Nontraditional Uses of US Contrast Agents in Abdominal Imaging and Intervention
Abstract
With the increasing availability of contrast-enhanced US (CEUS) worldwide and in the United States, the potential applications of this modality in abdominal imaging and intervention are continuing to expand. CEUS leverages the many inherent benefits of US with a safe and unique microbubble contrast agent. When injected intravenously, US contrast agents (UCAs) function as a pure blood pool agent, augmenting diagnostic US examinations such as vascular imaging. In the procedure suite, UCA can be used to improve needle visualization and depict active extravasation. UCA may also be injected through needles and tubes into various body spaces, allowing the assessment of the urinary system, indwelling catheters, and other tracts and cavities. Some venous and lymphatic lesions may be diagnosed with the direct injection of a UCA into these lesions. The authors highlight some of the many applications that are relevant to the abdominal imaging professional and interventional radiologist but should not be considered a complete list, and users of UCAs should continue to consider uses beyond those traditionally highlighted in recent literature.
Online supplemental material is available for this article.
©RSNA, 2022
SA-CME LEARNING OBJECTIVES
After completing this journal-based SA-CME activity, participants will be able to:
■ List uses for UCA outside of traditional intravenous uses.
■ Discuss how the properties of UCA can aid in the diagnosis of multiple entities.
■ Recognize how UCA can provide nonionizing portable alternatives to cross-sectional imaging and fluoroscopy.
Introduction
It is a reasonable assumption that at least one diagnostic or interventional request encountered in an abdominal imaging reading room each day would benefit from contrast-enhanced US (CEUS). Aside from the characterization of incidental liver and renal lesions, the abdominal imaging specialist may encounter indeterminate findings related to the vasculature, such as during a Doppler US examination with questionable findings of portal vein thrombosis, or a CT angiogram with equivocal findings of an endoleak. Evaluation of an indwelling percutaneous catheter may be needed, and fluoroscopy may be contraindicated or impractical. In the US procedural suite, an interventionalist may have difficulty visualizing their needle or may need to immediately confirm the presence of active hemorrhage. These indications, and many more, may be addressed by using CEUS through the intravenous or intracavitary administration of a US contrast agent (UCA) (1–7). In this article, we share our experience with some of the nontraditional applications of CEUS. We hope these cases stimulate the reader to learn more about these techniques and motivate the development of additional new applications.
US Contrast Agents
Microbubble-based UCAs have been used in diagnostic imaging applications for several decades and were first proposed for echocardiography in 1969 (8). Use of carbon dioxide (CO2) microbubbles for hepatic tumor characterization was among the earliest reported noncardiac uses of a UCA (9). Today, five UCAs from four manufacturers are approved by the U.S. Food and Drug Administration (FDA) as of the writing of this article, and CEUS is included in the Current Procedural Terminology register as of 2019 (10). These agents and the approved indications are summarized in Table 1 (11–15).
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Diagnostic and interventional applications of CEUS have primarily focused on intravenous use of UCAs for lesion conspicuity and characterization, particularly in the liver (16). An additional approved indication is the intravesicular administration of diluted contrast agent for the evaluation of vesicoureteral reflux and urethral abnormalities in children. Importantly, UCAs have approved on-label indications but under the direction of a licensed physician may be administered off-label for a wide variety of applications. This is no different than in most radiology departments that may use the same iodinated or gadolinium-based contrast agent with specific on-label indications (such as intravenous use for adult neurologic or angiographic imaging) for examinations that would be considered off-label (eg, enteric use for pediatric imaging).
Advantages of CEUS include the inherent benefits of US as a modality, including accessibility and portability, facilitating deployment in front-line emergency and critical care settings; a high safety profile, including lack of ionizing radiation and absent need to screen for implanted devices; and ability to continuously image with high temporal resolution (17). The safety profile of UCAs, which also affords advantages over other intravenous imaging contrast agents, includes lack of renal or hepatic toxicity and a low allergic reaction rate, without cross-reactivity with CT or MRI contrast agents. The contraindications to currently available UCAs are hypersensitivity to the specific agent and to polyethylene glycol (an ingredient in Lumason [Bracco Diagnostics], Definity [Lantheus], and Definity RT) (18). The rate of anaphylactoid reactions has been reported as 0.006%, of which 0.001% were deemed life threatening, with overall adverse event rates well below 1% (19–21). As pregnancy risk category B medications, UCAs should only be used if the benefits outweigh the risks. Conditions requiring postinjection observation include acute decompensated heart failure and unstable cardiac arrhythmias (22).
The sensitivity of US to microbubbles results in a high bubble-to-background contrast ratio such that single bubbles can be depicted. When injected intravenously, microbubbles function as a pure blood pool agent and do not cross into the extravascular interstitial space (7,17,22). These circulating microbubbles are rapidly cleared, with the gas core eliminated through pulmonary exhalation and the shell metabolized by the liver (11–14). Conversely, after nonintravenous administration of a UCA, microbubbles remain in the space into which they are injected and can have a long half-life (2,6).
In practice, microbubble clearance can be expedited by using US modes with high mechanical index (eg, color Doppler) or specialized flash or burst pulse sequences that are purposely designed and used to rupture microbubbles (22). Multiple injections are possible during a single examination, enabling repeated imaging during the preferred contrast phase. This avoids a need to use image fusion software for contrast-enhanced navigation or cognitive fusion based on relative anatomic landmarks during an interventional procedure. Readers are referred to Chong et al (22) for a comprehensive technical review of imaging with UCAs.
Technical Considerations for CEUS
The microbubble particles that make up a UCA are quite fragile and are susceptible to disruption by high positive or negative pressures and shear forces. Therefore, UCAs should be injected carefully by hand through an easily flushable line or catheter, followed by a 5–10 mL saline flush (23–25). It is recommended to use a three-way stopcock with the microbubbles passing linearly through the stopcock and the saline flush entering perpendicularly. To image microbubbles, a contrast agent–specific imaging mode is needed. This mode uses a low power (low mechanical index) setting to minimize unintentional microbubble destruction (eg, mechanical index ≤0.4 is recommended in the Lumason package insert [11]). The contrast agent mode image is often displayed side by side with a standard gray-scale US image. However, the quality of the gray-scale US image may be relatively poor given the low transmit power, and that several settings such as image compounding are deactivated.
The contrast agent–specific imaging mode utilizes techniques such as phase and amplitude modulation and pulse inversion harmonic filtering to create “contrast agent–only” images. The insonated microbubbles produce strong harmonics of the primary (fundamental) frequency (nonlinear response), whereas the surrounding structures predominately respond linearly. These signals can be electronically suppressed to create tissue-subtracted images. Although some artifacts may result in various nonenhancing structures persisting in the contrast agent–only image (eg, stones and bowel gas), nearly all other signal in the contrast agent–only image indicates enhancement (26). Conversely, if a structure is found to not contain UCA, a user may conclude that the structure is nonenhancing (or in the case of intracavitary injection, noncommunicating).
UCA dosing may be a source of confusion and concern, particularly for off-label applications. In general, the FDA-approved dose is often higher than that needed for most applications given recent improvements in imaging techniques. The authors have found that for most intravenous vascular applications, a dose one-fourth to one-half that of the FDA-approved dose is often sufficient (7). For intravenous imaging of small and peripheral targets, especially when using a higher-frequency linear transducer, much higher doses are required because a smaller proportion of microbubbles circulate through these structures, and linear transducers are often less sensitive to microbubbles compared with lower-frequency curved transducers. Finally, for intracavitary applications, a diluted UCA, often in saline, is needed, as a high dose of intracavitary microbubbles may result in significant acoustic attenuation and even shadowing (2,6,27). Suggested UCA dosing is detailed in Table 2. The short half-life of intravenously administered UCAs compared with iodinated and gadolinium-based contrast agents and the ability to clear intracavitary microbubbles by using high–mechanical index imaging modes allows multiple doses to be administered during a single examination. Although FDA dose limits exist, there is no practical maximum cumulative dose per examination.
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Limitations of Intraprocedural CEUS
In addition to the contraindications discussed above, several factors may preclude use or decrease utility of CEUS in the procedural setting. First, the use of a contrast agent add costs to a procedure and typically requires placement of an intravenous catheter, which adds time and additional expense and may not be immediately achievable in all patients. While UCA can increase target conspicuity compared with gray-scale US, this assumes an adequate sonographic acoustic window, which is not possible in all cases. Factors that may inhibit adequacy of the acoustic window include patient condition and mobility, intrinsic patient anatomy (including bowel gas), and external material such as bandages or ostomy bags that may not be amenable to repositioning. As with gray-scale US, there is operator dependency when using CEUS during procedures. Repeated contrast agent dosing is typically permissible and may facilitate some leeway. However, for time-dependent target visualization, coordinating contrast agent timing with patient positioning, respiration, and needle access may prove challenging. Last, additional personnel may be needed for CEUS preparation and administration while the proceduralist maintains a sterile field and the sonographer operates the US machine.
UCA Applications in Abdominal Imaging and Intervention
The following cases highlight the authors’ experience with some less frequently discussed applications of UCAs, particularly as they apply to abdominal imaging and intervention. However, this is not meant to be an all-inclusive review, as the list of new and emerging applications of UCAs is rapidly increasing.
Genitourinary Applications
Voiding Cystourethrography.—Voiding cystourethrography (VCUG) is commonly performed in pediatric patients who have a history of recurrent urinary tract infections (UTIs) to assess for vesicoureteral reflux (30). This fluoroscopic procedure, utilizing ionizing radiation, has an estimated effective radiation dose of 47 μSv (31). Contrast-enhanced voiding urosonography (CE-VUS) was first proposed as an alternative in 1998, separately by Bosio (32) and Darge et al (33). CE-VUS provides equivalent dynamic assessment and classification of vesicoureteral reflux as well as assessment of the penile urethra (Figs 1, 2). Additionally,
CE-VUS provides similar dynamic information as fluoroscopy without the use of ionizing radiation.
Figure 1. Vesicoureteral reflux in a 3-month-old infant girl with recurrent UTIs. Throughout the figures, the dual-screen “contrast agent–only” and gray-scale images appear on the left and right, respectively. (A) Dual-screen contrast agent–only and gray-scale CE-VUS images show the urinary bladder filled with diluted microbubble contrast agent (0.2% sulfur hexafluoride lipid–type A microspheres in normal saline) with an indwelling catheter to 21 mL on the basis of weight (*). (B–D) Dual-screen contrast agent–only and gray-scale CE-VUS images show spontaneous vesicoureteral reflux into both ureters (arrows in B) and upper pole caliectasis (arrows in C and D) bilaterally, compatible with grade 4 vesicoureteral reflux. See also Movie E1.
Movie E1: Vesicoureteral reflux in a 3-month-old infant girl with recurrent urinary tract infections (UTIs) in a 3-month-old infant girl. Real-time US cine clip shows vesicoureteral reflux bilaterally after intravesicular administration of a diluted microbubble contrast agent.
Figure 2. Penile urethra assessment in a 2-month-old infant boy with prior UTI. The urinary bladder was filled with diluted microbubble contrast agent (0.2% sulfur hexafluoride lipid–type A microspheres in normal saline) with an indwelling catheter (not shown). (A) Dual-screen contrast agent–only and gray-scale CE-VUS images show no vesicoureteral reflux into either left or right (not shown) kidneys. (B) CE-VUS image obtained during the voiding portion of the examination shows a normal male urethra into the penile segment (arrow). See also Movie E2.
Movie E2: Penile urethra assessment in a 2-month-old infant boy with prior UTI. The urinary bladder was filled with diluted microbubble contrast agent (0.2% sulfur hexafluoride lipid-type A microspheres in normal saline) with an indwelling catheter (not shown). CE-VUS cine clip obtained during the voiding portion of the examination show a normal male urethra into the penile segment.
A prospective noninferiority study in 2016 by Piskunowicz et al (27) demonstrated equivalence between VCUG and CE-VUS, and a recent meta-analysis corroborated this but also noted a false-negative rate of 3% (34). CE-VUS has also been recently reported as an effective means of evaluating transplanted kidneys for reflux (35). Readers are referred to Duran et al (28) for a comprehensive technical discussion of CEUS of the urinary tract.
Nephrosonography.—Nephrolithiasis is commonly treated with percutaneous nephrolithotomy. Postprocedure care can include the placement of a percutaneous nephrostomy catheter, nephroureteral stent, or similar devices. The percutaneous catheter typically remains in place until antegrade ureteral patency can be confirmed, which is usually accomplished with fluoroscopic nephrostography. The use of a UCA for nephrosonography was first proposed as a noninferior alternative for assessment of ureteral patency in 2017 by Chi et al (36). The authors’ institutional experience converting to a CEUS-based workflow was recently published by Fetzer et al (37). A UCA administered through a percutaneous nephrostomy catheter can also assist in the evaluation of retrograde leak along the catheter, urothelial injury, and urine extravasation (Fig 3).
CEUS can effectively evaluate ureteral and stent patency by direct injection through an indwelling catheter into the renal collecting system.
Figure 3. Contrast-enhanced US antegrade pyelography in a 62-year-old man 1 day after right percutaneous nephrolithotomy (PCNL). (A) Transverse gray-scale US image through the right kidney shows a percutaneous nephroureteral catheter passing through the cortex into the right renal collecting system (arrow). (B) Dual-screen contrast agent–only and gray-scale US images after 1 mL sulfur hexafluoride lipid–type A microspheres injected by catheter followed by a 5 mL saline flush shows filling of renal pelvis (arrow) with contrast agent tracking retrograde along the catheter (arrowhead). (C, D) Precontrast (C) and postcontrast (D) US images of the bladder show contrast agent filling the lumen (arrow), confirming ureteral patency.
Gastrointestinal Applications
Fistulography.—A fistula is an abnormal communication between two separate epithelialized spaces within the body. An enterocutaneous fistula (ECF)—an abnormal communication between the skin and bowel—is a difficult-to-treat condition with a 10%–30% mortality rate (38,39). Up to 85% are iatrogenic or occur within the postoperative setting (40). Characterization of a fistula tract can be difficult. Conservative noninvasive treatment is the first-line therapy, as up to 30% of ECFs heal spontaneously. More aggressive management may be needed. Although the surgical resection success rate is from 58% to 89%, there remains a 20% rate of recurrence and a 7% risk of mortality (41,42). Readers are referred to Rahman and Stavas (41) for a detailed discussion of ECF management and outcomes.
Various radiologic techniques may be used to confirm and further characterize a suspected ECF. CT or fluoroscopy is often attempted after the oral administration of a contrast agent with the goal of identifying extraluminal contrast agent extending to the skin surface, or vice versa. Fistulography may be attempted by cannulating the fistula at the skin, with retrograde contrast agent filling of the tract. However, these techniques carry relative contraindications, including radiation exposure and the risk of contrast agent allergy. SPECT/CT fistulography has also been reported with technetium 99m (99mTc) diethylenetriaminepentaacetic acid (DTPA) (43).
Hydrogen peroxide–enhanced US fistulography was first reported by Maconi et al (44) in 1999. Dedicated UCA use for ECF evaluation was first reported in 2003 by Chew et al (45), and intracavitary use for evaluation of ECF was first reported by Chen et al in 2016 (46). In the article by Chen et al, a preparation of 30–50 mL of 1:100–1:300 (0.33%–1.0%) diluted sulfur hexafluoride UCA in normal saline was injected into the suspected tract or cavity, followed by monitoring of the regional gastrointestinal tract for the presence of microbubble contrast agent. In our experience, 1:100 dilution has been effective in assessment of abscess cavities and fistula (Fig 4).
Figure 4. Recurrent pancreatic cancer with colonic fistula in a 58-year-old man after distal pancreatectomy. (A) Axial contrast-enhanced T1-weighted fat-suppressed MR image through the upper abdomen shows an irregular rim-enhancing collection within the resection bed (arrow). CT showed gas within the collection and a prior percutaneous drain tract (not shown). (B) Dual-screen contrast agent–only and gray-scale US images show how the drain tract was cannulated, and 1 mL of sulfur hexafluoride lipid–type A microspheres followed by 10 mL saline flush was injected intracavitarily, filling the collection (arrow). (C) Dual-screen US images depict how the contrast agent within the adjacent bowel confirmed the presence of a fistula (arrowhead).
Cholecystostomy Catheter Check.—Percutaneous cholecystostomy catheters (C-tubes) are used to access the gallbladder lumen, most commonly to decompress the gallbladder in the management of acute cholecystitis when endoscopic or surgical interventions are not possible or are contraindicated (47). Complications include C-tube dislodgement (most common complication) as well as disruption, occlusion, and bile leak, all of which may manifest with decreased C-tube output and recurrence of symptoms (47,48). However, cessation of tube output may also indicate resumption of cystic duct patency, a key requirement for C-tube removal.
Confirmation of cystic duct patency, or depiction of complications such as dislodgement and leak, is typically performed fluoroscopically with the administration of a radiopaque contrast agent through the C-tube. This often requires that the patient is in stable condition and is capable of traveling to the fluoroscopy suite, which may not be permissible for patients with critical illness, and carries a small risk of allergic reaction to the iodinated contrast agent.
CEUS is a nonionizing alternative to help confirm appropriate C-tube placement by identifying the UCA within the gallbladder lumen. Identification of extraluminal pericholecystic contrast agent would indicate a bile leak. Although visualization of the cystic duct may be difficult, identification of contrast agent within the distal common bile duct, and in particular within the lumen of the duodenum, would confirm cystic duct patency (Fig 5). Care must be taken to review the preinjection contrast agent–mode images to localize echogenic structures not attributable to the contrast agent, and these often include gallstones, vessel walls, and bowel gas. The presence of contrast agent in the pericholecystic peritoneal cavity may indicate a bile leak.
Figure 5. C-tube check in a 55-year-old man with critical illness with decreased drain output. (A) Dual-screen contrast agent–only and gray-scale US images of the gallbladder after instillation of 1 mL sulfur hexafluoride lipid–type A microspheres through the C-tube show only pseudoenhancement from multiple stones (arrow). (B) Dual-screen US images show contrast agent within the common bile duct (arrows), confirming cystic duct patency. (C) Dual-screen US images show contrast agent in the duodenum (arrows), confirming common bile duct patency.
A CEUS C-tube check is a viable alternative to confirm C-tube position and cystic duct patency when fluoroscopy is not feasible.UCA Oral Administration.—Radiologic assessment for anastomotic leaks is commonly performed postoperatively after head and neck or gastrointestinal surgery, typically with real-time fluoroscopy and ingestion of radiopaque contrast agent. There is limited literature on the use of orally ingested UCAs as an alternate modality in this setting. The use of cellulose-based UCA has been reported as an alternative to radionuclide gastric emptying examinations (49). As a space-constrained material (see previous technical considerations), orally ingested UCA remains in the gastrointestinal tract unless perforation is present. The use of an orally ingested contrast agent to differentiate abscess from the sinus tract is shown in Figure 6.
Figure 6. Oral administration of a UCA in a 72-year-old woman with a history of total laryngectomy and flap reconstruction who underwent evaluation for sensation of incomplete food passage from the cervical esophagus. (A) Axial contrast-enhanced CT image shows an air-fluid collection (arrow) along the right paraesophageal region, deep to the surgical incision. With clinical concern for abscess, US-guided aspiration was requested. Before attempted percutaneous access, the patient was given a diluted UCA (1 mL sulfur hexafluoride lipid–type A microspheres in 200 mL tap water) orally. (B) Dual-screen contrast agent–only and gray-scale transverse US image from a right lateral approach shows UCA tracking from the lumen of the cervical esophagus (arrowheads) into the sinus tract arising from the right lateral aspect of the esophagus (arrows) deep to the surgical scar (*).
Vascular Applications
Endoleak Assessment.—Endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms is associated with reduced mortality compared with that of open repair, and the number of annual endovascular repairs now exceeds that of open surgical repairs (29). Increasingly complex endovascular repairs include bridging, branched, modular, and fenestrated EVAR (FEVAR) techniques (50). With the inclusion of multiple components, the opportunities and available sites for type III endoleaks increase. Other complications include acute renal injury (15%), stent graft limb occlusion or thrombosis (5%), stent migration (3.6%), and bowel ischemia (1%–2%) (51).
Patients typically undergo post-EVAR or post-FEVAR surveillance to help ensure the excluded aneurysm sac remains stable in size. If enlargement is detected, an endoleak may be present. Endoleak is the most common EVAR complication, occurring in up to 30%–40% of patients. A type II endoleak (retrograde filling into the excluded sac by a small arterial branch such as the inferior mesenteric artery or a lumbar artery) is the most common type. Type III endoleak (leak through a graft or modular defect) may be becoming more common with increased use of fenestrations and multiple bridging modular components. New classification schemes have been proposed to describe the leaky junction, and a third type I endoleak subtype, type Ic, has been proposed to describe retrograde filling from the end of a side branch distal attachment (52).
An early publication proposing CEUS as an alternative to CT angiography (CTA) was published by Bendick et al (53) in 2003, and the first reported use as an accurate alternative for FEVAR evaluation was by Perini et al (54) in 2012. In comparison with CTA, CEUS can depict the excluded sac immediately adjacent to the stent graft, which can be obscured by streak artifact at CTA; has better sensitivity to low-flow endoleaks; and avoids concerns related to allergy, renal function, and radiation. However, operator expertise and variation in extra-aortic patient anatomy can introduce challenges (29). Several meta-analyses have found CEUS to be accurate compared with CTA and confirmed a higher sensitivity for low-flow endoleaks (55–57). Additionally, CEUS can help evaluate end-organ perfusion in patients with an endograft, which can be of particular concern if modular or bridging components extend into the branch vessels (Fig 7).
Figure 7. FEVAR that included renal artery branch stents bilaterally in a 65-year-old man. CEUS evaluation was requested owing to acute renal failure. (A) Transverse dual-screen contrast agent–only and gray-scale images through the midabdominal aorta after intravenous administration of 1.5 mL sulfur hexafluoride lipid–type A microspheres show an excluded sac without microbubble contrast agent, excluding endoleak (arrow in A). (B) Dual-screen US images show how the stent lumen enhances homogeneously, reflecting patency (arrow), as do the renal artery branch stents (arrowheads). (C) Dual-screen US images show symmetric perfusion in the right and left (not shown) kidneys.
CEUS can also provide dynamic information not available with CTA through real-time depiction of the leak, location, and flow characteristics (slow or fast), which may help guide diagnosis and therapy. For example, real-time visualization of excluded sac enhancement after aortic enhancement would suggest type II endoleak, whereas concurrent enhancement of the excluded sac and aorta would favor type III endoleak (Figs 8, 9). In summary,
CEUS can be performed to assess for stent patency and endoleak when CTA is inconclusive or not desirable.
Figure 8. Evaluation of FEVAR in an 86-year-old man with an aortobifemoral graft. (A) Sagittal CTA image in the delayed phase shows contrast agent accumulation in the posterior aspect of the excluded aneurysm sac (arrow). CEUS was performed for real-time assessment of endoleak. (B) Dual-screen contrast agent–only and gray-scale US images though the midabdominal aorta after intravenous administration of 1.0 mL sulfur hexafluoride lipid–type A microspheres show delayed puddling of the contrast agent in the posterior sac, suggesting type II endoleak from the lumbar perforator artery (arrow). (C) Digital subtraction angiogram obtained during translumbar access of the excluded sac shows the culprit vessel (arrow), guiding subsequent embolization (not shown).
Figure 9. Evaluation of FEVAR in a 75-year-old man. (A) Axial CTA image of a modular endograft shows a blush of contrast agent anterior to the left renal artery component (arrow). CEUS was performed for real-time assessment of the graft components. (B) Dual-screen contrast agent–only and gray-scale US images after intravenous administration of 0.5 mL sulfur hexafluoride lipid–type A microspheres show contrast agent in the excluded sac (arrow) anterior to and simultaneously with left renal artery graft enhancement (arrowhead). See also Movie 3. (C) Selective digital subtraction angiogram of the left renal artery confirms type III endoleak before graft revision (arrow).
Movie 3: Evaluation of FEVAR in a 75-year-old man. Dual-screen contrast agent-only and gray-scale US cine clips acquired after intravenous administration of 0.5 mL sulfur hexafluoride lipid-type A microspheres show contrast agent in the excluded sac anterior to and simultaneously with left renal artery graft enhancement.
Extravasation Assessment.—Interventional procedures performed on deep viscera carry a risk of complications, including hemorrhage. The reported rate of major bleeding is less than 1%, including 0.5% after liver biopsy (58–61). Postbiopsy observation of intravenously injected UCA flow along the biopsy needle tract has been reported in 33% of cases in one series, none of which developed into clinically significant hemorrhage (62). If clinically significant hemorrhage is suspected and an intravenous catheter is already in place, CEUS can be used to perform an en suite assessment for active extravasation in lieu of a time-consuming transfer to a CT scanner and connection to an iodinated contrast agent injector (Figs 10, 11).
Figure 10. Active hemorrhage in a 55-year-old woman who developed a large perinephric hematoma immediately after renal biopsy for medical renal disease. Dual-screen contrast agent–only and gray-scale US images of the kidney (arrowheads) at the biopsy site after intravenous injection of 1.5 mL sulfur hexafluoride lipid–type A microspheres show a large perinephric collection (*) with a stream of extraluminal microbubble contrast agent filling the most anechoic component, indicating active extravasation into a postbiopsy hematoma (arrow). The patient subsequently underwent endovascular intervention for embolization of a capsular artery (not shown).
Figure 11. Active hemorrhage in a 74-year-old man with cirrhosis who underwent liver biopsy for suspected hepatocellular carcinoma. (A) Dual-screen contrast agent–only and gray-scale US images obtained after intravenous administration of 2.4 mL sulfur hexafluoride lipid–type A microspheres show an enhancing subcapsular observation in the right liver (arrow). (B) Postbiopsy dual-screen US images show contrast agent accumulation in the perihepatic space, indicating active extravasation (arrow). The patient received conservative treatment and was discharged without further complication. Pathologic analysis results confirmed a dysplastic nodule.
UCAs can also be used to increase confidence that hemostasis has been achieved. If a UCA was used to increase lesion conspicuity during biopsy, postbiopsy administration to document hemostasis is an alternative to discarding any unused volume of reconstituted microbubble contrast agent. CEUS can also be useful for active extravasation evaluation in a hemodynamically stable patient with acute renal injury or relative contraindication to iodinated contrast agents (Fig 12).
Figure 12. Active hemorrhage in a 64-year-old woman with clinical pyelonephritis and acute anemia who underwent nonenhanced CT. (A) Sagittal reconstruction from CT through the left kidney shows a perinephric hematoma (arrow). (B) Dual-screen contrast agent–only and gray-scale US images show perinephric hematoma on the gray-scale image (arrowhead) with microbubbles present throughout the hematoma, indicating active extravasation (arrow). (C) Selective digital subtraction angiogram of the left renal artery shows active extravasation (arrow) and pseudoaneuryms (arrowheads) in the lower pole, which were subsequently embolized (not shown).
Other Interventional Applications
Vascular Lesion Characterization.—The relatively large microbubble particles that make up UCAs are too large to cross an intact vascular endothelium and remain within a space or cavity (22). This feature can be leveraged to demonstrate continuity of a lesion or collection with the vascular space (or biliary, urinary, or gastrointestinal spaces). If a UCA is injected directly into a solid soft-tissue mass, generally the microbubbles accumulate immediately at the needle tip and may dissect along tissue planes but will likely not intravasate.
A literature search performed by the authors did not find any previously reported cases describing the possibly novel application of intralesional injection of UCA to diagnosis of vascular malformations. As such, additional studies and validation are called for beyond the authors’ presented cases, provided here in this section.
In the first case, an 82-year-old woman with left lung adenocarcinoma was found to have a mildly fluorodeoxyglucose (FDG)-avid indeterminate left upper quadrant mass, with the primary concern being an adrenal metastasis. At the time of biopsy, the proceduralist became suspicious of a vascular anomaly, given the recognition that components of this lesion appeared to follow blood pool on prior images. A diluted microbubble contrast agent was injected intralesionally through the coaxial biopsy introducer needle (Fig 13). Real-time monitoring of the regional vasculature and viscera showed enhancement of the splenic vasculature 25 seconds after injection, followed by parenchymal enhancement 5 seconds later. This confirmed that the lesional space receiving the injection was in open communication with the blood pool. Then, 18-gauge core biopsy specimens were obtained through the introducer needle, and the results of a final pathologic analysis confirmed hemangioma.
The imaging finding of intralesionally injected microbubbles causing enhancement of vessels and solid organs confirms that a lesion directly communicates with the vascular space, supporting the imaging diagnosis of a vascular lesion.
Figure 13. Continuity with vascular space in an 82-year-old woman with left lung adenocarcinoma. (A) Fluorine 18 (18F) FDG PET/CT image shows a mildly FDG-avid indeterminate left upper quadrant mass, concerning for an adrenal metastasis (arrow). During a CT-guided biopsy attempt, CEUS was requested by the interventionalist given suspicions for a vascular mass. (B, C) Dual-screen contrast agent–only and gray-scale US images show the direct intralesional injection of 2.5 mL of diluted sulfur hexafluoride lipid–type A microspheres through the indwelling coaxial biopsy needle. There is enhancement of splenic vasculature 25 seconds after injection (arrow in B, Movie 4) with parenchymal enhancement 5 seconds later (* in C, Movie 4). Given the size of the microbubble contrast agent particles, this imaging finding indicates continuity of this lesion with the vascular space. Biopsy results confirmed hemangioma.
Movie 4: Continuity with vascular space in an 82-year-old woman with left lung adenocarcinoma. Dual-screen contrast agent-only and gray-scale US cine clips show the direct intralesional injection of 2.5 mL of dilute sulfur hexafluoride lipid-type A microspheres through the indwelling coaxial biopsy needle. There is enhancement of splenic vasculature 25 seconds after injection with parenchymal enhancement 5 seconds later.
In another case, a 69-year-old woman presented with a palpable soft-tissue neck mass that remained indeterminate after a fine-needle aspiration (FNA). The lesion was mildly enhancing at CT of the neck (Fig 14). Because of the sonographic appearance, there was suspicion for a vascular lesion. Through a spinal needle, a microbubble contrast agent was injected with immediate microbubble dispersion and prompt enhancement of the internal jugular vein and common carotid artery. A repeat 25-gauge FNA was then performed, followed by 18-gauge core biopsy, with histologic findings of anastomosing vascular spaces lined by bland-appearing endothelial cells, which is deemed consistent with lymphangioma or hemangioma. Subsequent surgical excision confirmed the diagnosis of cavernous hemangioma.
Figure 14. Cavernous hemangioma in a 69-year-old woman. (A) Axial contrast-enhanced CT image shows a palpable right neck mass (arrow) that was indeterminate at prior FNA. During a repeat FNA attempt, a 22-gauge spinal needle was introduced into the lesion, through which 1 mL of diluted sulfur hexafluoride lipid–type A microspheres was injected. (B) Dual-screen contrast agent–only and gray-scale US images show immediate diffuse microbubble dispersion, which is atypical for a solid mass (*). See also Movie 5. (C) Dual-screen US images show vascular communication with visualization of the microbubble contrast agent in the adjacent internal jugular vein (arrows) and common carotid artery (arrowheads), indicating that the mass directly communicates with vascular space. Subsequent core needle biopsy confirmed findings consistent with hemangioma. See also Movie 6.
Movie 5: Cavernous hemangioma in a 69-year-old woman. Dual-screen contrast agent-only and gray-scale US cine clips show immediate diffuse microbubble dispersion after injection of 1 mL of diluted sulfur hexafluoride lipid-type A microspheres.
Movie 6: Cavernous hemangioma in a 69-year-old woman. Dual-screen cine US image shows vascular communication with visualization of the microbubble contrast agent in the adjacent internal jugular vein and common carotid artery, indicating that the mass directly communicates with vascular space.
In a third case, a 50-year-old woman had a history of papillary thyroid cancer and melanoma with long-standing history of a palpable right lateral neck mass. Prior biopsy attempts were unsuccessful. Gray-scale US of the right level V depicted a patulous anechoic structure, into which a diluted microbubble contrast agent was injected (Fig 15). The cavity expanded and diffusely filled with the contrast agent, indicating a patent or potential space. No contrast agent was identified within the vascular space. The imaging findings were consistent with a soft-tissue lymphatic malformation, and further biopsy attempts were deferred.
Figure 15. Spatial injection in a 50-year-old woman with multiple prior malignancies who underwent evaluation for palpable right level V mass. (A) Gray-scale US image shows a patulous anechoic structure (*) that collapsed with compression and did not have flow at color Doppler US (not shown). Approximately 1 mL of diluted sulfur hexafluoride lipid–type A microspheres was injected with 25-gauge spinal needle. (B) Dual-screen contrast agent–only and gray-scale US images of the cavity show expanded and diffuse filling by the contrast agent (*). There is an absence of contrast agent in the vascular space (not shown), which was consistent with a soft-tissue lymphatic malformation.
Hysterosalpingo-Contrast Sonography.—Infertility is estimated to affect 6%–18% of couples (63,64). Tubal causes have been identified in 14%–35% of such couples, who have typically undergone assessment with fluoroscopic hysterosalpingography (65,66). Hysterosalpingo-contrast sonography (HyCoSy) was first proposed as a radiation free and less invasive alternative to fluoroscopic hysterosalpingography and chromolaparoscopy in 1989 by Deichert et al (67). Intraendometrial installation of UCA can depict each tubal segment and demonstrate peritoneal spillage needed to confirm patency (Fig 16). Comparison of saline-diluted microbubbles to foam-based UCAs has shown foam media to have higher sensitivity for demonstrating tubal patency (68). More recently, a meta-analysis comparing HyCoSy to MR hysterosalpingography (MR-HSG) showed similar overall performance, with higher sensitivity for MR-HSG but higher specificity for HyCoSy (69). Severe pain, a possible side effect of HyCoSy, is estimated to occur in 6% of patients (70).
Figure 16. Assessment of fallopian tube patency in a 28-year-old woman who underwent HyCoSy during a workup for primary infertility. After canalization of the cervical os, a reconstituted microbubble contrast agent (0.5 mL sulfur hexafluoride in 50 mL saline) was instilled into the endometrial cavity. (A, B) Contrast agent–only transvaginal US images show the endometrial cavity (* in A) and contrast agent extending through the interstitial (arrowhead in A), isthmic (arrow in A and B), and ampullary (arrowheads in B) segments of the fallopian tube. (C) US image shows a patent tube with intraperitoneal spill (*) and the ovarian rim sign (arrow). (Case courtesy of Shuchi K. Rodgers, MD, Thomas Jefferson University, Philadelphia, Pa.)
Enhanced Needle Visualization.—During US-guided interventions such as biopsies, aspirations, and drainage procedures, needle visualization can be challenging, particularly for inexperienced operators, with the inadvertent introduction of air along the tract and factors intrinsic to the patient, including obesity and hepatic steatosis. Dedicated needle visualization settings available on some machines and the use of purpose-designed echogenically enhanced needles may be beneficial, but identifying the precise location of the needle tip may still remain challenging (71,72).
Needle visualization can be dramatically improved by using UCAs. For instance, the stylet of a coaxial needle can be coated in a reconstituted US microbubble contrast agent, or a single drop of contrast agent can be placed into the introducer needle hub, followed by reinsertion of the stylet or a biopsy needle (“lightsaber” technique) (Fig 17). In both the contrast agent–only and B-mode images, the needle becomes highly echogenic, simulating a lightsaber in appearance (Figs 18, 19).
Figure 17. Improving visualization of a biopsy needle with a UCA (“lightsaber” technique). A single drop of reconstituted microbubble contrast agent can be placed into the hub of a coaxial needle, followed by replacement of the stylet, to improve needle visualization. Alternatively, the stylet can be coated with the UCA or the coaxial needle can be filled with diluted UCA (1 drop to 10 mL saline) before use.
Figure 18. Improving visualization of a biopsy needle with a UCA (lightsaber technique) in a 65-year-old woman with a history of breast cancer. (A) Axial contrast-enhanced CT image through the liver dome shows a hypoenhancing mass (arrow). CEUS was used as a component of multimodality registration and fusion to improve lesion visualization and navigation confidence. (B) A four-in-one view of contrast agent–only US (top left), gray-scale US (top right), axial CT image (bottom left), and axial CT-US overlay (bottom right) after intravenous administration of 1.5 mL sulfur hexafluoride lipid–type A microspheres shows rapid lesion washout at 25 seconds (arrow, lesion marked as T1). A single drop of sulfur hexafluoride lipid–type A microspheres was placed into the coaxial needle hub, and the stylet was reinserted. (C) Four-in-one view shows dramatically improved precise visualization of the needle and identification of its tip on both contrast agent–only and gray-scale images with the lightsaber sign (arrow). Biopsy results confirmed metastatic breast cancer.
Figure 19. Improving visualization of a biopsy needle with a UCA (lightsaber technique) in a 28-year-old woman undergoing FNA of a small hepatic lesion. A single drop of sulfur hexafluoride lipid–type A microspheres was placed into the hub of a 22-gauge spinal needle, then the stylet was reinserted. The needle remains poorly depicted on the gray-scale US image (right) but is clearly visualized on the contrast agent–only image (left).
Conclusion
CEUS is a versatile tool in abdominal imaging and intervention. CEUS leverages the many inherent benefits of US with a safe and unique contrast agent. A microbubble contrast agent has many intravenous uses, where it functions as a pure blood pool agent, and its short half-life allows multiple injections during a single examination. Emerging intravenous uses in abdominal US include vascular imaging for vessel patency assessment and EVAR endoleak characterization and the depiction of active extravasation. There is also an ever-expanding list of nonintravenous (off label) uses including catheter examinations such as those for assessment of C-tubes and percutaneous nephrostomy catheters; direct injection into fistulae, abscess cavities, or suspected venous or lymphatic malformations; and improvements in needle visualization. As availability and experience improve, we expect to see additional opportunities and applications emerge.
Presented as an education exhibit at the 2021 RSNA Annual Meeting.
For this journal-based SA-CME activity, the authors E.W.P. and D.T.F. have provided disclosures (see end of article); all other authors, the editor, and the reviewers have disclosed no relevant relationships.
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Article History
Received: Jan 31 2022Revision requested: Mar 10 2022
Revision received: Apr 19 2022
Accepted: Apr 22 2022
Published online: Oct 03 2022
Published in print: Oct 2022
