- Email: [email protected]
Contrast-Enhanced Ultrasound in Vascular Surgery: Review and Update
Accepted Manuscript Contrast Enhanced Ultrasound in Vascular Surgery: Review and Update K. Bredahl, X.M. Mestre, R.V. Coll, Q.M. Ghulam, H. Sillesen, J. Eiberg PII:
S0890-5096(17)30220-0
DOI:
10.1016/j.avsg.2017.05.032
Reference:
AVSG 3416
To appear in:
Annals of Vascular Surgery
Received Date: 15 February 2017 Revised Date:
19 May 2017
Accepted Date: 26 May 2017
Please cite this article as: Bredahl K, Mestre X, Coll R, Ghulam Q, Sillesen H, Eiberg J, Contrast Enhanced Ultrasound in Vascular Surgery: Review and Update, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2017.05.032. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Contrast Enhanced Ultrasound in Vascular Surgery: Review and Update
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K Bredahl (1), XM Mestre (2), RV Coll (2), QM Ghulam (1,3), H Sillesen (1,3), J Eiberg
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(1,3,4)
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1) Department of Vascular Surgery, Rigshospitalet, University of Copenhagen, Denmark
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2) Department of Vascular Surgery, Hospital Universitari de Bellvitge, Barcelona, Spain
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3) Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen,
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Denmark
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4) Copenhagen Academy for Medical Education and Simulation (CAMES), Rigshospitalet,
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Copenhagen, Denmark.
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Corresponding author
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Jonas Eiberg, MD, Ph.D.
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Department of Vascular Surgery, Rigshospital-3111, Blegdamsvej 9, 2100 Copenhagen,
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Denmark.
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Phone: +45 35 45 66 24
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Fax: + 45 35 45 31 11
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Email: [email protected]
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Category: topical review
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Running head: CEUS in Vascular Surgery
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No funding for research or publication has taken place
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Word count: 3200 ex. refs. / 5300 incl. refs.
ACCEPTED MANUSCRIPT Abstract
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Accurate imaging methods associated with minimum patient risk are important tools for
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clinical decision-making in vascular surgery. Today, traditional imaging methods, such as
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computed tomography angiography, magnetic resonance angiography and digital
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subtraction angiography are the preferred modalities. Ultrasound has only challenged
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these methods in assessment of carotid disease, aortic aneurysms, venous insufficiency
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and thromboembolism and in surveillance of in-situ bypasses. These practice patterns
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may change with the introduction of second generation ultrasound contrast agents which
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are easy to use, manageable and safe. This topical review attempt to summarize and
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highlight the current evidence and future prospects for contrast-enhanced ultrasound in
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vascular surgery, with a particular focus on opportunities in carotid and lower limb
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arteriosclerotic disease and surveillance after endovascular aneurysm repair.
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Keywords: Ultrasound; ultrasound-contrast; vascular ultrasound; duplex; vascular surgery;
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arteries, carotid, lower limb, EVAR, abdominal aneurysm
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ACCEPTED MANUSCRIPT Introduction
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There are many good reasons why vascular surgeons should be armed with ultrasound as
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a "point of care diagnostic method" which enables them to perform vascular imaging in
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real time at bedside. The core concept is to bring the diagnostic tools close to the patient
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and, in turn, to empower clinicians to obtain timely and accurate diagnoses. This bedside
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tool also allows a patient to gain a better understanding of his/her condition and to provide
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consent to future treatment. The use of ultrasound contrast agents (UCA) has the potential
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to take this development further. Contrast-enhanced ultrasound (CEUS) was introduced
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for vascular imaging several decades ago, but its role in the specialty remains still
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somewhat elusive. In the early CEUS era, the technique was hampered by the necessity
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of continuous contrast infusion and short-lived enhancement. However, today UCA can be
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given as a single bolus and repeated if necessary. Moreover, many ultrasound systems
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have a “built-in” contrast mode that optimizes the contrast signal and works by acoustic
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filters for suppression of non-UCA signals and a low mechanical index to reduce the
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destruction of the gas-bubbles. The simplicity and low cost of UCA as well as the better
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availability of ultrasound systems have increased the demand for this imaging tool in
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vascular surgery.
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The aim of this topical review is to summarize the existing and, in some cases, scant
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evidence for CEUS from a surgeon's perspective with a focus on opportunities within
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carotid, lower limb and surveillance after endovascular aneurysm repair (EVAR).
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Ultrasound contrast agents
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An UCA is a suspension of microbubbles filled with inert gas. These microbubbles are not trapped in the capillaries and, unlike previous contrast agents, they overcome the
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ACCEPTED MANUSCRIPT mechanical stress of the heart valves, allowing longer contrast enhancement1. Ultrasound
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contrast agents are not nephrotoxic and are exhaled with a T½ elimination of 6 minutes 2.
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The most important UCA’s in clinical practice come from a family of perfluoro gas-
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containing agents that use phospholipids as a membrane. They are indicated for non-
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cardiac imaging in cases where conventional ultrasound results in suboptimal
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visualization3.The effect of UCAs derives from two principles. First, in an ultrasound field
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the microbubbles emit a specific “bubble signal” which is distinct from tissue echoes.
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Second, the difference in acoustic impedance between blood and gas improves the signal-
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to-noise ratio. As such, CEUS depends less on insonation angle and the detection of low
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blood flow is improved.
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Ultrasound contrast agents are injected intravenously through an antecubital venous
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catheter (>20 gauge) resulting in arterial contrast-enhancement within 10-20 seconds. The
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dose required depends on the region or organ of interest4.
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In general, UCA’s are well-tolerated and the rate of life-threatening events is less than
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1/10.000 for non-cardiac imaging and is notably lower than the risk associated with
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iodinated contrast agents5. Special precautions must be taken in patients with acute
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coronary syndrome or pulmonary hypertension, unstable angina, acute or chronic (class
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III/IV) heart failure and severe rhythm disorders6. Taking these precautions, contrast-
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enhanced echocardiography is not associated with increased mortality7. Given that all
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reported life-threatening events (i.e. anaphylactic reactions) have occurred promptly after
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UCA administration, access to resuscitation facilities, and observation for approximately 15
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minutes after administration, is mandatory. Special precautions should be taken in patients
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suffering from acute coronary syndrome, pulmonary hypertension, unstable angina, acute
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or chronic heart failure (class III/IV) and severe cardiac arrhythmia5.
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Contrast enhanced ultrasound of the carotid arteries
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When CEUS became clinically available, carotid duplex ultrasound (DUS) was already
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established as a very accurate diagnostic method for the assessment of carotid artery
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disease. Carotid DUS makes it possible to assess the degree of stenosis and to
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distinguish between normal and diseased vessels with excellent sensitivity and specificity
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which in some cases could be challenging, was thought to be an area for CEUS9.
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Symptomatic patients with carotid stenosis may benefit from carotid endarterectomy,
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whereas those with occlusion may risk adverse outcomes if managed surgically. This stark
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contrast highlights the importance of accurately distinguishing between severe stenosis
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and occlusion. Although CEUS enhances the visualization of the lumen, the use of
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. For a period of time, the crucial distinction between severe stenosis and occlusion,
contrast only slightly reduced the frequency of inconclusive scans. For this reason CEUS
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failed to become an important tool for the imaging of carotid stenosis10. Moreover, with
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advances in computed tomography angiography (CTA), additional imaging was performed
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in symptomatic patients with uncertainty in their ultrasound diagnosis. As a result, the
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utilization of UCA was directed towards other applications within carotid DUS, such as
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improving the identification of small and unidentified plaques, assessment of plaque
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surface and ulceration as well as intra-plaque vascularization, all with the intent of
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improving risk stratification. Identification of carotid surface disruption suggestive of
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plaque ulceration, a marker traditionally correlated with increased risk of stroke, improved
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with the use of CEUS11. In a study of 100 asymptomatic persons with more than one risk
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factor for atherosclerosis, CEUS identified plaques in additional 10% of the patients that
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were missed by DUS, albeit, not validated by other imaging methods12.
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ACCEPTED MANUSCRIPT Most recently, CEUS has been used to explore plaque vascularization, with the thought
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that contrast-enhancement within the plaque could be a sign of increased activity, due to
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vulnerability (inflammation) or stabilization (repair). Intra-plaque vascularization visualized
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by CEUS was first described in 200613 and, subsequently, followed by several
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investigations studying the relationships between plaque vascularization and plaque
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morphology, histology, micro-embolic signals by transcranial Doppler monitoring, positron
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emission tomography (PET) and clinical outcomes. Carotid plaque studies using DUS
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indicated that differences in echo-pattern reflect differences in the histological composition
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of the plaque. It has been shown that differences in heterogeneity and echolucency seem
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to predict worse outcomes with respect to the risk of future ipsilateral cerebrovascular
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events 14–16. Plaque echogenicity, expressed as gray-scale median (GSM), demonstrates
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a positive correlation with UCA-uptake in the plaque, as shown in a “contrast quantification
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program” (CQP).17 Moreover, patients with ipsilateral TIA or stroke have higher CQP-
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values than asymptomatic patients17. Similarly, a higher rate of UCA uptake was found in
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echolucent plaque types18 and micro-embolic signals are typically more prevalent in
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patients with carotid plaques showing contrast uptake as compared to those without19.
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Functional imaging studies, such as FDG-PET, have shown greater FDG uptake in
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echolucent plaques supporting the hypothesis of increased metabolic activity in vulnerable
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plaques20 21 . Furthermore, histological analysis of surgically removed specimens has
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revealed positive correlations between UCA uptake and the proportion of inflammatory
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cells22. A similar correlation between UCA uptake and microvessel density has been
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demonstrated 23.
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To date, there are no published studies evaluating the effect of contrast uptake in carotid
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plaques as way to predict future ipsilateral cerebrovascular events. Two Japanese studies
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the first study, a high grade of visual contrast uptake was found to correlate with disease
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complexity on coronary angiograms and with a higher risk of acute coronary syndrome 24 .
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In a subsequent study, using contrast uptake quantification, it was confirmed that plaque
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UCA uptake is positively correlated with cardiac events during follow-up25. An important
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limitation for both of these studies is that 2D ultrasound is unable to visualize the entire
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plaque in contrast to other methods, including PET and histology.
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In summary, the addition of CEUS to high quality duplex-US for improved carotid stenosis
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assessment is limited and is primarily a tool in carotid plaque research.
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CEUS of lower limb occlusive disease
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While magnetic resonance angiography (MRA) and CTA have become more widely used,
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digital subtraction angiography (DSA) is still considered the gold standard for the
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evaluation of lower limb ischemia prior revascularization26. Duplex ultrasound, as a non-
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invasive and low-cost modality, is increasingly utilized for evaluation of peripheral arterial
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disease and it demonstrates good agreement with DSA 27–30. Using duplex ultrasound as
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the primarily imaging modality, the concept of a “one-stop clinic” could be made available
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to many newly referred patients, who subsequently leave the outpatient clinic with a
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diagnosis, a treatment plan and a date for surgery31,32. Unfortunately, in patients with
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multilevel disease and slow flow, DUS can be associated with poor diagnostic accuracy
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when attempting to visualize the tibioperoneal trunk and the origin of the crural arteries27.
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In these inconclusive DUS studies, CEUS has proved to be a valuable adjunct by
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identifying the most optimal runoff and, in most cases, ensuring patency of the
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tibioperoneal trunk32. In two recent large studies of critical limb ischemia, with 622 and 565
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DUS alone was possible in 87% and 84% of the patients – without the aid of CEUS32,33 .
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With the addition of CEUS and the use of surgical findings as the gold standard it was
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possible to improve the diagnostic accuracy from 87% to 95% 32. Thus, in the hands of
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experienced “lower limb sonographers”, CEUS can “rescue” an otherwise non-diagnostic
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DUS of the proximal crural arteries. Several studies have compared segments of the crural
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arteries, and demonstrated a 35% to 70% improvement in diagnostic accuracy when
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adding CEUS to DUS, using DSA as the gold standard32,34–37. The number of inconclusive
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DUS examinations of target vessels for bypass surgery were, furthermore, significantly
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reduced with the use of CEUS32,34,36. Additionally, CEUS is the obvious modality in
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patients with compromised renal function where both iodine and gadolinium based
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contrast are problematic.
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In recent studies, one or maximally two, intravenous bolus-injections of approximately 2,5
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ml of a second generation UCA (SonoVue, Bracco, Milan, Italy) were sufficient for most
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lower limb arterial segments32,37The non-diagnostic segments were scrutinized during
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approximately 5 minutes of contrast enhancement per injected contrast bolus. Only the
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most recent studies have used a built-in contrast application32 as opposed to the earlier
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where the ultrasound system “only” were adjusted to low flow patterns35.
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Using DUS, the diagnostic criteria are mainly hemodynamic (velocity-increase indicating
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stenosis), whereas in CEUS the diagnostic criteria are mainly morphologic, i.e. the vessel
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is patent or not.
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In summary, CEUS serves as a means of ”rescuing” inconclusive DUS exams in
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peripheral arterial disease (PAD). This can rationalize the need for more invasive
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investigations and further expand the concept of the “one-stop vascular clinic”.
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EVAR surveillance
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For patients suffering from an abdominal aortic aneurysm with a suitable anatomy, EVAR
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is becoming the preferred treatment option for elective repair. Endoleaks are a lifelong
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concern, and in order to prevent rupture, continued surveillance is recommended38,39. For
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EVAR surveillance, CTA is the most commonly used imaging modality, but it is limited by
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cumulative radiation burden, missing hemodynamic information and unsuitability for
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patients with compromised renal function40. Surveillance using DUS is associated with
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different challenges and not only dependent on operators experience but also by the
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patient’s body habitus, fasting status and artefacts caused by the hyperechoic EVAR
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device and the surrounding bowel. Moreover, wall filters aimed at reducing noise may
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unintentionally block important low flow signals and in turn mask endoleaks.
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It’s been shown that CEUS has a higher accuracy than DUS for endoleaks detection. 41,
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and that its accuracy is similar to CTA, 41–43. Moreover, a recent systematic review
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concluded that CEUS was able to detec significantly more endoleaks than CTA, but mainly
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type II, with similar results for type I and III endoleaks44. Compared with a biphasic CTA,
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CEUS has a unique ability to image delayed type II endoleaks which is seen as a subtle
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echo-enhancement several minutes after UCA injection45. This unique delayed
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enhancement may also explain why the majority of endoleaks detected by CEUS (and not
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by DUS) are mainly clinically unimportant endoleaks type II (at least in intermediate follow-
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up)46. It has also been pointed out that CEUS is more effective than CTA in visualizing the
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origin of the endoleak47. Thus, the decision to use CEUS, instead of DUS and CTA,
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depends in some degree on how aggressive type II endoleaks are handled. In a
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retrospective single centre study with more than 900 patients, approximately one fifth
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other hand, several studies, including the EVAR trials, report that delayed rupture is rare
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but usually associated with persistent type II endoleak 49–51. To date, most will agree that
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the most important element in a surveillance program is sac diameter, leaving endoleak
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detection with more sophisticated studies such as CEUS for cases with a growing sac. In
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addition, ultrasound is unable to accurately detect migration or stent fracture and this is
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why EVAR surveillance with US should always be complemented with plain X-ray 51.
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There is no consensus regarding continuous infusion or bolus injection, nor which dosage
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is preferable, with a range from 1 ml to 2.5 m42,43,52,53. In our experience, one or two
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intravenous injections of 1 ml UCA is sufficient in most cases, with injection of the second
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bolus when the first contrast-enhancement fades, typically after < 5 minutes. Similarly to
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colour Doppler, that a delay in appearance helps to differentiate the type of endoleak,
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during contrast-enhancement, endoleaks related to the stent-graft (type I and III) or from
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patent lumbar or mesenteric artery (type II), can often be distinguished by wash-in time.
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Since type II endoleaks are retrograde and fill through aortic collaterals, wash-in time will
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be delayed compared to type I and type III, as characterized by simultaneous contrast
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enhancement in both sac and stent-graft54. European Federation for Societies in
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Ultrasound Medicine and Biology (EFSUMB) recommends CEUS for endoleak detection
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with the highest evidence level55. Despite the supporting evidence favouring CEUS instead
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of CTA, routine use of CEUS seems limited to dedicated centres 16–18, 22 ,23.
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Educational considerations
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Strategies for teaching and implementing CEUS are not well-described. In general,
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however, it seems appropriate to distinguish between technically easy and difficult
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with significant risk 30. In situations when conventional ultrasound has failed, we consider
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the use of CEUS in peripheral arterial disease and EVAR to be among the most
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challenging. In addition to being able to administer the contrast and having a basic
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theoretical knowledge of CEUS, one should have mastered the unenhanced parallel
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before attempting the CEUS version. In our experience, most will master the technique in
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lower limb and EVAR after approximately 100 supervised unenhanced examinations.
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Adding another 20-50 supervised CEUS examinations would be enough to acquire
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expertise to perform these examinations.
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Ultrasound examination of PAD and EVAR patients has often been considered to be too
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time-consuming, time that of course is not diminished by adding UCA. We acknowledge
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that an ultrasound of crural arteries with low or absent flow, as well as an ultrasound of an
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obese or otherwise difficult EVAR patient, places demands on sonographers and planning
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with respect to experience, skills, training, supervision and duration of the exam.
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Nevertheless, the alternatives do not reduce procedure time (for the patient) or procedure
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related risks. All in all, having vascular ultrasound, with or without UCA, based in the
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vascular surgical clinic and performed by vascular surgeons or sonographers seems most
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appropriate.
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Future perspectives
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In EVAR-surveillance, the role of CEUS spans from being integrated into the standard
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surveillance programme to serving as an adjunct, if at all. It is well documented that CEUS
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can detect type II endoleak in EVAR patients with sac-expansion even when DUS and
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CTA were without leak41,45. Future studies should address the long-term clinical
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ACCEPTED MANUSCRIPT consequences of missing an endoleak type II by ultrasound and CEUS, and identify what
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and when to treat56,57. In our experience, an endoleak type II missed by CEUS is less likely
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to lead to reintervention than endoleak type II missed by DUS58.
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In carotid imaging, we foresee that contrast-enhanced 3D ultrasound (3D-CEUS) will lead
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to better risk prediction and monitoring of disease, since UCA-uptake seems to highlight
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processes related to plaque vulnerability. Future “intelligent UCA” containing “targeted”
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microbubbles is likely to open up a new field of research in carotid imaging and provide
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opportunities for earlier diagnosis and treatment of plaques with increased inflammatory
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activity and vulnerability59,60.
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In research settings, CEUS has been used to correlate muscular perfusion with ankle
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pressure, clinical stage and revascularization61,62. Studying muscular flow reserve with
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CEUS with the use of parameters such as “time to peak intensity” or “washout time”, can
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objectively assess the effect of contractile exercise, pharmacologic vasodilatation and
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revascularization - and potentially measure the outcome of stem-cell infusion,
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hemorheologic drugs etc62.
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Conclusion
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Currently, the role of CEUS in the routine vascular testing landscape is primarily limited to
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EVAR surveillance, where it remains unclear whether CEUS should be first choice or aid
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inadequate DUS examinations. For lower extremities, CEUS undoubtedly also has a role
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to play, but here DUS alone is sufficient for the evaluation of the vast majority of patients.
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Again, CEUS can be considered as a supplement, if and when conventional DUS studies
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fails. In both situations, CEUS is characterized by being accurate and sensitive for
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detection of very slow flow. The clinical usefulness of CEUS in carotid disease is more
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uncertain at present, however, it appears to be a promising research tool.
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Acknowledgements
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The authors would like to thank Dr. Kirsten Engel, CAMES, Copenhagen, for help in
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proofreading the manuscript.
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Conflict of interest
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Co-author Sillesen H. has received research grant from Philips Ultrasound. No other
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potential conflicts of interest exist.
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Karthikesalingam A, Page AA, Pettengell C, Hinchliffe RJ, Loftus IM, Thompson MM, et al.
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Heterogeneity in Surveillance after Endovascular Aneurysm Repair in the UK. Eur J Vasc Endovasc
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magnetic resonance in detecting endoleak after endovascular abdominal aortic aneurysm repair. Eur
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EVAR. Eur J Vasc Endovasc Surg 2011;42(6):797–802. Doi: 10.1016/j.ejvs.2011.09.003.
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Abdominal Aortic Aneurysm Repair. JVIR 2010;21:638–43. Doi: 10.1016/j.jvir.2010.01.032.
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Wyss TR, Brown LC, Powell JT, Greenhalgh RM. Rate and predictability of graft rupture after
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endovascular and open abdominal aortic aneurysm repair: data from the EVAR Trials. Ann Surg
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aneurysm repair 2008;39:121–32. Doi: 10.3233/CH-2008-1075.
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abdominal aortic aneurysm repair. J Vasc Surg 2009;49(3):552–60. Doi: 10.1016/j.jvs.2008.10.008. 54
Carrafiello G, Laganà D, Recaldini C, Mangini M, Bertolotti E, Caronno R, et al. Comparison of
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contrast-enhanced ultrasound and computed tomography in classifying endoleaks after endovascular
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treatment of abdominal aorta aneurysms: preliminary experience. Cardiovasc Intervent Radiol
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evidence is insufficient to define an optimal threshold for intervention in isolated type II endoleak after
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endovascular aneurysm repair. J Endovasc Ther an Off J Int Soc Endovasc Spec 2012;19(2):200–8.
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Replace Computed Tomography Angiography for Surveillance After Endovascular Aortic Aneurysm
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S0890-5096(17)30220-0
DOI:
10.1016/j.avsg.2017.05.032
Reference:
AVSG 3416
To appear in:
Annals of Vascular Surgery
Received Date: 15 February 2017 Revised Date:
19 May 2017
Accepted Date: 26 May 2017
Please cite this article as: Bredahl K, Mestre X, Coll R, Ghulam Q, Sillesen H, Eiberg J, Contrast Enhanced Ultrasound in Vascular Surgery: Review and Update, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2017.05.032. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 2
Contrast Enhanced Ultrasound in Vascular Surgery: Review and Update
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K Bredahl (1), XM Mestre (2), RV Coll (2), QM Ghulam (1,3), H Sillesen (1,3), J Eiberg
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(1,3,4)
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1) Department of Vascular Surgery, Rigshospitalet, University of Copenhagen, Denmark
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2) Department of Vascular Surgery, Hospital Universitari de Bellvitge, Barcelona, Spain
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3) Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen,
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Denmark
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4) Copenhagen Academy for Medical Education and Simulation (CAMES), Rigshospitalet,
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Copenhagen, Denmark.
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Corresponding author
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Jonas Eiberg, MD, Ph.D.
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Department of Vascular Surgery, Rigshospital-3111, Blegdamsvej 9, 2100 Copenhagen,
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Denmark.
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Phone: +45 35 45 66 24
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Fax: + 45 35 45 31 11
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Email: [email protected]
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Category: topical review
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Running head: CEUS in Vascular Surgery
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No funding for research or publication has taken place
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Word count: 3200 ex. refs. / 5300 incl. refs.
ACCEPTED MANUSCRIPT Abstract
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Accurate imaging methods associated with minimum patient risk are important tools for
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clinical decision-making in vascular surgery. Today, traditional imaging methods, such as
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computed tomography angiography, magnetic resonance angiography and digital
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subtraction angiography are the preferred modalities. Ultrasound has only challenged
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these methods in assessment of carotid disease, aortic aneurysms, venous insufficiency
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and thromboembolism and in surveillance of in-situ bypasses. These practice patterns
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may change with the introduction of second generation ultrasound contrast agents which
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are easy to use, manageable and safe. This topical review attempt to summarize and
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highlight the current evidence and future prospects for contrast-enhanced ultrasound in
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vascular surgery, with a particular focus on opportunities in carotid and lower limb
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arteriosclerotic disease and surveillance after endovascular aneurysm repair.
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Keywords: Ultrasound; ultrasound-contrast; vascular ultrasound; duplex; vascular surgery;
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arteries, carotid, lower limb, EVAR, abdominal aneurysm
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ACCEPTED MANUSCRIPT Introduction
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There are many good reasons why vascular surgeons should be armed with ultrasound as
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a "point of care diagnostic method" which enables them to perform vascular imaging in
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real time at bedside. The core concept is to bring the diagnostic tools close to the patient
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and, in turn, to empower clinicians to obtain timely and accurate diagnoses. This bedside
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tool also allows a patient to gain a better understanding of his/her condition and to provide
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consent to future treatment. The use of ultrasound contrast agents (UCA) has the potential
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to take this development further. Contrast-enhanced ultrasound (CEUS) was introduced
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for vascular imaging several decades ago, but its role in the specialty remains still
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somewhat elusive. In the early CEUS era, the technique was hampered by the necessity
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of continuous contrast infusion and short-lived enhancement. However, today UCA can be
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given as a single bolus and repeated if necessary. Moreover, many ultrasound systems
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have a “built-in” contrast mode that optimizes the contrast signal and works by acoustic
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filters for suppression of non-UCA signals and a low mechanical index to reduce the
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destruction of the gas-bubbles. The simplicity and low cost of UCA as well as the better
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availability of ultrasound systems have increased the demand for this imaging tool in
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vascular surgery.
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The aim of this topical review is to summarize the existing and, in some cases, scant
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evidence for CEUS from a surgeon's perspective with a focus on opportunities within
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carotid, lower limb and surveillance after endovascular aneurysm repair (EVAR).
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Ultrasound contrast agents
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An UCA is a suspension of microbubbles filled with inert gas. These microbubbles are not trapped in the capillaries and, unlike previous contrast agents, they overcome the
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contrast agents are not nephrotoxic and are exhaled with a T½ elimination of 6 minutes 2.
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The most important UCA’s in clinical practice come from a family of perfluoro gas-
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containing agents that use phospholipids as a membrane. They are indicated for non-
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cardiac imaging in cases where conventional ultrasound results in suboptimal
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visualization3.The effect of UCAs derives from two principles. First, in an ultrasound field
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the microbubbles emit a specific “bubble signal” which is distinct from tissue echoes.
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Second, the difference in acoustic impedance between blood and gas improves the signal-
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to-noise ratio. As such, CEUS depends less on insonation angle and the detection of low
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blood flow is improved.
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Ultrasound contrast agents are injected intravenously through an antecubital venous
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catheter (>20 gauge) resulting in arterial contrast-enhancement within 10-20 seconds. The
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dose required depends on the region or organ of interest4.
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In general, UCA’s are well-tolerated and the rate of life-threatening events is less than
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1/10.000 for non-cardiac imaging and is notably lower than the risk associated with
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iodinated contrast agents5. Special precautions must be taken in patients with acute
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coronary syndrome or pulmonary hypertension, unstable angina, acute or chronic (class
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III/IV) heart failure and severe rhythm disorders6. Taking these precautions, contrast-
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enhanced echocardiography is not associated with increased mortality7. Given that all
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reported life-threatening events (i.e. anaphylactic reactions) have occurred promptly after
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UCA administration, access to resuscitation facilities, and observation for approximately 15
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minutes after administration, is mandatory. Special precautions should be taken in patients
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suffering from acute coronary syndrome, pulmonary hypertension, unstable angina, acute
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or chronic heart failure (class III/IV) and severe cardiac arrhythmia5.
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Contrast enhanced ultrasound of the carotid arteries
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When CEUS became clinically available, carotid duplex ultrasound (DUS) was already
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established as a very accurate diagnostic method for the assessment of carotid artery
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disease. Carotid DUS makes it possible to assess the degree of stenosis and to
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distinguish between normal and diseased vessels with excellent sensitivity and specificity
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which in some cases could be challenging, was thought to be an area for CEUS9.
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Symptomatic patients with carotid stenosis may benefit from carotid endarterectomy,
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whereas those with occlusion may risk adverse outcomes if managed surgically. This stark
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contrast highlights the importance of accurately distinguishing between severe stenosis
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and occlusion. Although CEUS enhances the visualization of the lumen, the use of
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. For a period of time, the crucial distinction between severe stenosis and occlusion,
contrast only slightly reduced the frequency of inconclusive scans. For this reason CEUS
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failed to become an important tool for the imaging of carotid stenosis10. Moreover, with
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advances in computed tomography angiography (CTA), additional imaging was performed
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in symptomatic patients with uncertainty in their ultrasound diagnosis. As a result, the
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utilization of UCA was directed towards other applications within carotid DUS, such as
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improving the identification of small and unidentified plaques, assessment of plaque
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surface and ulceration as well as intra-plaque vascularization, all with the intent of
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improving risk stratification. Identification of carotid surface disruption suggestive of
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plaque ulceration, a marker traditionally correlated with increased risk of stroke, improved
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with the use of CEUS11. In a study of 100 asymptomatic persons with more than one risk
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factor for atherosclerosis, CEUS identified plaques in additional 10% of the patients that
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were missed by DUS, albeit, not validated by other imaging methods12.
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that contrast-enhancement within the plaque could be a sign of increased activity, due to
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vulnerability (inflammation) or stabilization (repair). Intra-plaque vascularization visualized
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by CEUS was first described in 200613 and, subsequently, followed by several
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investigations studying the relationships between plaque vascularization and plaque
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morphology, histology, micro-embolic signals by transcranial Doppler monitoring, positron
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emission tomography (PET) and clinical outcomes. Carotid plaque studies using DUS
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indicated that differences in echo-pattern reflect differences in the histological composition
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of the plaque. It has been shown that differences in heterogeneity and echolucency seem
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to predict worse outcomes with respect to the risk of future ipsilateral cerebrovascular
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events 14–16. Plaque echogenicity, expressed as gray-scale median (GSM), demonstrates
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a positive correlation with UCA-uptake in the plaque, as shown in a “contrast quantification
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program” (CQP).17 Moreover, patients with ipsilateral TIA or stroke have higher CQP-
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values than asymptomatic patients17. Similarly, a higher rate of UCA uptake was found in
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echolucent plaque types18 and micro-embolic signals are typically more prevalent in
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patients with carotid plaques showing contrast uptake as compared to those without19.
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Functional imaging studies, such as FDG-PET, have shown greater FDG uptake in
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echolucent plaques supporting the hypothesis of increased metabolic activity in vulnerable
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plaques20 21 . Furthermore, histological analysis of surgically removed specimens has
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revealed positive correlations between UCA uptake and the proportion of inflammatory
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cells22. A similar correlation between UCA uptake and microvessel density has been
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demonstrated 23.
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To date, there are no published studies evaluating the effect of contrast uptake in carotid
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plaques as way to predict future ipsilateral cerebrovascular events. Two Japanese studies
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the first study, a high grade of visual contrast uptake was found to correlate with disease
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complexity on coronary angiograms and with a higher risk of acute coronary syndrome 24 .
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In a subsequent study, using contrast uptake quantification, it was confirmed that plaque
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UCA uptake is positively correlated with cardiac events during follow-up25. An important
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limitation for both of these studies is that 2D ultrasound is unable to visualize the entire
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plaque in contrast to other methods, including PET and histology.
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In summary, the addition of CEUS to high quality duplex-US for improved carotid stenosis
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assessment is limited and is primarily a tool in carotid plaque research.
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CEUS of lower limb occlusive disease
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While magnetic resonance angiography (MRA) and CTA have become more widely used,
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digital subtraction angiography (DSA) is still considered the gold standard for the
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evaluation of lower limb ischemia prior revascularization26. Duplex ultrasound, as a non-
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invasive and low-cost modality, is increasingly utilized for evaluation of peripheral arterial
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disease and it demonstrates good agreement with DSA 27–30. Using duplex ultrasound as
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the primarily imaging modality, the concept of a “one-stop clinic” could be made available
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to many newly referred patients, who subsequently leave the outpatient clinic with a
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diagnosis, a treatment plan and a date for surgery31,32. Unfortunately, in patients with
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multilevel disease and slow flow, DUS can be associated with poor diagnostic accuracy
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when attempting to visualize the tibioperoneal trunk and the origin of the crural arteries27.
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In these inconclusive DUS studies, CEUS has proved to be a valuable adjunct by
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identifying the most optimal runoff and, in most cases, ensuring patency of the
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tibioperoneal trunk32. In two recent large studies of critical limb ischemia, with 622 and 565
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DUS alone was possible in 87% and 84% of the patients – without the aid of CEUS32,33 .
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With the addition of CEUS and the use of surgical findings as the gold standard it was
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possible to improve the diagnostic accuracy from 87% to 95% 32. Thus, in the hands of
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experienced “lower limb sonographers”, CEUS can “rescue” an otherwise non-diagnostic
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DUS of the proximal crural arteries. Several studies have compared segments of the crural
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arteries, and demonstrated a 35% to 70% improvement in diagnostic accuracy when
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adding CEUS to DUS, using DSA as the gold standard32,34–37. The number of inconclusive
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DUS examinations of target vessels for bypass surgery were, furthermore, significantly
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reduced with the use of CEUS32,34,36. Additionally, CEUS is the obvious modality in
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patients with compromised renal function where both iodine and gadolinium based
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contrast are problematic.
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In recent studies, one or maximally two, intravenous bolus-injections of approximately 2,5
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ml of a second generation UCA (SonoVue, Bracco, Milan, Italy) were sufficient for most
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lower limb arterial segments32,37The non-diagnostic segments were scrutinized during
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approximately 5 minutes of contrast enhancement per injected contrast bolus. Only the
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most recent studies have used a built-in contrast application32 as opposed to the earlier
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where the ultrasound system “only” were adjusted to low flow patterns35.
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Using DUS, the diagnostic criteria are mainly hemodynamic (velocity-increase indicating
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stenosis), whereas in CEUS the diagnostic criteria are mainly morphologic, i.e. the vessel
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is patent or not.
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In summary, CEUS serves as a means of ”rescuing” inconclusive DUS exams in
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peripheral arterial disease (PAD). This can rationalize the need for more invasive
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investigations and further expand the concept of the “one-stop vascular clinic”.
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EVAR surveillance
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For patients suffering from an abdominal aortic aneurysm with a suitable anatomy, EVAR
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is becoming the preferred treatment option for elective repair. Endoleaks are a lifelong
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concern, and in order to prevent rupture, continued surveillance is recommended38,39. For
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EVAR surveillance, CTA is the most commonly used imaging modality, but it is limited by
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cumulative radiation burden, missing hemodynamic information and unsuitability for
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patients with compromised renal function40. Surveillance using DUS is associated with
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different challenges and not only dependent on operators experience but also by the
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patient’s body habitus, fasting status and artefacts caused by the hyperechoic EVAR
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device and the surrounding bowel. Moreover, wall filters aimed at reducing noise may
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unintentionally block important low flow signals and in turn mask endoleaks.
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It’s been shown that CEUS has a higher accuracy than DUS for endoleaks detection. 41,
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and that its accuracy is similar to CTA, 41–43. Moreover, a recent systematic review
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concluded that CEUS was able to detec significantly more endoleaks than CTA, but mainly
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type II, with similar results for type I and III endoleaks44. Compared with a biphasic CTA,
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CEUS has a unique ability to image delayed type II endoleaks which is seen as a subtle
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echo-enhancement several minutes after UCA injection45. This unique delayed
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enhancement may also explain why the majority of endoleaks detected by CEUS (and not
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by DUS) are mainly clinically unimportant endoleaks type II (at least in intermediate follow-
204
up)46. It has also been pointed out that CEUS is more effective than CTA in visualizing the
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origin of the endoleak47. Thus, the decision to use CEUS, instead of DUS and CTA,
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depends in some degree on how aggressive type II endoleaks are handled. In a
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retrospective single centre study with more than 900 patients, approximately one fifth
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ACCEPTED MANUSCRIPT developed type II endoleak without any increase in aneurysm-related mortality48. On the
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other hand, several studies, including the EVAR trials, report that delayed rupture is rare
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but usually associated with persistent type II endoleak 49–51. To date, most will agree that
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the most important element in a surveillance program is sac diameter, leaving endoleak
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detection with more sophisticated studies such as CEUS for cases with a growing sac. In
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addition, ultrasound is unable to accurately detect migration or stent fracture and this is
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why EVAR surveillance with US should always be complemented with plain X-ray 51.
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There is no consensus regarding continuous infusion or bolus injection, nor which dosage
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is preferable, with a range from 1 ml to 2.5 m42,43,52,53. In our experience, one or two
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intravenous injections of 1 ml UCA is sufficient in most cases, with injection of the second
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bolus when the first contrast-enhancement fades, typically after < 5 minutes. Similarly to
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colour Doppler, that a delay in appearance helps to differentiate the type of endoleak,
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during contrast-enhancement, endoleaks related to the stent-graft (type I and III) or from
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patent lumbar or mesenteric artery (type II), can often be distinguished by wash-in time.
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Since type II endoleaks are retrograde and fill through aortic collaterals, wash-in time will
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be delayed compared to type I and type III, as characterized by simultaneous contrast
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enhancement in both sac and stent-graft54. European Federation for Societies in
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Ultrasound Medicine and Biology (EFSUMB) recommends CEUS for endoleak detection
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with the highest evidence level55. Despite the supporting evidence favouring CEUS instead
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of CTA, routine use of CEUS seems limited to dedicated centres 16–18, 22 ,23.
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Educational considerations
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Strategies for teaching and implementing CEUS are not well-described. In general,
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however, it seems appropriate to distinguish between technically easy and difficult
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ACCEPTED MANUSCRIPT ultrasound examinations and to identify those for which a missed diagnosis is associated
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with significant risk 30. In situations when conventional ultrasound has failed, we consider
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the use of CEUS in peripheral arterial disease and EVAR to be among the most
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challenging. In addition to being able to administer the contrast and having a basic
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theoretical knowledge of CEUS, one should have mastered the unenhanced parallel
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before attempting the CEUS version. In our experience, most will master the technique in
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lower limb and EVAR after approximately 100 supervised unenhanced examinations.
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Adding another 20-50 supervised CEUS examinations would be enough to acquire
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expertise to perform these examinations.
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Ultrasound examination of PAD and EVAR patients has often been considered to be too
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time-consuming, time that of course is not diminished by adding UCA. We acknowledge
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that an ultrasound of crural arteries with low or absent flow, as well as an ultrasound of an
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obese or otherwise difficult EVAR patient, places demands on sonographers and planning
245
with respect to experience, skills, training, supervision and duration of the exam.
246
Nevertheless, the alternatives do not reduce procedure time (for the patient) or procedure
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related risks. All in all, having vascular ultrasound, with or without UCA, based in the
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vascular surgical clinic and performed by vascular surgeons or sonographers seems most
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appropriate.
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Future perspectives
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In EVAR-surveillance, the role of CEUS spans from being integrated into the standard
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surveillance programme to serving as an adjunct, if at all. It is well documented that CEUS
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can detect type II endoleak in EVAR patients with sac-expansion even when DUS and
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CTA were without leak41,45. Future studies should address the long-term clinical
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ACCEPTED MANUSCRIPT consequences of missing an endoleak type II by ultrasound and CEUS, and identify what
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and when to treat56,57. In our experience, an endoleak type II missed by CEUS is less likely
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to lead to reintervention than endoleak type II missed by DUS58.
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In carotid imaging, we foresee that contrast-enhanced 3D ultrasound (3D-CEUS) will lead
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to better risk prediction and monitoring of disease, since UCA-uptake seems to highlight
261
processes related to plaque vulnerability. Future “intelligent UCA” containing “targeted”
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microbubbles is likely to open up a new field of research in carotid imaging and provide
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opportunities for earlier diagnosis and treatment of plaques with increased inflammatory
264
activity and vulnerability59,60.
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In research settings, CEUS has been used to correlate muscular perfusion with ankle
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pressure, clinical stage and revascularization61,62. Studying muscular flow reserve with
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CEUS with the use of parameters such as “time to peak intensity” or “washout time”, can
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objectively assess the effect of contractile exercise, pharmacologic vasodilatation and
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revascularization - and potentially measure the outcome of stem-cell infusion,
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hemorheologic drugs etc62.
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Conclusion
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Currently, the role of CEUS in the routine vascular testing landscape is primarily limited to
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EVAR surveillance, where it remains unclear whether CEUS should be first choice or aid
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inadequate DUS examinations. For lower extremities, CEUS undoubtedly also has a role
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to play, but here DUS alone is sufficient for the evaluation of the vast majority of patients.
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Again, CEUS can be considered as a supplement, if and when conventional DUS studies
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fails. In both situations, CEUS is characterized by being accurate and sensitive for
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detection of very slow flow. The clinical usefulness of CEUS in carotid disease is more
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uncertain at present, however, it appears to be a promising research tool.
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Acknowledgements
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The authors would like to thank Dr. Kirsten Engel, CAMES, Copenhagen, for help in
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proofreading the manuscript.
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Conflict of interest
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Co-author Sillesen H. has received research grant from Philips Ultrasound. No other
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potential conflicts of interest exist.
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