Introduction
The use of ultrasound (US) in intervention is well established and widespread practice
due to inherent benefits. These include a dynamic examination, absence of radiation
as well as being inexpensive and available at a bedside. As a result, many interventions
have become solely US-guided (e.g., biopsies) or have an US-guided element (e.g.,
vascular puncture). However, US is conventionally only able to provide a static assessment
of the macrovascular circulation, limiting visceral assessment and that of physiological
and nonphysiological cavities. A further potential downfall is the reliance on operator
technique, and thus variability, which may limit operator confidence. In many cases
difficulty may be due to the lack of inherent contrast in grayscale US.
Contrast-enhanced US (CEUS) is a technique that has been developed over the last 3
decades with increasing popularity. The microbubble contrast agent consists of an
inert gas (sulfur hexafluoride) encased in a phospholipid shell approximately the
size of a red blood cell. When exposed to low acoustic pressure in contrast-specific
mode this causes microbubble resonation and nonlinear signal which is displayed after
static signal cancellation giving a true micro- and macrovascular image. The microbubbles
have transpulmonary stability and are true blood pool agents meaning they recirculate
to a capillary bed level within the blood stream until they are excreted via the pulmonary
circulation, with the phospholipid shell metabolized within the liver. As a result,
there is no hepatic or renal toxicity and no blood tests are required prior to use.[1] Studies have shown safety of US contrast agents (UCA) in both the adult and pediatric
population, as well as more recent depiction of safety in pregnancy.[2]
[3] Benefits of CEUS also include those inherent to conventional US, including dynamic
real-time visualization and lack of radiation exposure. It is also suitable for patients
who are unable to tolerate magnetic resonance imaging (MRI) due to claustrophobia
or implanted devices.
CEUS lends itself well to use in interventional radiology (IR) and can be used either
to aid diagnosis preintervention, guide intervention interprocedurally, or confirm
endpoint postprocedure. Typically, this is through better visualization of a lesion
(including viable/necrotic areas), determining critical structures and planning a
pathway, confirming placement/communication of cavities, determining endpoint of a
procedure, or identifying complications. Diagnostically, CEUS may also be used in
surveillance.
Procedure
Procedural technique will be based on requirements broadly speaking these are either
intravascular or intracavity.
Intravascular administration is typically via a peripheral or central venous access
and will usually require between 1.2 and 4.8 mL UCA (typically SonoVue [Bracco]) followed
by a normal saline flush. Doses are dependent on the area evaluated and probe used
as the contrast resonates best at 3 to 5 MHz meaning higher doses are needed at higher
frequencies. It is important to use correct dosing to avoid excessive flair artifact
inhibiting visualization. Less frequently, intra-arterial administration can be performed
via an indwelling catheter when targeting a specific region, e.g. prostatic artery.
Lower doses are required due to lack of systemic circulation (typically less than
1 mL followed by saline flush).
Intracavity CEUS requires an indwelling tube, for example, gastrostomy, nephrostomy,
etc. Due to the small comparative volume to the circulating blood only 0.1 mL UCA
is required diluted in 20 mL normal saline to allow volume for administration.[4]
CEUS is typically done preprocedure along with optimized grayscale imaging and, if
needed, intraprocedural for real-time guidance. After optimized grayscale imaging
contrast-specific mode is entered and UCA administered. An onscreen timer is started
and video clip recorded usually using a split screen or overlay mode for concurrent
grayscale imaging.
A vial of contrast is viable for 6 hours so can be reused for multiple patients once
infection control protocols are performed adequately.
Nonvascular CEUS in IR
Biopsy
Increasingly, histological confirmation is required in diagnosis and frequently subtyping
is needed to guide treatment. US-guided biopsy offers the benefit of no radiation
or iodinated contrast exposure, with real-time imaging. CEUS can provide four areas
of benefit in biopsies; increasing diagnostic certainty, increasing lesional conspicuity,
avoiding nonviable tissue/critical structures, and identifying complications.
Preprocedure diagnostic CEUS is advised to identify and characterize a focal lesion,
including in the diseased liver. In some cases characterization of a benign or regressing
lesion may prevent the need for biopsy.
Lesions may be difficult to identify at grayscale mode US, similarly computed tomography
(CT)-guided biopsy may become landmark-based once an appropriate contrast phase has
passed. CEUS provides tissue contrast and can be evaluated continuously to determine
peak visualization and allow accurate target identification. This can be facilitated
in the arterial phase by a short high mechanical index pulse to burst the microbubbles
in the field of view and identify early phase replenishment ([Fig. 1]). The well recognized safety of US contrast in both adults and pediatrics means
repeated injection can be performed.[2]
[3]
[5] In patients with chronic liver disease and multiple nodules CEUS has been shown
to increase biopsy sensitivity.[6]
[7] CEUS has also been shown in thoracic biopsies to distinguish central lung tumors
from adjacent atelectasis as well as mediastinal structures facilitating lesional
biopsy.[8] Evaluation of the surrounding tissue can also be performed and identification of
significant intervening structures, such as arteries or compressed bowel, can be performed
without the need of artifact associated with Doppler mode.
Fig. 1 (A) Axial contrast-enhanced (CE) computed tomography (CT) showing a subtle hepatic lesion
(arrow) which was confirmed on (B) positron emission tomography (PET)-CT scan (arrow). The lesion was not seen on grayscale
ultrasound but on (C) simultaneous CEUS in split screen mode arterial enhancement is seen (arrow) and
the lesion was could be targeted for biopsy in the arterial phase with reinjection.
As UCA are pure intravascular agents, they are able to define clearly viable portions
of lesion increasing the ability to target vascularized lesions. Studies demonstrating
CEUS to facilitate US-guided biopsy of lesions not visible on B-mode US, or targeted
biopsy of heterogeneous lesions with enhancing and necrotic components, emerged over
a decade ago.[7] Use of CEUS has changed biopsy pathway trajectory in up to 80% of cases as conventional
US poorly visualizes necrosis by comparison.[8] Peak target visualization can be achieved on temporal overlay imaging with CEUS,
whereby the postcontrast images are stacked to demonstrate overlapping vasculature
over time. Potentially, this may decrease the number of passes required and improve
sample integrity.[9]
Drainage CEUS
CEUS can be used via the intravascular or endocavity route to support US-guided drainage
procedures. Grayscale appearances of collections may create diagnostic difficulty,
with echogenic contents giving the impression of solid tissue, which may be further
confounded if needle aspirate fails to yield fluid. CEUS clearly delineates the nonenhancing
areas of the collection compared with adjacent vascularized tissue or viscera ([Fig. 2]). Vascularized septations may be present and often shown a typical honeycomb appearance,
while perilesional hypervascularity and early washout can also be seen in abscesses.
The fluid aspect of the collection can be easily differentiated allowing operator
confidence for drainage. In addition, preprocedure CEUS can delineate adjacent vascular
structures and abnormality such as mycotic pseudoaneurysm formation. In selected cases
of gallbladder wall perforation, the drain can be sited through the preexisting wall
defect if appropriate to avoid further loss of wall integrity. This may be useful
in percutaneous management of perforated cholecystitis[10] ([Fig. 3]).
Fig. 2 (A) T2-weighted axial magnetic resonance (MR) sequence showing multiple cystic areas
with internal debris (arrow). (B) Grayscale ultrasound (US) image showing multiple hepatic lesions (arrows). (C) Simultaneous grayscale and contrast-enhanced US (CEUS) performed with dilute contrast
via the access needle (thick arrow) which showed filling of the collection (thin arrow)
communication with the biliary tree (arrowheads) indicating biliary abscesses.
Fig. 3 Simultaneous grayscale and contrast-enhanced ultrasound (CEUS) of the gallbladder
showing a mildly thick-walled gallbladder with focal perforation on the medial aspect
with loss of wall integrity (arrow).
Once percutaneous cavity access has been obtained endocavity UCA administration can
be used to determine the degree of communication between multiple collections or within
one loculated collection. This can be used to help determine if thrombolytic therapy
or mechanical disruption will be required to allow maximal drainage. Communication
with multiple adjacent collections can also be evaluated preventing the requirement
for multiple drains. CEUS clearly delineates the drain lumen and tip as well as better
highlights residual fluid component of the collection and potential fistulation. Fistulous
communications can subsequently be delineated in recurrent collections to facilitate
tract closure. This includes oral ingestion of UCA or enteric administration to highlight
fistulous communication.
Postprocedure a drain which no longer has output often requires assessment of position
and patency. Grayscale images may be difficult to identify the drain tip and as a
result require cross-sectional imaging. Endocavitary CEUS clearly delineates the drain
lumen and tip as well as better highlights residual fluid component of the collection
and potential fistulation. Intravascular CEUS can be used to assess for residual nonenhancing
abscesses.[4]
Ablation CEUS
CEUS-guided ablation can be performed using similar principles to CEUS-guided biopsy
and is a well-recognized alternative to other imaging modalities as it allows delineation
and accurate depiction of further sites of disease.[11] In addition to radiation and contrast sparing, the technique allows continuous imaging
throughout the procedure and can confirm the successful ablation zone.[12]
CEUS-guided ablation has been used in a multitude of regions, including the liver,[13] kidneys,[14] thyroid,[15] parathyroids,[16] retroperitoneum,[17] uterine fibroids, and abdominal wall endometriosis.[18]
[19] CEUS has been applied in a range of ablative modalities, including microwave ablation,
alcohol ablation, radiofrequency ablation, cryoablation, and irreversible electroporation.[20]
[21] Solbiati et al demonstrated much lower partial ablation rates using CEUS than conventional
means (16.1% vs. 5.9%).[22]
CEUS can supplement ablative therapy by facilitating add-on ablation of the feeding
artery in hypervascular tumors to reduce perfusion.[23] It can also be used to detect complications during and following ablation.[24] Detectable vascular complications include bleeding, pseudoaneurysm formation, and
thrombosis. Some operators have used US guidance to treat bleeding after microwave
ablation with glue embolization.[25]
Surveillance postablation to monitor for recurrence has been shown to be possible
following different ablative therapies in different tissues[26] ([Fig. 4]).
Fig. 4 (A) Axial computed tomography (CT) showing a left renal tumor. (B) Placement of cryoablation probes on three-dimensional (3D) reconstructed CT images.
(C) Contrast-enhanced ultrasound (CEUS) 1 year later showing no enhancement and reduced
size of the lesion in keeping with adequate ablation.
Nephrostomy and Nephrostograms with CEUS
Fluoroscopy-guided nephrostomy is a relative contraindication in several clinical
scenarios, including pregnancy and iodinated or gadolinium contrast allergy. Differentiation
of the collecting system from renal parenchyma may be difficult when there is increased
calyceal echogenicity such as in urosepsis, collecting system hemorrhage, or malignancy.
Intravenous CEUS can delineate the nonenhancing collecting system to be targeted and
subsequent confirmation of successful collecting system access in these cases can
be achieved by instillation of dilute UCA via the access needle ([Fig. 5]).[27] Should there be failure of collecting system access, injecting UCA does not result
in obscuration of the target as the microbubbles can be burst using short-duration
high mechanical index imaging, unlike fluoroscopic-guided puncture.
Fig. 5 Contrast-enhanced ultrasound (CEUS) image with simultaneous on grayscale imaging.
After Chiba needle access (arrowhead) dilute ultrasound contrast administered fills
the collecting system (thin arrow) indicating appropriate placement in a patient too
unwell for transfer to the interventional radiology facility.
When nondilated collecting systems require a nephrostomy (e.g., urinary diversion),
several techniques can be performed. Initially, intravenous CEUS can better demonstrate
the nonenhancing renal calyces through the access needle or the collecting system
may be expanded by retrograde instillation of dilute microbubble contrast by retrograde
ureteral contrast injection. These approaches reduce the number of punctures needed
to achieve access, improve puncture site accuracy, and reduce procedural bleeding.[28]
Following collecting system access or nephrostomy placement, a nephrostogram may be
performed by endocavitary UCA to confirm correct nephrostomy position, delineate the
ureter and confirm contrast passage to the urinary bladder, and is potentially more
sensitive than conventional iodinated contrast.[29] There is also the potential to evaluate ureteric strictures or fistulation.
Percutaneous Transhepatic Cholangiography CEUS
The use of the microbubble contrast agent to perform percutaneous transhepatic cholangiography
(PTC) has been successfully reported for both puncture confirmation and assessment
of biliary drainage.[30] The major benefits are reduced radiation burden and the ability to perform PTC in
patients with iodinated and gadolinium contrast agent allergy. CEUS PTC is used as
an alternative to fluoroscopy-guided biliary puncture with radiodense contrast which
may obscure the image. While CEUS has been shown to be a good alternative to fluoroscopically
guided PTC, it is limited mainly when wire manipulation is required.[30] Intravenous administration can be particularly helpful in the nondilated system
to better visualize the biliary system, while when given through the access needle
allows confirmation of position without creating poor visualization as occurs with
iodinated contrast. CEUS through the biliary tree can also confirm enteric biliary
drainage. Endobiliary UCA administration has been used to demonstrate biliary leakage
following T-tube removal[31] and identified an occult biliary-arterial fistula.[32]
Lymphatics CEUS
Lymphatic system evaluation and intervention is emerging. Currently, the evidence
is being driven by case reports and series; however, some techniques such as sentinel
node localization are well established.[33] Breast cancer patients with lymphoedema following axillary dissection may also benefit
from CEUS lymphatic mapping before lymphaticovenous anastomosis surgery.[34]
Early work has also shown feasibility of improved lymphatic needle placement for MRI
lymphangiography in pediatrics with CEUS confirmation.[35] Retrograde pyelography has been used to delineate a fistula between the kidney and
the lymphatic system in a child with nonparasitic chyluria.[36] Intranodal CEUS administration matches conventional lymphangiography in the assessment
of thoracic duct patency[37] and treatment of lymphatic malformations.[38]
Vascular IR
Angioplasty
Peripheral vascular disease is a common condition, often symptomatic through claudication
or progressive to critical limb ischemia. Revascularization through angioplasty is
often performed and the result assessed through Doppler US, symptom improvement, or
visual improvement on angiography postprocedure. While CEUS can provide angiographic
assessment of a focal stenosis it can also be used to assess muscle perfusion. Amarteifio
et al[39] performed CEUS after revascularization and showed a decreased time to maximum enhancement
as well as a shorter time to maximum improvement predicting more successful outcome.
Dialysis Fistula
For US-guided percutaneous endovascular treatment of arteriovenous fistula, the superficial
location lends itself well to US guidance and can be done without iodinated contrast
given to the renally impaired population. Taurisano et al have demonstrated the potential
effectiveness of CEUS providing detail on the likelihood of restenosis post-percutaneous
transluminal angioplasty. Similarly to angioplasty the angiographic nature means CEUS
can guide intervention in hemodialysis fistulas and detect complications such as rupture.[40] Reinjection can be performed as required given the absence of nephrotoxicity and
excellent safety profile.
Vascular and Lymphatic Malformation
Vascular malformations (VMs) are complex congenital or iatrogenic lesions with quiescent
endothelium often involving multiple tissues planes. While MRI is the default imaging
modality used in their assessment, CEUS using intravascular contrast agent can offer
additional information on the mapping of these lesions.
In the setting of intracranial arteriovenous malformations (AVM) repair, CEUS has
been employed to provide the surgeon with real-time adjunctive information to distinguish
between involved, feeding vessels and normal vessels in the intraoperative setting,
particularly as increasing intraoperative edema can blur margins.[41]
IR is well-established in the definitive management of VMs. CEUS has been demonstrated
to add to the safety and efficacy profile of cornerstone IR procedures such as embolization
and sclerotherapy in the management of VMs.[42]
Similar to the evaluation in venous malformations, CEUS can be performed prior to
sclerotherapy of lymphatic malformations. UCA can be injected into cystic spaces to
glean further detail on the structure of the malformation prior to sclerosis. This
is particularly useful as often these lesions can comprise of multiple adjacent but
separate cystic components which each require sclerosis for definite treatment of
the lesion or to determine whether multiple treatments will be required. Furthermore,
as a pure intraluminal agent the absence of vascular filling on CEUS can provide confidence
as nontarget treatment will be a low risk.
CEUS can also be used to quantify the perfusion in VM before and after embolization
treatment. This is done through time-intensity curve (TIC) analysis and calculation
of time to peak (TTP) as well as area under the curve (AUC). TTP increase and AUC
decrease indicate therapy-induced changes post-embolization. With this, dynamic CEUS
can quantitatively determine the level of microvasculature involvement with significant
alteration in TIC parameters.[42]
Carotid Stenosis
Recent guidance has reaffirmed the role of duplex US in evaluation of carotid disease
with further literature established in the vulnerability of the intravascular plaque,
identified through neovascularity.[43] This modality may be particularly useful in a patient population whereby brittle
renal function and susceptibility to iodinated contrast is common. In assessment of
the macrovasculature CEUS can provide angiographic images of plaque morphology. This
has led to poststenting evaluation with CEUS which was shown to be more sensitive
than conventional Doppler.[44] Furthermore, the use interprocedural US in carotid stenting has already been shown
to decrease contrast load and, although not yet studied, CEUS may also provide further
intraprocedural confidence and information.[45]
Abdominal Aortic Aneurysm
Endovascular aortic repair (EVAR) is an alternative to open aortic aneurysm repair,
which provides a minimally invasive apprach and similar initial outcomes.[46] Endoleaks are a known complication due to persistent aneurysmal filling outside
the graft in EVAR. The dynamic nature of CEUS and ability to perform prolonged imaging
allows great accuracy in assessment of endoleaks. In particular, the late nature can
be assessed and so can cause reclassification of endotension on CT, where sac size
increases but no source is seen often due to late filling.[47] Three-dimensional CEUS has further been shown to increase diagnostic accuracy for
endoleaks with better performance than CT angiography.[48]
While still experimental, intraoperative CEUS-assisted EVAR in patients with infrarenal
aortic aneurysms represents a new option for intraoperative visualization of aortoiliac
segments and identification of type I endoleaks, especially in those patients with
contraindications for usage of iodinated contrast agents.[49]
[50] Intraoperative CEUS has also demonstrated to detect a greater number of type II
endoleaks compared with digital subtraction angiography. Limitations of CEUS use in
EVAR include patient body habitus whereby it is often difficult to visualize the aneurysmal
sac in the case of severe obesity. While no particular graft material has demonstrated
superiority in EVAR, the use of expanded polytetrafluoroethylene is common and causes
echo reflection which decreases the power of endoleak detection. There has been a
small study of patients with reported iodinated contrast allergy using carbon dioxide
angiography combined with intraprocedural CEUS to perform EVAR safely and effectively
entirely free of iodinated contrast.[51]
Bleeding
CT angiography provides the mainstay for the emergency assessment of bleeding. However,
inherent disadvantages associated with this modality involve the need to transfer
a potentially unstable patient to scan department, (usually distant to dedicated resuscitation
facilities), the contrast load needed, and duration of time involved. Furthermore,
the increased spatial and temporal resolution of CEUS may mean it has the potential
to identify hemorrhage not seen on CT, particularly if there is a single phase ([Fig. 6]). In a mixed splenic and liver trauma population, Lv et al evaluated the performance
of CEUS in comparison to CT angiography to identify bleeding. The authors observed
a sensitivity of 76% for CEUS to detect active bleeding.[52] Limitations are due to the inability to screen the entire abdomen simultaneously,
limiting features of general US such as body habitus and intervening gas. In cases
of embolization of active bleeding, intraprocedural CEUS can be performed either through
intravascular or catheter intra-arterial administration to ensure endpoint of embolization.
This is of particular use when coil artifact may obscure detailed evaluation on CT
or angiography, even in cases where B-mode US may seem insufficient.[53]
Fig. 6 Contrast-enhanced ultrasound (CEUS) image post-liver biopsy with split screen grayscale
image. Pooling contrast (arrow) is seen in a pulsatile fashion into the perihepatic
hematoma (arrowhead) adjacent to the liver (star) indicating active arterial hemorrhage.
Pseudoaneurysms
Pseudoaneurysms are a common complication of procedures involving arterial puncture,
but may also occur in the context of trauma or infection.[54] Partial loss of the arterial wall results in risk of spontaneous rupture and life-threatening
hemorrhage. When superficial (particularly at femoral access sites), US-guided thrombin
injection is usually performed if compression fails. Visceral pseudoaneurysms may
be observed, embolized, or treated with thrombin injection.[55] When observation is undertaken focused CEUS can prevent the need for multiple CTs
and is of particular use in pediatrics.[56] CEUS allows accurate definition of the viable pseudoaneurysm as well as anatomy
such as the neck, which may be difficult to determine in the context of hematoma,
edema, or artifact from color Doppler. UCA allows intraprocedural assessment of completeness
of treatment and can assess distal vasculature for evidence of infarction or distal
thrombus.[57]
Uterine Artery Embolization
Uterine artery embolization is an established technique. Currently, MRI is the reference
standard for assessment of fibroids pre- and postintervention. However, the expense
and relative inaccessibility of MRI for many mean a need for more ubiquitous imaging
technology.[58] As well as providing information on the location, size, and number of tumors, CEUS
provides additional detail on the fibroid pseudocapsule, central necrosis, and intralesion
vascular pattern compared with other US modes.[59] CEUS can be used as an adjunct to determine vascularity in cases of equivocal enhancement
in persistent symptoms.
Intraprocedural CEUS allows determination of complete devascularization and endpoint
of embolization ([Fig. 7]), and may be of use when iodinated contrast taken up by the lesion obscures assessment.
Fig. 7 Split screen contrast-enhanced ultrasound (CEUS) and simultaneous grayscale imaging
(A) pre- and (B) post-embolization showing post-embolization devascularization of the uterus.
In the follow-up period CEUS has been suggested to effectively demonstrate treatment
failure on day 1 by evidencing enhancement. Beyond the immediate postoperative period,
its role requires further evaluation but has been postulated in ensuring normal myometrial
ischemia does not occur.[60]
Embolization endpoint assessment can also be performed for other viscera in a similar
fashion including the prostate ([Fig. 8]), kidneys, and chemoembolization of the liver.
Fig. 8 Simultaneous grayscale and contrast-enhanced ultrasound (CEUS) image of the prostate
(A) prior to embolization showing enhancement with (B) angiographic confirmation and (C) post-embolization showing no enhancement on CEUS or (D) angiography.
