Keywords
contrast-enhanced ultrasound - endoleak - thermal ablation - transarterial chemoembolization
- interventional radiology
Contrast-enhanced ultrasound (CEUS) has emerged as a pivotal diagnostic tool by leveraging
the use of intravascular contrast agents through the form of microbubbles to enhance
visualization of blood flow and tissue perfusion. While its use as a diagnostic tool
is routine in many parts of the world (e.g., CEUS LI-RADS,[1] contrast-enhanced echocardiography, and contrast-enhanced voiding urosonography),
new and novel applications of CEUS for an “interventional” application are constantly
emerging.
In the United States, three main contrast agents are predominantly utilized in CEUS:
sulfur hexafluoride (Lumason), perflutren lipid microspheres (Definity), and perflutren
protein-type A microspheres (Optison).
Lumason (Bracco Diagnostics, Princeton, NJ; marketed as Sonovue in Europe), a sulfur
hexafluoride microbubble-based contrast agent, is encapsulated within a phospholipid
shell, allowing for prolonged circulation and sustained enhancement during imaging.
It is primarily utilized in the assessment of vascular structures related to solid
organs. Its high echogenicity and consistent enhancement make it particularly valuable
in delineating vascular abnormalities and characterizing lesions.
Definity (Lantheus Medical Imaging, North Billerica, MA), composed of perflutren lipid
microspheres, exhibits rapid clearance from the bloodstream and is thus well suited
for dynamic imaging studies including the assessment of myocardial perfusion and the
evaluation of cardiac function.
Optison (GE Healthcare AS, Oslo, Norway), containing perflutren protein-type A microspheres,
is unique in its albumin-based shell, and its compatibility with harmonic imaging
techniques is particularly advantageous in echocardiography, facilitating the evaluation
of intracardiac shunts, valvular regurgitation, and myocardial perfusion defects.[2]
Of the aforementioned three agents, only Lumason does not require refrigeration and
can be reconstituted via three-way stopcock mixing immediately prior to use. Additionally,
Lumason is the only FDA-approved agent for both liver lesion characterization and
contrast-enhanced voiding urosonography (radiation-free alternative to voiding cystourethrography).
The versatility of CEUS has demonstrated a myriad of diagnostic and interventional
applications. We will review several of its applications in this article with the
attention to endoleak diagnosis and classification, periprocedural thermal ablation,
and other investigational uses such as intra-arterial administration to evaluate for
lesion coverage in transarterial chemoembolization (TACE).
Applications of Contrast-Enhanced Ultrasound in Endoleak Detection and Classification
Applications of Contrast-Enhanced Ultrasound in Endoleak Detection and Classification
Currently, the endovascular aneurysm repair (EVAR) technique accounts for over 56%
of all abdominal aortic aneurysm (AAA) repairs in the United States.[3] Between 20 and 50% of these patients treated with EVAR develop endoleak—some requiring
reintervention within the first 30 days after placement.[4]
[5]
[6]
CEUS offers several advantages in the detection and characterization of endoleak after
endovascular AAA repair. Its improved visualization, ability to detect small endoleak,
and noninvasive nature make it a valuable tool in clinical practice.[7]
CEUS can identify and differentiate endoleak more accurately than computed tomography
(CT) angiography with the analysis of flow direction and velocity with sensitivity
of 98% and specificity of 88%.[8] It is radiation free, avoids the need for iodinated contrast, and allows for real-time,
dynamic detection of endoleak after EVAR. Diagnostic assessment is continuous and
can visualize vascular flow along multiple minutes—as opposed to the few, static images
in time obtained in multiphasic CT and magnetic resonance angiography. Compared with
conventional US, CEUS provides good sensitivity despite technically difficult conditions
caused by the patient's body habitus and the presence of bowel gas.[9] The absence of metal streak artifacts on US also allows for the detection of endoleak
with high spatial resolution, especially after prior endoleak repair. Ultimately,
it is the dynamic nature of CEUS which allows for accurate diagnosis and classification
of endoleak, as the contrast microbubbles can be visualized flowing along their preferred
path and entering the excluded aneurysm.
Technical Approach to CEUS in EVAR Surveillance
To minimize bowel gas and its associated comet-tail artifact, patients are instructed
not to eat or drink anything the morning prior to the CEUS examination. Peripheral
intravenous access of at least 22 gauge is obtained to administer the contrast microbubbles.
A standardized non-contrast diagnostic sonographic evaluation of the aortic endograft
and the aneurysm sac is performed prior to contrast injection. The abdominal aorta
and iliac arteries, including the endograft and excluded aneurysm, are evaluated in
their entirety in both transverse and sagittal planes—noting optimal sonographic windows
for the endograft and aneurysm sac for the upcoming contrast administration. The flow
and waveforms in the peripheral endograft limbs are assessed with color and spectral
Doppler. Additionally, color and spectral Doppler are used to assess the excluded
aneurysm sac for residual flow and interrogate vessels that commonly cause type II
endoleak, such as a patent inferior mesenteric artery or lumbar arteries.
For the contrast-enhanced portion of the exam, dual screen monitoring is performed
with B-mode on one side—to guide anatomic landmarks—and contrast display mode on the
other side—to assess for enhancement. The focal zone is set at the deep margin of
the aorta. For adequate signal intensity at this focal length, the mechanical index
(MI) can be increased but should be balanced against the consequences of increased
contrast microbubble destruction. Ideally, the MI should remain less than 0.2, except
in extremely difficult evaluations. Prior to contrast injection, the gain should be
lowered to have the aorta slightly below detection on the contrast view. Subsequently,
a bolus dose of 1.5 mL of Lumason (Bracco Diagnostics) or 0.2 mL of Definity (Lantheus
Medical Imaging) is injected intravenously and flushed with 10 mL of saline. Alternative
contrast injection protocols have also been described.
It is beneficial to start a timer when injecting the intravenous contrast, as the
enhancement timing of the aneurysm sac relative to the endograft lumen is important
for distinguishing endoleak etiology. Endoleak types I, III, and IV can be diagnosed
by synchronous enhancement of the endograft lumen and aneurysm sac and are differentiated
by direct visualization of where contrast can be seen extruding from the graft ([Fig. 1]). Delayed leaks (e.g., types II and V) are suggested by delayed enhancement of the
aneurysm sac relative to the endograft lumen ([Fig. 2]). Dual-screen B-mode and contrast mode interrogation is continued for 5 to 7 minutes
after contrast injection in order to evaluate for slow-flow and delayed endoleak.
If delayed enhancement of the aneurysm sac is identified, the operator should allow
for the contrast to be physiologically cleared (approximately 10 minutes), and a repeat
bolus can be administered to attempt to visualize the arterial source and direction
of the endoleak.[10]
Fig. 1 (a) Routine monitoring CT abdomen and pelvis without contrast due to decreased renal
function in a patient with AAA repaired with Endologix graft over 10 years ago shows
an enlargement of the aneurysm compared to (b) CT scan from 1 year prior. (c) B-mode US shows the endograft (arrowhead) within the aneurysm (arrow). (d) Dual-screen CEUS shows type III endoleak with the synchronous enhancement of the
endograft (arrowhead) and the aneurysm sac (arrow).
Fig. 2 (a) Color Doppler ultrasound shows a partially thrombosed right common iliac artery
aneurysm after Endologix endovascular repair with the question of type II endoleak
from the right hypogastric artery (arrow). (b) CEUS demonstrates filling of the right limb of the endograft (arrowhead) and (c) subsequent delayed opacification of the right hypogastric artery (arrow), confirming
type II endoleak.
Applications of Contrast-Enhanced Ultrasound in Periprocedural Thermal Ablation
Applications of Contrast-Enhanced Ultrasound in Periprocedural Thermal Ablation
Thermal ablation techniques are increasingly utilized for the treatment of various
solid tumors, and CEUS can provide several periprocedural advantages. CEUS provides
accurate delineation of an ablation target, particularly in focal lesions that are
difficult to appreciate with standard B-mode US.[11] CEUS often improves visualization of ill-defined tumors by demonstrating arterial-phase
hyperenhancement and/or tumor washout ([Fig. 3]). Furthermore, CEUS may delineate viable areas of tumor in large tumors with necrosis.
Accurate delineation of the ablation target allows clinicians to strategize the ablation
approach, ensuring adequate coverage of the target lesion while minimizing damage
to adjacent structures.
Fig. 3 (a) Subtle region of hypoechogenicity on B-mode (arrow), which is (b) well delineated after intravenous contrast injection (arrow). (c) Successful placement of the ablation electrode (arrowhead) through the target lesion
with (d) visualization of the treatment zone (arrow).
CEUS can be used to guide probe placement and provide real-time monitoring of tissue
perfusion changes.[12] Procedures are typically done with two injections, or an infusion can be performed
(∼1 mL/min) when prolonged contrast-enhancement is required. Post-ablation CEUS can
also be performed, thereby facilitating immediate assessment of adequate treatment
coverage by evaluating changes in tumor vascularity and perfusion patterns. This allows
for rapid identification of residual tumors, enabling performance of re-ablation in
the same session and reduction of reintervention in up to 31% of patients.[13]
[14]
The efficacy of periprocedural CEUS has been further demonstrated in other studies.
For example, patients with hepatocellular carcinoma (HCC) poorly imaged by grayscale
US and selected for radiofrequency ablation demonstrated complete response with a
single session of treatment in 95.2% of the patients treated by CEUS guidance versus
32% in patients treated by grayscale US guidance alone.[15]
Applications of Contrast-Enhanced Ultrasound in Transarterial Chemoembolization
Applications of Contrast-Enhanced Ultrasound in Transarterial Chemoembolization
HCC is the most common type of primary liver cancer and its incidence and mortality
rates have been rising for the last decade.[16] Transarterial embolization therapies rely on localized catheter delivery of embolic
agents via hepatic arteries. For example, TACE is performed by the injection of chemotherapeutic
drugs mixed with lipiodol or drug-eluting beads containing doxorubicin. CEUS has been
demonstrated to be effective for both intraprocedural evaluation and postprocedural
follow-up with several advantages.
Shiozawa et al described a study including 39 HCC lesions treated with DEB-TACE with
intraprocedural intra-arterial US (IAUS) guidance. US contrast was injected intra-arterially
via the microcatheter in order to sonographically appreciate vascular supply to the
tumor and lesion coverage prior to DEB-TACE administration (conceptually analogous
to cone beam CT performed during mapping angiography). Following administration of
therapy, 13 of the 39 lesions were identified as incompletely treated on IAUS, as
evidenced by persistent enhancement characteristics, allowing for further administration
of drug-eluting microspheres.[17]
Per Society of Interventional Radiology guidelines, follow-up imaging is typically
performed 4 to 6 weeks postprocedure with either contrast-enhanced CT or contrast-enhanced
magnetic resonance imaging. The delay in evaluation is thought to allow for differentiation
of peritumoral inflammation and viable tumor, but also to minimize artifact from intraparenchymal
lipiodol on CT.[18] CEUS has an excellent safety profile with data suggesting residual tumor enhancement
accurately detected as early as 1-week post embolization due to the purely intravascular
nature of US contrast agents and lack of lipiodol artifact on US.[19] When evaluated with CEUS, residual, viable tumors would manifest as internal residual
enhancement or nodular peripheral enhancement. A tumor that is completely treated
by TACE should demonstrate smooth tumor margins without internal flow in any enhancement
phase.[20] CEUS can also be considered as an alternative for follow-up in patients who have
contraindications to contrast-enhanced CT/contrast-enhanced magnetic resonance.
Conclusion
CEUS has many useful applications and substantial advantages in interventional radiology,
including precise detection and classification of endoleak after EVAR, periprocedural
guidance for thermal ablation, and the evaluation of real-time lesion perfusion changes
in TACE for HCC. With its excellent safety profile and ability to provide detailed,
dynamic, real-time imaging, CEUS is a valuable tool with the ability to enhance patient
care by improving diagnostic accuracy, treatment efficacy, and patient outcomes.
