Journal of Medical Imaging

and Radiation Sciences

Journal de l’imagerie médicale

et des sciences de la radiation
Journal of Medical Imaging and Radiation Sciences xx (2019) 1-6
www.elsevier.com/locate/jmir
Review Article

The Role of Contrast-Enhanced Ultrasound in Managing Vascular

Pathologies
Dixa B. Thakrar, MBChB, PGCert and
Muhammad Junaid Sultan, MBBS, MRCSEd, MRCS, PGCert, MD, FEBVS*
Department of Vascular Surgery, Hull University Teaching Hospitals NHS Trust, Hull, UK

vasculaires. En comparaison des autres modalit
es, elle est relativement

ABSTRACT
Introduction: Ultrasound is a useful first-line imaging modality for
diagnosing and monitoring vascular pathologies. Compared with
other modalities, it is relatively low cost, requires no ionizing radiation,
is often available at bedside, and is noninvasive. However, the modality
can have limitations when differentiating normal from pathologic tis-
sues. In this review, we discuss the role of contrast-enhanced ultrasound
(CEUS) in carotid, aortic, and peripheral vascular conditions.
Discussion: CEUS is a developing modality that supersedes standard
vascular ultrasound imaging and complements other modalities such
as computed topography and magnetic resonance angiograms.
Administered intravenously, the contrast are microbubbles filled
with gas, surrounded by a stabilizing shell. They have the ability to
enhance the quality of images and quantify vascular pathologies by
acting as intravascular tracers of ultrasound energy. Based on these
properties, CEUS has the potential to play a pivotal role in the man-
agement of vascular pathologies through its utility in detection, diag-
nosis, risk-stratification, follow-up, and monitoring.
Conclusion: Studies have suggested that CEUS is superior compared
with standard ultrasound and on-par with computed topography an-
giograms in the detection of vascular pathologies, concluding that
CEUS should be part of standardized routine practice.
peu co^ uteuse, n’exige pas de rayonnement ionisant, est souvent dis-
ponible au chevet du patient et est non invasive. Cependant, la modal-
it
e peut avoir des limitations dans la diff
erentiation entre les tissus
sains et pathologiques. Dans cet examen, nous discutons du r^ole de
l’
echographie avec agents de contraste (EAC) dans les problemes tou-
chant la carotide, l’aorte et le systeme vasculaire p
eriph
erique.
Discussion : L’EAC est une modalit
e en d
eveloppement qui remplace
l’
echographie vasculaire conventionnelle et sert de compl
ement a
d’autres modalit
es comme la tomodensitom
etrie et l’angiographie par
r
esonance magn
etique. Administr
e par intraveineuse, l’agent de con-
traste est form
e de microbulles remplies de gaz, entour
ees d’une coquille
stabilisatrice. Il a la capacit
e unique d’am
eliorer la qualit
e des images et
de quantifier les pathologies vasculaires en agissant comme traceur intra-
vasculaire parfait de l’
energie des ultrasons. En raison de ces propri
et
es,
l’EAC a le potentiel de jouer un r^ ole essentiel dans la gestion de la
m
edecine des pathologies vasculaires par son utilit
e dans la d
etection,
le diagnostic, la stratification du risque, le suivi et la surveillance.
Conclusion : Les
etudes laissent voir que l’EAC pr
esente une
efficacit
e sup
erieure a celle de l’
echographie standard et similaire a
celle de l’angiographie par tomodensitom
etrie dans la d
etection des
pathologies vasculaires, de sorte qu’on peut se demander si l’EAC
ne devrait pas ^etre mise en œuvre dans le cadre de la pratique de
routine standard.

RESUM

E
Introduction : L’
echographie est une modalit
e d’imagerie de pre-
miere ligne utile pour le diagnostic et le suivi des pathologies

Keywords: Vascular; contrast-enhanced ultrasound; carotid; aorta; aneurysm; peripheral vascular

Background and History

The use of contrast agents to enhance the visualization of
* Corresponding author: Muhammad Junaid Sultan, MBBS, MRCSEd,
MRCS, PGCert, MD, FEBVS, Department of Vascular Surgery, Hull Univer-
anatomy dates back to the late 19th century, shortly after
sity Teaching Hospitals NHS Trust, Anlaby Road, Hull HU3 2JZ, UK. Roentgen discovered x-rays [1]. The agents developed at the
E-mail address: drjunaidsultan@gmail.com (M.J. Sultan). time were unsafe for routine clinical use, and it was not until
1939-8654/$ - see front matter Ó 2019 Published by Elsevier Inc. on behalf of Canadian Association of Medical Radiation Technologists.
https://doi.org/10.1016/j.jmir.2019.08.010
the 1920s that a safe contrast agent was found; namely, iodine
[2]. Over time, contrast agents have evolved and are now
routinely used in clinical radiography, most commonly in
computed tomography (CT) and magnetic resonance imag-
ing. Although contrast in ultrasound (US) is not as prevalent
as its use in other modalities, the area is expanding with a va-
riety of contrast agents in development. This review aims to
explore the use of contrast-enhanced US (CEUS) in vascular
pathologies: carotid artery disease, aortic disease, and periph-
eral vascular disease.
The standard, grey-scale US scan helps to differentiate be-
tween and within the different tissue structures. US produces
images that are generated by sending pulses of US into tissue.
These pulses reflect off tissues with different reflection or ultra-
sonic properties to produce an image and hence distinguish be-
tween tissues. However, the challenge arises when attempting to
differentiate between normal and abnormal tissue. Although
the tissues may be pathologically different, the ultrasonic or
reflective properties of the tissues may not be sufficiently
distinct to be demonstrated via US. It is hypothesized, however,
that abnormal tissue can uptake substances, such as contrast
agents, differently from normal healthy tissue, which can be
appreciated through US. This theory leads to the development
of contrast agents in ultrasonography. Microbubbles have a
higher degree of echogenicity and act as nearly perfect intravas-
cular reflectors of acoustic waves. There are two approaches. In
the first approach, the agent increases the echogenicity of blood
and enhances the Doppler signals. In the second, the medium
collects within or around abnormalities to increase the differ-
ence in reflectivity to help to differentiate between normal
and abnormal tissues. Vascular contrasts are based on the
former approach. Blood and surrounding tissue are similar in
echogenicity, but the addition of microbubble contrast agents
may be used to enhance the overall contrast and quality of
US images. Following insonification with US, the gaseous
core of microbubbles causes a very high echogenic response
that results in a contrast to tissue background ratio on US im-
ages. Microbubble shell prevents both gas leakage and aggrega-
tion of gas bubbles as well. Gramiak and Shah introduced the
first US compatible vascular contrast agents in 1968 [3]. Dur-
ing echocardiography, they injected the agitated saline in to the
ascending aorta and cardiac chambers. The contrast allowed for
anatomic validation of the aortic origin when using echocardi-
ography to visualize the aortic root.
Principle
Free gas bubbles are the simplest form of US contrast agents.
Through the years, however, more sophisticated agents have
been developed and introduced into the clinical area, such as
encapsulated gas bubbles, colloid suspensions, liquid emulsions,
and aqueous. Contrast agent development and clinical utiliza-
tion have been governed by agent toxicity, route of administra-
tion, ability to travel through capillaries, and stability to provide
visual enhancement over multiple heart cycles. Different
commercially available vascular and cardiac US contrast agents
2 D.B. Thakrar and M.J. Sultan/Journal of Medical Imaging and Radiation Sciences
are Albunex and Optison (Molecular Biosystems Inc, San
Diego, CA), Echovist and Levovist (Schering AG, Berlin, Ger-
many), EchoGen (Sonus Pharmaceuticals, Bothell, WA), Im-
agent US (Alliance Pharmaceutical Corp., San Diego, CA),
and Sonovue (Bracco Diagnostics, Princeton, NJ) [4].
US contrast agents typically involve the use of microbubbles,
commonly with a diameter range of 1–7 mm. The pulmonary
capillaries have the narrowest lumen in the human body.
This serves as a target size for the clinical microbubbles, as
they must be able to cross the pulmonary vascular bed after
intravenous injection to produce systemic enhancement [5].
The most critical factors to maintain the effectiveness of
contrast agents after injection, to render them sufficiently sta-
ble, are the gas they contain (air or perfluoro gas) and the stabi-
lizing shell (denatured albumin, surfactants, or phospholipids).
Colour Doppler greatly improves the vascular imaging, but
a further advance with introduction of microbubble contrast
allows previously undiagnostic examinations to be interpreted
and avoids further cross-sectional imaging, termed Doppler
rescue. Doppler rescue results because of the major impedance
mismatch produced by the change in the density at the surface
of a bubble in plasma; thus, the echogenicity generated is ex-
ploited in the use of microbubbles to improve Doppler studies
[6]. Gases are more compressible than soft tissues giving rise to
a more complex and sophisticated signal that is then picked up
by US. When microbubbles are exposed to the compression-
rarefaction sequence of an US pulse, they vibrate more readily
because they undergo alternate contraction and expansion [7].
Microbubbles reflect strong signals compared with red blood
cells and hence act as an effective US contrast agent.
The safety of microbubbles has been studied extensively and
recommendations concerning appropriate use have been pub-
lished in the literature too. There has not been any evidence
of nephrotoxicity or cardiotoxicity found to date in patients [8].
Clinical Applications in Vascular US
Microbubble contrast agents have created exciting oppor-
tunities for US and have opened new horizons in vascular
US imaging. Modern US contrast agents, in conjunction
with contrast-specific imaging modes and techniques, are be-
ing increasingly utilized for diagnostic imaging. Injected mi-
crobubbles act as intravascular tracers. Their ability to act as
almost perfect intravascular reflectors of US energy put
them in a unique position to enhance the overall contrast
and quality of the images produced by US [9]. CEUS has
the potential to expand detection, characterization, and risk
stratification of various vascular disorders [10]. Here we
describe a few clinical applications.
Clinical Applications of CEUS in Carotid Arterial
Disease
Duplex ultrasonography remains the first-line imaging mo-
dality for carotid artery disease. European Carotid Surgery
Trial and North America Symptomatic Carotid Endarterec-
tomy Trial highlight the importance of accurate assessment
- (2019) 1-6
of degree of internal carotid artery diameter particularly with
US [11,12].
Cerebral thromboembolic events are most likely the result
of rupture of unstable carotid plaques in vulnerable patients.
Arguably, the most sensitive predictor of an embolism because
of carotid pathology is a recent history of neurological symp-
toms ipsilateral to a carotid stenosis [13]. The assessment of
high-risk asymptomatic patients who have vulnerable plaques
remains unclear, suggesting the need for a noninvasive, cost-
effective, sensitive method for detection of these unstable
plaques.
An atherosclerotic plaque requires a nutrient blood supply,
which is predominantly derived from arterial vasa vasorum
[14]. Intraplaque neovascularization and inflammation are
considered as important indicators of plaque vulnerability,
which when ruptured, may cause a cerebrovascular accident
[13,15,16]. Current literature concludes CEUS examination
makes a significant improvement in the diagnosis of carotid
disease, especially in difficult clinical cases [17].
With the introduction of an echo-enhancing blood pool
agent, CEUS can be used for the detection and quantification
of intraplaque neovascularization for risk-stratification
[13,14,18–20]. Using microbubbles, CEUS can examine pla-
que biology and composition. Hence, CEUS can aid in the
identification of vulnerable carotid lesions with a high risk
of rupture and peripheral embolization [13].
The use of CEUS has shown to reduce interphysician
interpretation variability and improve overall image quality
when assessing visualization of far field, quality of Doppler
envelope, and plaque morphology in patients with moderate
carotid artery stenosis [21].
In addition, studies have validated the efficacy of CEUS to
detect neovascularization through correlating the visual
enhancement with histology in animal and humans
[14,22,23]. These studies validated what was observed using
CEUS with histologic staining of carotid plaques. Shah et al
found a correlation value of 0.68 using Spearman’s rank
method in 17 human carotid plaque samples [14]. Liu et al
[23] also found positive Spearman correlation in rabbit models
(r > 0.58). To determine diagnostic accuracy, the quantitative
parameters need to be correlated with the degree of neovascula-
rization. Qualitative approaches are prone to inter- and intra-
observer variation [24]. Quantitative approaches have been
developed using Semiautomated methods via specialized soft-
ware. With these methods, the variations of contrast enhance-
ment of the plaque are analysed as a function of time in a
predetermined region of interest [13]. Quantitative methods
have the advantage of being reproducible and helping reduce
operator-related bias. Accompanying these methods are algo-
rithms for the detection of motion corresponding to microbub-
ble circulation and calculation of the ratio of enhanced to total
plaque surface [13,25].
A limitation of quantitative methods is that the images
from which a quantitative outcome is produced are two
dimensional and hence not necessarily representative of a
three-dimensional plaque. This can be resolved by
D.B. Thakrar and M.J. Sultan/Journal of Medical Imaging and Radiation Sciences
implementing use of three-dimensional techniques for quan-
tifying neovascularization with plaques [15,19].
A systematic review and meta-analysis of seven studies was
conducted to evaluate the accuracy of CEUS-detected carotid
atherosclerotic plaques, looking at quantitative CEUS inten-
sity and the visual grading of plaque CEUS [26]. For qualita-
tive CEUS, pooled sensitivity was 0.80 (95% confidence
interval [CI] 0.72–0.87) and pooled specificity was 0.83
(95% CI 0.76–0.89); and for quantitative CEUS, pooled
sensitivity was 0.77 (95% CI 0.71–0.83) and pooled speci-
ficity was 0.68 (95% CI 0.62–0.73).
Based on the previously mentioned studies, it seems that
CEUS have potential to be valuable noninvasive tools for de-
tecting intraplaque neovascularization and hence detect
vulnerable plaques that are at high risk of rupture and periph-
eral embolization. This process of risk stratification of the
atherosclerotic lesions can aid in the process of tailoring indi-
vidual treatments in the era of personalized medicine [10].
However, before this can be implemented into routine prac-
tice, international or national standardization of quantitative
analysis and visual grading classification are needed to increase
reliability and reduce technical variability. In addition, the
findings of the current retrospective studies need to be vali-
dated by larger prospective studies.
Clinical Applications of CEUS in the Aorta
CEUS is well placed to study aorta and improve the visu-
alization of different pathologies, such as stenosis, dissection,
and aortocaval fistula [27,28].
Furthermore, duplex US has also been investigated as an
alternative to CT scan for the follow up of postoperative pa-
tients after Endovascular Aneurysm Repair (EVAR). CEUS is
less expensive when compared with CT and does not have the
hazards of ionizing radiation or contrast-induced nephrotoxi-
city. Henao et al demonstrated the use of CEUS to detect the
endoleak successfully after EVAR and recommended CEUS
as the primary surveillance modality. However, a continuous
infusion of the contrast was administered to permit longer dura-
tion for imaging rather than a bolus dose [29]. Cantisani et al
[30] further supported the idea and concluded that CEUS is
similar to CT angiogram (CTA) and magnetic resonance angio-
gram (MRA) in diagnosing endoleaks after EVAR and con-
siders CEUS to be a feasible tool in the long-term surveillance
after EVAR. CEUS may eventually replace certain CTA exam-
inations during the post-EVAR surveillance protocol. The ad-
vantages of CEUS for the detection of endoleaks include
increased sensitivity for slow flow, greater spatial and temporal
resolution, and a real-time pattern of flow visualization [31].
Mirza et al conducted a meta-analysis on 21 studies in 2,601
patients and compared the US with CTA. However, only seven
studies of 21 compared CEUS vs. CTA. They concluded that
unenhanced US scans have poor sensitivity for detecting endo-
leaks after EVAR, whereas CEUS is a highly sensitive tool for
this purpose [32]. A 4-year retrospective study comprising of
318 CEUS, comparing to CTA, found that CEUS had 100%
sensitivity and 100% specificity in classifying endoleaks [33].
- (2019) 1-6 3
No differences in endoleak, reinterventions, and sac shrinkage
percentage were seen between the two groups at 4 years [34].
Similarly, a prospective study with 278 EVAR cases found
that CEUS and CTA were diagnostically equivalent. The sensi-
tivity and specificity of CEUS were 93%, and 95%, respec-
tively. This was confirmed by a meta-analysis compromising
of 1,099 patients [35]. CEUS has also been used intraopera-
tively during EVARS to detect endoleaks [36].
The evidence for the use of CEUS as the primary modality
in detecting endoleaks following EVAR is ever expanding, with
studies showing good sensitivity and specificity. However,
these results should still be interpreted with caution because
of heterogeneity in analysed trials. There is a clear need for a
definitive trial with appropriate sample size and good design
to evaluate it further. This will inform any decision to modify
guidelines about the primary imaging modality for detecting
endoleaks after EVAR and for continued surveillance.
CEUS can also be utilized in the diagnosis of aortic dissec-
tion. Aortic dissections account for most aortic emergencies.
A thorough history and physical examination are crucial in
the accurate diagnosis, which includes acute chest pain and a
difference in blood pressure in the arms or signs of organ
dysfunction. However, in the current practice, a definitive diag-
nosis relies on imaging, usually CTA with iodinated contrast
[37]. The first-line modality readily available in an acute setting
is US. US may be able to identify an aortic dissection and indi-
cate the need for a CTA examination. Contrast may increase the
detection of aortic dissections to allow earlier diagnosis and im-
mediate treatment for a better prognosis. However, once de-
tected, this should be followed by a CTA for further
characterization of the dissection, including Stanford classifica-
tion [31]. This approach will be cost saving to avoid unnecessary
CTA scans in every patient suspected of aortic dissection. In
addition, the use of nephrotoxic iodinated contrast agent will
also be reduced significantly in only selective patients identified
by CEUS. Studies have shown that adding contrast to transtho-
racic echocardiography increases the sensitivity and specificity
of that modality compared with conventional transthoracic
echocardiography, in some studies up to 100%, when using
CTA as reference [38,39].
Complementary to this, Liang et al [40] investigated the role
of CEUS compared with CTA in the follow-up of DeBakey
type III aortic dissection after thoracic endovascular aortic
repair. The two modalities produced similar false and true
lumen diameters. CEUS was less sensitive at detecting ruptures.
CEUS, however, had the advantage of clearly showing the he-
modynamic characteristics of abdominal aortic intimal tear,
the size and position of rupture, and the true or false lumen,
which ultimately provided more useful data for the long-term
abdominal aortic remodelling after thoracic endovascular aortic
repair.
Clinical Applications of CEUS in Peripheral Vascular
Disease
The National Institute for Health and Care Excellence
provides evidence-based guidelines on the prevention and
4 D.B. Thakrar and M.J. Sultan/Journal of Medical Imaging and Radiation Sciences
management on a number of conditions for health care pro-
fessionals in England. Current National Institute for Health
and Care Excellence guidelines offers US scan as first-line im-
aging modality to diagnose peripheral vascular disease fol-
lowed by MRA before any definitive treatment is offered [41].
At this time, CEUS has not been thoroughly evaluated to
assess its diagnostic efficacy for peripheral vascular disease,
compared with the carotid and aortic diseases. Duerschmied
et al introduced this novel technique in a pilot study. They
found that CEUS could provide additional relevant informa-
tion in the diagnosis of peripheral vascular disease [42].
Duerschmied et al suggested further evaluation with larger
sample size to further establish this particular technique.
Womack et al [43] further evaluated the technique and
concluded that CEUS could be potentially used to evaluate
the perfusion reserve in limb muscles and can diagnose pe-
ripheral vascular disease superiorly compared with noninva-
sive methods, especially in diabetics. Similarly, Mancini
et al [44] used CEUS to document the effects of smoking
on the peripheral microcirculation in diabetic patients by
looking at the microvascular blood flow in the gastrocnemius
muscle were evaluated. In addition, dynamic CEUS has suc-
cessfully been used to visualize the treatment-induced
improvement of muscular microperfusion in patients with pe-
ripheral arterial disease, who underwent lower limb angio-
plasty thrombendarterectomy or bypass surgery [45].
Other investigators have used animal models to investigate
the utility of CEUS in measuring the severity of peripheral
arterial disease by measuring blood flow reserve in limb skel-
etal muscle with CEUS [46,47]. Thomas et al, however,
found that within-individual reliability was poor (coefficient
of variation range: 15%–87%) when evaluating the reliability
of CEUS for the assessment of muscle perfusion and periph-
eral arterial health [48].
Similar to its use in carotid arteries, CEUS has been trialed
on animal femoral arteries to evaluate atherosclerosis (validated
by histology) to understand the relationship between vasa vaso-
rum and plaque vulnerability [49]. In essence, CEUS has great
potential in the assessment of the microcirculation of the skel-
etal muscle in patients with peripheral artery disease. This tech-
nique is still in the early stages with regards to the in-depth
evaluation of peripheral vascular disease. It may prove to have
both a therapeutic and diagnostic role in the future, but it needs
further evaluation through well-conducted clinical trials
comparing CEUS with MRA and conventional angiograms
for such a conclusion to be warranted.
Limitations of CEUS
A major limitation of CEUS, across all pathologies, is that
interpretation is user specific; hence, appropriate training and
quality control of sonographers are needed. Technique is
heavily operated dependent, and quality of images can vary
because of body habitus. Adverse effects have been reported,
and the most serious is anaphylactic reaction (1 in
100,000). Procedures involving arterial puncture could have
- (2019) 1-6
iatrogenic pseudoaneurysm, arteriovenous fistula, dissection,
or haematoma [50]. The learning curve is complex, so it
will take longer to completely replace the existing protocol
for EVAR surveillance. In addition, much of the evidence is
from small studies, subject to biases and interlaboratory vari-
ability. Hence, rigorous clinical trials are needed to validate
findings before implementing CEUS into routine practice.
Future Use of CEUS
In addition to its diagnostic role, there is some evidence in
animal models that contrast may exert a therapeutic effect.
Ebben et al [51], looking at porcine models of induced acute
peripheral arterial occlusion, comparing the administration of
urokinase (n ¼ 4) vs. urokinase plus microbubbles (n ¼ 6),
found that in the group receiving microbubbles, median
thrombus weights were lower, and microcirculation and lower
limb arterial pressure levels were greater than in the other
group. This suggests that CEUS increases the effects of low-
dose, intra-arterial thrombolysis in peripheral arterial occlu-
sion. Further investigation is needed, however, to better eluci-
date this conclusion.
Because of the unique properties of microbubbles to
enhance and quantify the macro- and micro-circulation,
CEUS has the potential to play a pivotal role in vascular med-
icine although its utility in diagnosis, risk stratification,
follow-up, and monitoring the effects of treatment. In some
instances, it can act in a complementary manner or as a pre-
cursor to CTA and MRA. There is also potential for CEUS to
be the primary modality in monitoring after EVAR. Better
designed clinical trials with adequate sample size are needed
to validate CEUS utility. The evidence, as discussed, is
encouraging and provides a solid foundation for future clin-
ical trials.
In addition, the use of microbubbles has great potential to
expand into the area of molecular processes involved in
vascular pathology. There is potential for a therapeutic role
through drug and gene administration using microbubble
contrast agents guided by US [10]. These unique possibilities
highlight the exciting future of US in vascular medicine.
Needless to say, as the modality is user specific, to maximize
the true diagnostic and therapeutic benefits of CEUS, stan-
dardized training of sonographers and clinicians in the areas
of device and contrast agent quality control is paramount.
Conclusions
Microbubble contrast agents have created new opportu-
nities for US. From the initial Doppler detection with micro-
bubble demonstrates that these types of clinical applications
are expanding. However, there are different levels of clinical
efficacy in each subclinical area of vascular ultrasonography.
The advantages of this modality are that it is relatively inex-
pensive compared with other modalities, requires no radiation
or nephrotoxic contrast, is noninvasive, and can be readily
available at the patients’ bedside.
D.B. Thakrar and M.J. Sultan/Journal of Medical Imaging and Radiation Sciences
Footnotes
Contributors: All authors contributed to the conception or
design of the work, the acquisition, analysis, or interpretation
of the data. All authors were involved in drafting and com-
menting on the paper and have approved the final version.
Funding: This study did not receive any specific grant
from funding agencies in the public, commercial, or not-
for-profit sectors.
Competing interests: All authors declare: no financial rela-
tionships with any organizations that might have an interest in
the submitted work in the previous three years; no other rela-
tionships or activities that could appear to have influenced the
submitted work.
Ethical approval: Not required.
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