Contrast-enhanced ultrasound (CEUS) in abdominal intervention

Microbubbles in the UCAs consist of an inert filling gas, such as sulfur hexafluoride, encapsulated by phospholipid shells [14]. Microbubbles resonate with low acoustic power and oscillate in a nonlinear fashion, and the harmonic signals produced can be selectively detected on US systems with special multipulse CEUS-specific software [15]. The biocompatible shells of microbubbles are metabolized by the liver, and filling gas exhaled by the lungs. UCA are not nephrotoxic, thus dispensing of any laboratory renal function tests prior to intravenous administration. Contraindications for the administration of UCA are few, namely, known allergic reaction to the UCA, severe pulmonary hypertension, and pregnancy [16]. Despite the low risk, resuscitation equipment should be accessible and trained personnel should be available for adverse events.

Microbubbles in UCA remain exclusively intravascular when administered intravenously, making them ideal for assessment of both micro- and macro vasculatures. Visualization of the vascularity of an abnormality offered by CEUS conveys its use to image-guided intervention through improved localization of a focal abnormality. Conversely, lack of perfusion can be established conclusively in avascular abnormalities such as abscesses.

CEUS should be performed after an unenhanced conventional US examination is fully evaluated. This allows the operator to identify the area of interest, and establish suitability of a subsequent CEUS examination. UCA are most commonly manually injected as a bolus through an intravenous line, usually via an antecubital vein, followed by 10 mL of 0.9% normal saline flush. It is generally best to insert the intravenous line after the baseline conventional US examination to avoid unnecessary cannulation in case a CEUS examination is not deemed worthwhile. However, due to logistical reasons, patients who are likely to benefit from intravenous UCA administration may need placement of an intravenous line prior to conventional US study at many facilities. The volume of UCA administered varies depending on the structure investigated, sensitivity of ultrasound machines and the UCA used. Conventionally, intravenous use of UCA requires 1.2–4.8 mL depending on the site examined. A dose of 2.4 mL of Lumason per injection is considered adequate for the liver and other abdominal procedures. After administration by intravenous injection, UCA lasts for about 4–5 min in the circulation. A second dose of equal volume can be administered if required.

Endocavitary CEUS is a developing technique [17, 18]. Manual injection of air through agitated saline solution has been utilized in many endocavitary ultrasound applications [19, 20] as the technique is inexpensive and readily available. Ultrasonography contrast media for endocavitary application has, however, evolved with new microbubble UCA with improved contrast media stabilization and small but sufficiently echogenic microbubbles, resulting in superior image quality. It is currently recommended that endocavitary CEUS could be considered if alternative imaging methods carry a higher risk for the patient, e.g., need to transport critically ill patients [11]. Broadly speaking, clinical indications for endocavitary CEUS include confirmation of drain placement and effective drainage, evaluation of a physiological or non-physiological cavity, and detection of communication between two cavities through a fistula tract. The use of endocavitary CEUS in the biliary system [21], urinary collecting system [22], and “hysterosalpingo–contrast sonography” [23] has been evaluated in clinical studies.

Endocavitary CEUS differs from intravenous CEUS, in that the volume of the solvent is much smaller than the full blood circulation volume, so a much smaller dose of UCA is required. Endocavitary CEUS can be performed by first diluting UCA in 0.9% normal saline, and the resulting solution is then injected into tubes or cavities. Adequate dilution of UCA is essential to avoid posterior acoustic shadow artifacts secondary to a high concentration of microbubbles. In our experience, this could be achieved with a dilution of 0.1 mL Lumason in approximately 40–50 mL of 0.9% saline. The administered volume of the solution with diluted UCA varies on a case-by-case basis dependent on the estimated volume of the cavity. The lack of circulation of UCA in a confined cavity means microbubbles remains stable within a collection for up to 20–30 min [24]. Destruction of microbubbles by a high-energy ultrasound pulse is, therefore, necessary before repeating an endocavitary CEUS evaluation. No adverse reactions relating to endocavitary CEUS have been documented in a limited number of clinical studies. Nevertheless, contraindications for intravenous administration of UCA should be taken into consideration when performing an endocavitary CEUS.

One of the main issue to be confronted in image-guided percutaneous biopsy procedures is the lack of imaging differentiation between the target and adjacent structures [7]. Poor differentiation of the target lesions from adjacent tissue is a common reason for failed US-guided procedures [28]. Not infrequently, a focal lesion is visible only on post-contrast diagnostic CT and cannot be adequately discerned during an US-guided biopsy procedure. CEUS is well placed to solve this problem because of its capacity to differentiate between the altered vascularization of a tumor and surrounding parenchyma [10]. CEUS guidance has been widely applied during biopsies in liver, kidneys, and other abdominal locations [29‐32]. CEUS offers the potential to improve positive biopsy yield by revealing the vascularized, potentially viable or more active, portion of a lesion [33]. CEUS guidance can also be advantageous in providing spatial information of necrotic areas to avoid during biopsy, such as in biopsy of a large tumor with central necrosis [34] (Fig. 5). Furthermore, sampling of atrophic, often echogenic, renal cortex of kidneys in patients with renal insufficiency for evaluation for nephropathies [35] could be better assisted with CEUS guidance, as small, but enhancing, kidneys are better visualized on CEUS than on gray-scale US (Fig. 6).

US-guided percutaneous nephrostomy (PCN) is routinely used in patients with clinical necessity of urinary drainage or urinary diversion. Frequent technical difficulties contributing to a failed PCN include lack of visibility of a target calyx [36] in cases of non-dilated collecting systems or when echogenic blood clots, pus, or debris is present within the renal calices. Intravenous CEUS improves the visibility of the calices by revealing the non-vascularized renal pelvicaliceal system against the background enhancing renal parenchyma [33]. In addition, specific techniques for CEUS-assisted puncture for PCN, with administration a small volume of diluted UCA through the puncture needle, have been described [33, 37]. With these techniques, a successful puncture can be instantly confirmed either when microbubbles reflux back along the needle due to back pressure of urine, or when microbubbles are visualized in the renal collecting system (Fig. 7). CEUS-assisted PCN offers a problem-solving adjunct in challenging cases including in non-dilated systems, showing high success rate and acceptable complications [36]. When compared to conventional fluoroscopic guidance, CEUS guidance offers a further technical advantage that if the initial placement is inaccurate, microbubbles can be destroyed and, therefore, would not leave a distracting blob of contrast material that interferes with the procedure, as in the cases of procedures performed with iodinated contrast material.

Following a successful PCN, it is frequently deemed necessary to assess the renal collecting system and ureter for free passage of urine prior to nephrostomy removal. The existing experience in CEUS voiding urosonography has showed safety of administration of endocavitary UCA within the urinary tract without side effects [22]. UCA can be injected through nephrostomy catheters to verify the correct placement (Fig. 8). Unobstructed drainage into the bladder can also be confirmed with a CEUS nephrostography with visualization of microbubbles in the bladder (Fig. 9). The degree of spatial resolution of endocavitary CEUS nephrostography gives a high degree of confidence of free ureteric drainage and a recent study shows 100% concordance with fluoroscopy [38]. CEUS nephrostography thus has the potential to become a feasible alternative to conventional fluoroscopic nephrostography [39]. CEUS nephrostography is particularly suitable in patients with contraindications to iodinated contrast material, or for ill patients as it can be performed at bedside.

Percutaneous trans-hepatic biliary drainage is commonly performed for the treatment of biliary obstruction. It is critical to determine whether the biliary drainage catheter is positioned adequately to ensure the effectiveness of the drainage. The position of the tip of a biliary drain is often difficult to visualize on conventional US due to bowel gas. A fluoroscopic cholangiography is often required following percutaneous biliary drain insertion or a biliary stent placement. In patients with contraindication to iodinated contrast material or in children in whom ionizing radiation exposure is undesirable, CEUS cholangiography has the potential to offer a practical alternative. CEUS percutaneous trans-hepatic cholangiography was first described in 2009 [40]. Percutaneous access to biliary system can be assisted with CEUS with intravenous administration of UCA to better depict the biliary system, particularly in cases where the biliary system is non-dilated [41]. Endocavitary CEUS with administration of UCA into the biliary system through drainage catheter enables determination of the adequacy of the drainage catheter position [41]. In addition, studies evaluating CEUS cholangiography have shown favorable results in delineating the anatomy of the bile duct tree and confirming bile drainage or the level of impediment to the drainage of bile [21, 42‐44] (Fig. 10). It has also been reported that CEUS cholangiography can reveal complications associated with the percutaneous trans-hepatic biliary drainage, such as an arterial communication with a percutaneous biliary drainage tube [45], due to its superior temporal and spatial resolution. Furthermore, evaluation of post-surgical complications such as a bile leakage can be performed with CEUS (Fig. 11) but the accuracy for this may be limited on occasion by the presence of bowel gas [41] or pooling of microbubble contrast within a cystic duct remnant. Despite this, CEUS cholangiography following percutaneous drainage could be an advantageous alternative for the assessment of the function of a biliary drain over conventional fluoroscopy in critically ill patients by allowing bedside examination [11].

With the advent of thermal ablation technologies, percutaneous ablation has emerged as a viable treatment option as an alternative to surgery in the management of solid abdominal tumors. Frequently utilized ablative mechanisms include radiofrequency ablation (RFA), microwave ablation (MV), cryoablation, particularly for hepatocellular carcinoma [46, 47], hepatic colorectal metastases [48] and renal tumors [49].

Percutaneous ablation of solid abdominal tumors involves the placement of ablation probes into the tumor masses under image guidance. Accurate intra-procedure delineation of tumors and post-ablation evaluation of the ablation zone are fundamental to the effectiveness of treatment. Conventionally, procedural guidance can be achieved with CT or US. US allows multiple planes to perform the procedure in real time. However, even in the most experienced hands, some lesions are poorly visualized on gray-scale US and there can be difficulty in differentiating viable tumors from areas of normal parenchyma or necrosis [50]. CEUS facilitates the treatment as it provides enhancement information that allows lesions inconspicuous on conventional US to be demonstrated during ablation procedures in real time [51]. CEUS also allows improved visualization of residual disease either intra-operatively or immediate post-procedure. With its improved resolution for micro-vascularity, US performed with UCA permits definitive exclusion of any residual vascularity post-ablation [52] (Fig. 12). Abnormal nodular hypervascular region at the peripheral ablation zone on CEUS can be regarded as residual viable tumor [53], and potentially be treated in the same setting [54]. However, in this regard, operators should be mindful of the presence of confounding periablation hyperemia or gas bubbles at the ablation site, which could bring challenges to the interpretation of CEUS appearances immediately post-ablation [55]. Periablation hyperemia often demonstrates a uniform rim of enhancement which, unlike residual tumor, persists throughout the different enhancement phases. Gas bubbles at the ablation site are markedly echogenic on gray-scale US and can be recognized prior to the start of CEUS exam.

Extravasation of intravenous contrast medium is a well-known angiographic and CT finding of active bleeding. Conventional US imaging is able to recognize clots and hematoma but cannot determine whether intra-abdominal bleeding has spontaneously stopped or is still ongoing [73]. Active hemorrhage could be identified on CEUS as extravasation of microbubbles [74] paralleling the known CT and angiographic appearances. CEUS offers additional benefit of the capability to scan the region of interest continuously without radiation burden, allowing exclusion of the theoretical risk of missing a delayed extravasation. In additional to active bleeding, a pseudoaneurysm can develop following an arterial injury which can also be detected with CEUS (Fig. 15). CEUS detection of arterial injuries can also help identify the likely anatomic source of the ongoing bleeding without delay and guide the targeted surgical or angiographic treatment (Fig. 16). CEUS also represents an alternative to contrast-enhanced CT in the followup imaging of arterial injury relating abdominal intervention, arterial complication, without the need for irradiation or administration of iodinated contrast, which may be undesirable for patients with renal insufficiency [75].

US is routinely used as the imaging modality of choice for interventions in the pediatric population because of concern over medical ionizing radiation exposure of children. CEUS is a safe and potentially cost-effective imaging modality for pediatric population [76]. Pediatric CEUS-guided intervention represents a complementary technique for intervention guided by grayscale and color Doppler US. Lumason (Bracco Diagnostics; Monroe Township, NJ) has received regulatory approval for pediatric hepatic use for assessment of pediatric focal liver lesions in the United States [10, 77]. Pediatric CEUS has also been extensively in an “off-label” manner [78] for further indications [79] with promising results, such as in abdominal trauma [75] and in established endocavitary use in voiding urosonography [21]. Furthermore, CEUS-guided pediatric intervention has been reported for chest drainage [80]. The strength of CEUS-guided abdominal intervention over alternative imaging modalities described in current review would also apply to patients in the pediatric population to address specific clinical need, particularly as CEUS negates the need for ionizing radiation or general anesthesia required for alternative therapeutic approach.

CEUS-guided abdominal intervention shares with conventional US-guided procedures some common causes for potential failure. First, when performing an interventional procedure, the acoustic window often needs to be larger than the window for a diagnostic US exam. Poor acoustic windows, resulting from rib shadows, respiratory movement, limited patient mobility and intervening bowel gas, may all increase procedural difficulty. Second, CEUS and US lack the panoramic properties of CT, and deep positions of abdominal organs or some retroperitoneal areas are not always adequately visualized. Moreover, as a prerequisite, CEUS-guided intervention requires adequate operator experience and expertise in interpreting diagnostic CEUS findings in addition to skills in conventional US-guided intervention. Finally, despite growing experience in the literature on CEUS-guided intervention [33], further comparative clinical trials may be required to fully validate the benefit of CEUS over other imaging modalities for a variety of abdominal interventional procedures.

Contrast-enhanced US, as a natural progression from conventional US, lends itself well to abdominal interventions as it combines traditional advantages of ultrasound guidance with real-time enhancement information without significant side effects. The current state of knowledge suggests CEUS offers a valuable armamentarium for abdominal intervention, not only as a credible alternative to other imaging modalities such as CT, but has the potential to even surpass conventional alternatives and offer solutions for complex logistical or clinical challenges encountered in image-guided abdominal intervention.