed
separately or simultaneously. Furthermore,
VRI is the first contrast-specific
imaging mode to discreminate moving
from stationary bubbles and to display the
flow direction of bubbles. Stationary bubbles
are shown in green, while moving
bubbles are either red or blue, depending
on their flow direction (Fig. 5).
High versus low
MI imaging
From the above it is clear, that the
transmit energy has crucial influence on the
signal returned from the microbubble. Different
contrast media require different
transducer out-put settings and scanning
techniques. The two main categories are
high and low MI imaging.
High MI imaging
Air-based agents such as Levovist provide
only weak harmonic signals at low MI.
At high MI (> 0.5), however, they show
strong SAE producing bright transient signal
enhancement. High MI techniques are
thus required for clinically useful enhancement
with air-based agents. On Advanced
Dynamic Flow (ADF, Toshiba), SAE is displayed
as bright high resolution colour signals
superimposed on a conventional Bmode
image. Again, the tissue and contrast
information can be displayed separately or
simultaneously (Fig. 6).
The main limitation of high MI imaging
is that the SAE signal occurring during bubble
destruction is highly transient, lasting
only 3 or 4 frames when scanning in the
same position. After that, almost all bubbles
have been destroyed prohibiting further
enhancement. One way to overcome
this problem is intermittent imaging at low
frame rates (one image every few seconds)
to allow refilling of the image plane before
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Pulse Subtraction Imaging
Pulse subtraction imaging is based on the
principle of phase modulation for detection
of non linear echo signals. It is a broad band
technique, that displays signals returned
from micro bubbles at a high spacial resolution
in the entire B-mode image. PSI uses
two pulses which are 180° out of phase (two
exact mirror images). The two pulses are
transmitted immediately back and the reflected
echoes from these these pulses are
summed to form one image frame.
If the transmitted pulses encounter an
exclusively linear reflector (such as tissue at
low MI) the responses to the two inverted
pulses are again identical mirror images of
each other. if two pulses are added, the signal
is completely cancelled, so that linear reflectors
are not shown in the image. If, on
the other hand, non-linear reflectors such as
microbubbles are encountered by the two
pulses, each of these pulses is distorted due
to the production of harmonics. The distortion
also means that the two reflected pulses
are no longer identical mirror images to
each other. As a consequence, addition of
these two pulses will no longer result in cancellation;
the harmonic component of the
two pulses is used for the image. Since microbubbles
are strong harmonic reflectors,
this technique is idealy suited selectively to
display microbubbles and suppressing tissue
signal at low MI.
At high MI the first of the two
pulses will destroy the bubble and
lead to an intense broad band nonlinear
signal. The second pulse can no
longer be reflected by the destroyed
bubble and there is subsequently no
response from the second pulse.
Adding the two pulses means that the
strong reflections from the first pulse
will be displayed without modification.
In clinical practice this means
that there is a strong but extremely
short lived response from micro bubbles
such as Levovist on high MI PSI.
PSI is a B-mode technique with non-linear
signals displayed in the entire imaging
independent of any region of interest or
colour box. The stronger the non-linear signal
intensity from the micro bubbles, the
brighter is the signal in the image of the pixel
representing that bubble in the image.
At high MI, tissue also produces harmonics.
For that reason, PSI is also used for tissue
harmonic imaging.
Principle of PSI. Two pulses that are 180°
out of phase are sent immediately back-toback,
and the returned signals are summed
to build a US frame. In case of exclusively
linear scattering without distortion, this
summation produces a signal void.
Nonlinear response from microbubbles,
including harmonic resonance and stimulated
acoustic emission (//SAE), distorts the
returned signals; thus, the summation of
two pulses no longer results in a signal void.
The resultant signal is particularly strong in
the presence of bubble destruction, as the
destroyed bubble can no longer produce a response
to the second pulse so that the strong
signal from the first pulse is used without any
subtraction from the second pulse.

Figure 5: Kidney of a healthy subject on
Vascular Recognition Imaging (VRI) post
SonoVue. Stationary microbubbles are
displayed in green, flowing bubbles are
coded in red and blue, depending on flow
direction relative to the transducer.
the next destructive US frame. Alternatively,
the so-called sweep technique can be
used: The transducer is continuously
moved through an organ so that a new
area with undestroyed bubbles is scanned
with each new frame. This allowes one to
obtain one or two brightly enhanced
sweeps of an entire organ and the cine loop
is used to review the sweeps. The images
obtained using this approach are of high
quality and in has been shown to be clinically
usefull in experienced hands. However,
the sweep technique requires training
and is somewhat cumbersome, as the real
time nature of the examination is lost and
further sweeps can often not be performed
unless a second injection is administered.
Low MI imaging
The more recent perfluor agents such
as SonoVue have a much stronger harmonic
response even at low MI. The optimal
MI for imaging with SonoVue is between
approx. 0.07 and 0.2 . Imaging at
such low amplitude provides for good signal
enhancement with little bubble destruction.
Contrast-enhanced real time imaging
is thus possible. It can be used e.g.for
dynamic assessment of perfusion of tumours
or for complete real time assessment
of organs such as the liver by multiple slow
sweeps performed over several minutes.
Low MI imaging is very similar to conventional
US and much more user friendly than
the high MI technique. Low MI imaging
has thus replaced the high MI approach in
most centres. PSI and VRI are well suited for
low MI imaging with SonoVue.
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Figure 6: Normal liver
scanned at high MI using
Advanced Dynamic flow
in the liver-specific late
phase 4:50 min post
Levovist. ADF can be
displayed (a) as conventional
B-mode only,
(b) as a combination
of B-mode and colourised
contrast information
or (c) as a contrast only
image.
a
b
c

USCA can also be used as tracers for
functional imaging of organs or tumours.
Such applications are currently at an experimental
stage and is discussed below in
a separate section.
Clinical applications
Doppler enhancement, which was the
original indication for USCA, has become
almost obsolete in most areas due to improvements
in equipment performance. It
still has a role, however, in transcranial
Doppler studies 18-20 and in some rare abdominal
applications such as evaluation of
TIPS shunts 21-24 , Budd-Chiari-Syndrome or
renal vein thrombosis.
a
b
Figure 7: (a) Baseline
US shows ascites and
a slightly heterogenous
liver but no focal
lesions. (b) On VRI in
the delayed phase post
SonoVue (2.59 min p.i.)
several non-enhancing
small metastases
(arrows) are shown.
Current clinical use of USCA is mainly
based on the dynamic assessment of contrast
enhancement of vessels, organs and
pathologies such as tumours or absesses
and parallels the use of contrast agents in
CT or MRI. The most established clinical
application of USCA is the liver, followed
by kidney (especially testing for reflux in
children) and spleen. In these areas, the
clinical value of USCA has been proven
and they are increasingly used in routine
practise. Other potential areas for use are
e.g. pancreas, small bowel, prostate,
breast and eye, but these should be regarded
as mainly experimental at the current
stage.
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Figure 8: Dynamic CEUS
of a haemangioma
(arrows) using VRI
and SonoVue.
(a) Peripheral nodular
enhancement in the arterial
phase.
(b) Partial centripetal
filling of the lesion in the
portal venous phase.
(c) Subtotal filling of the
lesion in the delayed
phase (2:30 min p.i.).
a
b
c

Liver
Levovist and SonoVue (albeit to a lesser
extent) have a property which makes
them particularly suitable for liver imaging:
Several minutes after administration the
micobubbles accumulate in normal liver
parenchyma, while other tissue such as
metastases and most HCC are spared from
this delayed enhancement effect. The
cause of the delayed enhancement effect
remains unknown. There is circumstantial
evidence that the liver- specific late phase
of Levovist is mediated by interaction with
the Kuppfer-cells of the RES. In case of
SonoVue, pooling in the liver sinusoids is
the more likely explanation, therefore the
term sinusoidal phase is also used.
Delayed phase imaging is important
for detection (and characterization, as discussed
below) of malignant liver lesions. By
analogy with MRI using liver specific contrast
agents, detection of metastases is substantially
improved since metastases show
little or no contrast up-take and are therefore
easily discriminated from the enhancing
normal liver tissue 28-34 . The same effect
can usually also be observed during the
portal venous phase in most patients, albeit
to a lesser extent. The contrast between
metastases and surrounding hepatic
parenchyma is increased during the delayed
phase of Levovist by approximately 11 dB in
comparison to baseline imaging 28 . In principle,
HCC have similar properties on delayed
phase imaging as metastases, however
some HCC (typically highly differentiated
tumors) will show delayed enhancement
similar to surrounding liver and this makes
their detection more difficult.
Delayed phase imaging is particularly
useful for detection of small malignant lesions
or lesions which are isoreflective on
baseline imaging and therefore often invisible.
Lesions up to 5 mm in size are well
demonstrated by CEUS and even lesions
smaller than 5 mm are not infrequently
found 28,29,32 . The sensitivity of CEUS in the
detection of liver metastases is comparable
to that of dual phase spiral-CT 33 . The de-
tection of other malignant liver tumours
such as HCC or cholangio carcinoma is also
improved.
UCA have also been shown to improve
characterization of focal liver lesions substantially.
When low MI real time imaging
with SonoVue is used, the dynamic contrast
properties of a lesion can be assessed during
the arterial, portal venous and delayed
phase. The dynamic images are interpreted
using essentially the same criteria that
are used for dynamic CT or MRI. Haemangioma
show typical peripheral nodular enhancement
in the arterial phase followed
by partial or complete centripetal filling in
the subsequent phases (Fig. 8). Focal nodular
hyperplasia shows strong arterial hyperenhancement
(often with a “spoke wheel”
central feeding artery) followed by isoechogenecity
compared to normal liver in
the portal venous and delayed phases.
Some FNH also show a non-enhancing
central scare on delayed imaging. Focal fatty
change will show the same contrast enhancement
as normal liver in all three phases.
In summary, all common benign liver
lesions show considerable contrast up-take
during the delayed phase, they are therefore
easily differentiated from malignant lesions
which do not enhance at this stage.
Up to 90 % of all focal liver lesions can
be characterized by contrast enhanced ultrasound
(CEUS) with regards to their specific
diagnosis 36,38 . Differentiation of benign
and malignant lesions is possible than in
over 90 % of cases 38,40 . In our clinical experience
CEUS is superior to CT in characterization
of focal liver lesions and comparable
to MRI. In patients with inconclusive CT (or
MRI) examinations, CEUS can serve as a
fast and non-invasive a problem solver in
many instances.
Kidney
Testing for reflux in children after intravesical
administration of USCA – so called
voiding urosonography – is a well established
examination in paediatric radiology.
Voiding urosonography is highly sensitive
15

16
Figure 9: Dynamic CEUS
of a FNH (arrows) using
PSI and SonoVue.
(a) Unenhanced power
Doppler shows no intralesional
vessels. The FNH is
slightly hyperechoic.
(b) Homogenous
enhancement of the lesion
in the arterial phase,
additionally a typical
feeding artery is identified
(arrow head).
(c) Early in the portal
venous phase (45 s p.i.)
the lesion becomes
isoechoic and is hardly
discernable from
normal liver.
a
b
c

a
b
c
Figure 10: (a) Baseline
image of a large almost
isoechoic HCC (arrows).
(b) Strong arterial enhancement
of the HCC
17 s post SonoVue on PIS.
The contrast between the
tumour and surrounding
liver is increased.
(c) In the portal venous
phase (1:47 min p.i.)
the lesion shows as a well
defined relative enhancement
defect on PSI.
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18
Fig. 11: Dynamic CEUS of
“hypovascular” hepatic
metastasis from breast
carcinoma using PSI and
SonoVue.
(a) In the arterial phase
the lesion displays strong
peripheral rim enhancement
(arrow).
(b) Portal venous phase
imaging shows fading of
the rim.
(c) In the delayed phase,
the lesion presents as a
hypoechoic enhancement
defect with sharp
margins.
a
b
c

and specific to reflux and at least equivalent
to X-ray voiding cystourethrography in this
application 41-43 .
The disadvantage of voiding urosonography
is incomplete visualization of the
male urethra, so that the initial investigation
of a reflux in boys still requires the use
of X-ray voiding cystourethrography. All
other investigations (initial investigations in
girls and all follow up imaging) should
nowadays be performed using ultrasound
as this avoids significant radiation exposure
of these young children.
Another application of USCA in the
kidney is assessment of focal lesions. Tumours,
infarcts and traumatic hemorrhage
are better visualized following contrast administration.
This is particularly relevant for
a
b
Fig. 12: Renal cell
carcinoma.
(a) Baseline US shows
a 6 cm heterogenous
hyperechoic tumor.
(b) The tumour is seen
as a hypovascular lesion
50 s p.i. on VRI.
Courtesy of: Dr. Cochlin,
Radiology Department,
University Hospital
Wales, UK
infarcts and haematomas which are often
occult on conventional sonography. Probably
the most important clinical application
with regards to focal renal lesions is the differentiation
of pseudo tumors from true lesions.
Pseudo tumors will show the same
enhancement characteristics as normal
parenchyma with normal vessels, while tumours
show either more or less enhancement
than the surrounding parenchyma
and often an abnormal and irregular
macro-vascular pattern. Conversely, the
role of CEUS in the characterization of true
renal tumours is currently very limited,
since various types of tumours such as renal
cell carcinoma and angiomyolipoma
show a considerable overlap of their contrast
behaviour 47 .
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Spleen
The delayed phase of Levovist and
SonoVue applies not only to the liver
but also to the spleen: both agents
pool in normal splenic parenchyma for
many minutes. This can be exploited
for detection of tumors such as focal
lymphoma (Fig.14), infarcts and
haematomas 48-50 . In children with blunt
abdominal trauma, injuries of the
spleen (and other organs) are readily
visualised on CEUS, which is a good alternative
to CT. Characterisation of
splenic tumors with CEUS is much
more difficult and probably not possible
at this stage.
Summary
Recent contrast-specific imaging
techniques are highly sensitive
to USCA and provide
contrast-enhanced
images at excellent
quality. The clinical use
of USCA is similar that
of contrast agents for
CT and MRI as. They
give crucial additional
information for the diagnosis
of abdominal
organs, especially for
detection and
characterisation
of focal liver lesions.
CEUS often
provides a definitive
diagnosis
and obviates the
need for further imaging
in many patients.
Functional
haemodynamic
studies
with USCA
USCA can be used as tracers for dynamic
studies of arterio-venous transit
time of organs such as the liver, kidney
or brain. This is based on time-intensity
curves measured in artery and vein.
There are three advantages of CEUS in
this application:
1. The contrast volume is small (in the order
of 1 ml) which makes an injected bolus
very compact (short and dense).
2. At frame rates of 10 – 20/s, CEUS has
very high temporal resolution.
3. There is a linear relationship between
contrast agent concentration and signal
intensity, which is a prerequisite
for meaningful quantification.
The Aplio system (Toshiba)
has a software package that generates
time-intensity curves. The
relevant organ is scanned in a
single imaging plane during and
after contrast injection. The scan
is recorded as a digital loop for
analysis. Several regions of interest
(ROI) can be placed in vessels
and/or parenchyma. For each
ROI, the signal changes are calculated
over time and displayed
as a curve (Figure). From these
curves, indices such as arrival
time, paek enhancement or
transit time can be extracted.
There are some promising
applications for this technique,
which are however still at an experimental
stage. It has been
shown that patients with cirrhosis
have a much shorter transit time

than patients with normal livers or chronic
hepatitis (9-11) . This is due to arterialisation
that occurs in cirrhotic livers. Arterialsation
and shortening of transit time is also observed
in livers with early metastases (13,14) .
Exploiting this phenomonen, hepatic transit
time analysis may become useful for early
detection of metastases in the future.
Anther approach for haemodynamic
studies of organs or tumours are the destruction
reperfusion or negative bolus technique.
For this technique a steady state of
microbuuble concentration is required and
this is achieved by continuous infusion of
USCA. During the steady state, microbubbles
in the imaging plane are destroyed by
short insonation at high MI. Subsequent
scanning (either intermittend at high MI or
continuous t low MI) is performed to assess
the time required for the signal to recover
from the destruction, as this time is directly
related to perfusion. Again time-intensity
curves are used; perfusion is calculated
based on the slope of the curve and fractional
vascular volume depends on the high
of the plateau. The most important clinical
application of the destruction reperfusion
technique is assessment of myocardial perfusion,
which is starting to find its way into
clinical practise. Other applications such as
assessment of renal perfusion in various
conditions or of tumour perfusion e.g. during
anti-angiogenic therapy are still experimental.
Time intensity curves generated in the
porta hepatis with ROIs in the hepatic
artery, portal vein and hepastic vein.
The frame shown corresponds to the
white vertical line in the graph: at this
time point the contrast has arrived in the
artery (ROI and curve A) but not yet in
the veins (ROIs and curves B and C).
21

22
a
Fig. 13: Splenic haematoma.
(a) Baseline shows a poorly
defined, slightly hyperechoic
band-like area (arrow) in the
spleen and some perisplenic
fluid (arrow). Courtesy
of Dr. Cochlin, Radiology Dept.
University Hospital Wales, UK.
(b) Post SonoVue an extensive
haematoma is shown as an
irregular non-enhancing area on
PSI. Courtesy of Dr. C. Klemm,
St. Georg Hospital, Leipzig,
Germany.
Fig. 14: Large focal splenic
lymphoma. (a) The lymphoma
shows as a large hypoechoic area
in the lower half of the spleen.
(b) Post SonoVue, there is
homogenous enhancement of
the normal part of the spleen
(showing in green, VRI) while
there is almost no up-take in the
lymphoma. Courtesy of: Dr.
Cochlin, Radiology Department,
University Hospital Wales, UK
b
a
b

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25

Aplio
The most important
requirement for complex
diagnosis and research is
the ability to perform
high-quality examinations.
Aplio’s groundbreaking
system architecture produces
excellent diagnostic
performance and offers
great potential for new
and advanced applications.
But Aplio has
even more to offer like
innovative workflow
management, sophisticated
quantification analysis
tools or communication
and data management
facilities just to name but
a few advantages.

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