Current Practice
Endocavitary Contrast-Enhanced Ultrasound: A Technique Whose Time Has Come? Thomas M€ uller, MD, Wolfgang Blank, MD, Jens Leitlein, MD, Stefan Kubicka, MDx, Alexander Heinzmann, MD Klinikum am Steinenberg, Medizinische Klinik I, Reutlingen, Germany Received 24 May 2013; accepted 7 September 2014
ABSTRACT: Endocavitary use of contrast agents in sonography (US) is a relatively new method in diagnostic imaging, competing against gray-scale US, fluoroscopy, and endoscopy. This article describes established indications, demonstrates the techniques of evolving applications, and discusses their potential benefits. These benefits include the ability to obtain precise information about the placement of drains and the extent of fluid collections, and to accurately identify the location and features of strictures in various organs, and those of complications of fluid collections or abscesses, without resorting to ionizing C radiation. V 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:71–80, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ jcu.22250 Keywords: contrast-enhanced ultrasound; ultrasoundguided intervention; endocavitary; ultrasonography
INTRODUCTION
T
he first sonography (US) contrast media (USCMs), introduced in the 1980s, improved the sonographic visibility of heart cavities, blood vessels, blood flow, and pathologic entities such as arteriovenous shunts. During the 1990s, several first-generation USCMs were approved for intravenous administration. A second-generation USCM, sulfur hexafluoride (SonoVue; Bracco Imaging S.p.A., Milan,
Wolfgang Blank received financial support from Bracco (travel grants, lectures). The other authors declare no conflict of interest. Correspondence to: T. M€ uller C 2014 Wiley Periodicals, Inc. V
VOL. 43, NO. 2, FEBRUARY 2015
Italy), was approved in Europe in 2001 solely for intravenous use in adults.1,2 Second-generation USCMs permit continuous visualization when using a low mechanical index, thus enabling real-time imaging of perfusion patterns.3 Almost immediately, however, the search began for additional applications of this new tool in diagnostic US. Shortly after its approval, a preparation of galactose, palmitic acid, and air (Levovist; Schering AG, Berlin, Germany) was administered into the bladder to detect vesicoureteral reflux in voiding urosonography in a child, thus avoiding the use of ionizing radiation. Hysterosalpingo-contrast-sonography (HyCoSy) using various USCMs has been successfully performed and evaluated against fluoroscopic or laparoscopic procedures in controlled trials.4–12 In the assessment of other diseases or organs, however, the situation is very different. Various possible indications for endocavitary contrastenhanced US (eCEUS) have been proposed in case reports, abstracts, or feasibility studies from Europe and Asia, but in most cases reliable dosage recommendations are not available and the method is not well-established compared with standard methods such as fluoroscopic imaging or the administration of saline solution under US guidance. Proposed indications for eCEUS include locating tubes and drains in body cavities, abscesses, or collections13,14; estimating the dimensions and detecting the communications of fluid collections13,15–17; percutaneous, transpapillary, or intraoperative visualization of the biliary system16–23; demonstrating thoracoabdominal communication in cases of suspected hepatic hydrothorax24–26; detecting and quantifying fistulae in various locations27–29; assessing the 71
€ MULLER ET AL
digestive tract after oral or colonic administration of USCMs17,30–34; confirming correct placement of a percutaneous nephrostomy35; and evaluating obstructive disease of the salivary glands.36 Endocavitary administration of USCMs has recently been included in guidelines from the European Federation of Societies for Ultrasound in Medicine and Biology, which emphasize that no well-established indications exist at present but recommend considering the use of eCEUS if alternatives (eg, fluoroscopy, need to transport critically ill patients) may carry a higher risk for the patient.37 Against the background of this miscellany of publications, it seems useful to try to attain clarity about where eCEUS is rewarding and where it may be superfluous. Some advantages are obvious. eCEUS can be done at the bedside, without radiation, and is minimally invasive. When performing several examinations successively, the costs of sulfur hexafluoride are relatively low: a multidose vial of SonoVue contains 5 ml sulfur hexafluoride, and each examination requires only 1 drop. Other USCMs like perflutren lipid microspheres (Definity Injectable Solution; Lantheus Medical Imaging, North Billerica, MA) are marketed for single use only, and the costs may be significantly higher. To justify its use, eCEUS must be diagnostically equivalent to standard procedures, provide additional information, or avoid possible risks of other methods. In our US department we do more than 12,000 US examinations and around 600 USguided interventions per year and frequently perform eCEUS in various settings preliminarily described by Heinzmann et al,17 in an attempt to gain information beyond that provided by gray-scale US or to reduce patient risk to less than that associated with fluoroscopic imaging or endoscopy. In this article, we provide examples of eCEUS from our own investigations, discuss possible benefits, and point out where eCEUS seems to be unnecessary. For well-established indications, we provide data from recent studies.
MATERIALS AND METHODS
All of our studies were performed using sulfur hexafluoride (SonoVue) and an Acuson Sequoia 512 US machine (Siemens Medical Solutions USA, Inc., Malvern, PA) with cadence contrast pulse sequencing technology using the low 72
mechanical-index mode. A convex array multifrequency transducer (4C1, Acuson Siemens) was used for all examinations. Unless otherwise stated, the dosages given below relate to sulfur hexafluoride. One milliliter of SonoVue contains approximately 8 ml of sulfur hexafluoride as microbubbles in a phospholipid shell.1 All eCEUS applications have in common the use of a solvent (eg, 0.9% saline) to which a small amount of USCM is added. The resulting solution is shaken vigorously and administered directly into a body cavity through a drain, catheter, or cannula. When imaging the gastrointestinal tract, we use tap water at room temperature as the solvent. Specific preparations are described together with the indications below. Because our studies were performed in daily practice, each based on an individual decision rather than forming part of a clinical trial, they were not subject to the Declaration of Helsinki. Oral informed consent was obtained from each patient. Risks and Possible Side Effects of eCEUS Endocavitary administration of USCM is a relatively new method. Trials involving its use in voiding urosonography, HyCoSy, or biliary imaging mention no adverse reactions except for localized pain during injection, which probably was due to distension rather than to the USCM itself.5,8–12,19,21 A postmarketing multicenter analysis claims a fairly low rate of adverse reactions seen after intravenous administration of sulfur hexafluoride in 23,188 investigations: major complications seemed to occur at a rate between 0.0086% and 0.012%. The vast majority of these complications were direct allergic reactions, including allergic shock syndrome and spastic bronchial reactions. These allergies appear to be related to the bubbles’ polyethylene glycol sheath. Fatalities are rare: among more than 150,000 administrations, three deaths were reported (0.002%), and causality could not be proved. All three of the patients involved had severe cardiac disease.38,39 A smaller singlecenter analysis of cardiac indications for the use of sulfur hexafluoride in 352 consecutive patients reported a much higher rate of severe allergic reactions, 0.9%.40 Local cytotoxic effects are related to a high mechanical index of the US beam and are not expected to appear when the low mechanical index mode is used.41 Nevertheless, contraindications for intravenous administration (hypersensitivity to any of the components of the product, right-to-left-shunt, pulmonary or untreated JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND
FIGURE 2. An 82-year-old woman with pancreatic carcinoma and fever. A hepatic abscess (A) was diagnosed on gray-scale US. After the instillation of 15 ml of diluted USCM into an abscess drainage catheter, USCM bubbles also appeared in the dilated bile ducts (BD) and in a hepatic vein (arrows). The connection of the abscess with the biliary system had not been detectable on gray-scale US alone. The appearance of USCM bubbles in the hepatic vein indicates a complication of catheter placement. One of the catheter’s holes must have been placed in a vein close to the abscess. The catheter was repositioned because of this finding.
Resuscitation equipment should be available nearby and especially trained personnel available to take care of adverse events. The administration of USCMs other than intravenously is currently an off-label use, so we recommend obtaining the patient’s informed consent. Patients must be informed about the method itself, potential risks (eg, allergic reactions), possible benefits, and alternatives. Possible Indications for eCEUS
FIGURE 1. A 76-year-old man with fever and shivering. (A) Gray-scale US imaging shows a hypoechoic liver lesion with ill-defined margins (1 1). (B) Intravenous CEUS performed in the expectation of finding liver abscesses. The lesion remains anechoic, although the size and shape of the abscess are well depicted. Pus was aspirated. (C) A pigtail drain (arrow) was inserted into the abscess under ultrasound guidance. After injection of diluted USCM (1 drop of sulfur hexafluoride in 10 ml saline solution), the abscess can be depicted for a long time. In eCEUS, the margins appear irregular compared with those on the CEUS image (B) and depict more precisely the extent and shape of the cavity containing liquid pus.
systemic hypertension, acute dyspnea, and pregnancy or lactation)1 should be taken into consideration when delivering diluted USCMs to body cavities. VOL. 43, NO. 2, FEBRUARY 2015
Fluid Collections. Fluid collections such as abscesses and effusions can be diagnosed by gray-scale US (Figure 1A), but detecting complications such as fistulae, communications, or loculations can be a challenge. Drains can be placed under US guidance, but a misplaced drain tip is sometimes hard to detect with grayscale US alone. For eCEUS, after insertion of the drain, depending on the estimated volume of the collection, 10–20 ml of 0.9% saline solution with the addition of 0.1 ml of sulfur hexafluoride is administered via the tube. This concentration of USCM seems sufficient for most purposes in the abdominal and retroperitoneal space. When searching for communicating fluid collections (eg, in the case of loculated ascites or ascites with concomitant pleural effusion [hepatic hydrothorax]), a larger amount of saline solution may be useful. It is rarely necessary to increase the amount of USCM in the solution. 73
€ MULLER ET AL
FIGURE 3. A 72-year-old man suffering weight loss, fever, and nightly sweats. (A) A complex structure of 9 cm diameter (1 1) showing probable air within a cavity is seen in the gray-scale image of the spleen. It was suspected to be a splenic abscess. (B) After drain placement, eCEUS of the abscess (arrowheads) was performed. The distribution of diluted sulfur hexafluoride in the abscess cavity is shown here. (C) Surprisingly, USCM bubbles appeared in the left colonic flexure simultaneously. They are distinguished from colonic air (arrow) by bubble destruction (not shown). (D) In this case, eCEUS allows detection of a fistula (arrow) between the splenic abscess (arrowheads) and the colonic flexure. Subsequent colonoscopy depicted the fistula orifice. At surgery, a splenic lymphoma with a fistula to the colon proved to be the origin of the abscess.
FIGURE 4. A chest tube (arrow) has been placed in a 77-year-old man with pneumonia and loculated pleural empyema. Dual images obtained in contrast mode (left) and gray-scale (right). eCEUS shows poor distribution of the bubbles within the effusion. Forceful injection does not lead to wider distribution of bubbles in the pleural cavity. The patient’s treatment was supplemented with urokinase instillation.
Intravenous CEUS facilitates the identification and sizing of abscesses (Figure 1B) and hence the placement of tubes. Performing 74
eCEUS also allows more precise estimation of the cavities’ shape and the size of the fluid collections (Figure 1C). This information could perhaps be useful in treatment monitoring. However, in our experience, the most important advantage of eCEUS compared with saline instillation alone is that it will dependably detect fistulae, both those occurring as complications and those indicating the origin of an abscess (Figure 2, Figure 3A–3D).17 In some cases, this information will lead to important changes in management (eg, from antibiotic treatment and drainage to surgery). In the thorax, too, the instillation of USCM via drains can be useful to confirm correct tube placement. If dislodgment occurs, it can be correctly diagnosed.17 In gray-scale US, inadequate drainage can be suspected when septa are seen in a pleural effusion. eCEUS can prove loculation (Figure 4), and the patient’s management can be changed. JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND
FIGURE 5. A 68-year-old woman with carcinoma of the common bile duct with a nasobiliary tube in place. Because of biliary sepsis with renal failure, she was being treated in the intensive care unit. Because of interruption of bile flow in the drain, the nasobiliary tube is believed to have become displaced. Bedside eCEUS via the tube (arrowheads) was performed. USCM bubbles appear in the whole biliary system, thus confirming correct tube placement. After flushing the tube carefully with another 10 ml of saline solution, bile flow recurred.
As in abdominal cavities, USCM in the pleural space is visible for up to 20 minutes, much longer than after intravenous administration. Biliary Applications. For biliary applications, we use 0.1 ml of sulfur hexafluoride diluted in 10–20 ml of saline solution. Injection is performed slowly under constant US visualization. The patient is supine when the nasobiliary tube is used, and in the left lateral position during endoscopic retrograde cholangiography. Tubes and Chiba needles can be detected sufficiently well in gray-scale owing to the high differences in impedance between their material and the surrounding tissue, but visualizing the tip is often difficult. When injected slowly, USCM shows the lumen of the drain as a thread, and the point where the bubbles disperse shows the tip of the drain. Placement of a percutaneous transhepatic cholangiography (PTC) catheter can be made more easily because the correct position of the tip can thus be established. The position of the drain tip can also be monitored during treatment (eg, if draining is interrupted) to elucidate the cause.17,18,21 eCEUS–PTC may also be useful to confirm passage of a drain into the small bowel or patency of the cystic duct. In cases of concurrent aerobilia, it can be useful to destroy bubbles by means of a high-energy US impulse (bubble destruction) to distinguish refluxed air from USCM. Injecting the whole content of the syringe allows the biliary system to be visualized in its VOL. 43, NO. 2, FEBRUARY 2015
FIGURE 6. A 69-year-old man who had undergone Whipple resection 1 year earlier presented with jaundice. (A) A stenosis (arrow) in the region of the bilioenteric anastomosis is visualized on percutaneous cholangio-eCEUS. DHC, common bile duct. (B) Fluoroscopic view of the same stenosis (arrow). The two imaging modalities provide equivalent diagnostic information.
entirety (Figure 5). Gallstones in the bile duct are seen only as poor negative contrast; they can be identified more precisely on gray-scale US.17 In our experience, stenoses are adequately shown by eCEUS (Figure 6A and 6B), but more subtle alterations of the bile ducts (eg, in primary sclerosing cholangitis) are not depicted satisfactorily. This agrees with the results of two single-center studies from China comparing eCEUS–PTC and fluoroscopic PTC. The authors of those studies report rates of more than 90% for locating stenoses and determining their grade with eCEUS–PTC.19,21 One of those studies was blinded; it comprised 58 patients, and the accuracy of biliary eCEUS in determining the cause of obstruction was reported to be 93.1% (PTC, 79.3%).19 Contrast fluoroscopy and eCEUS both allow precise imaging of the configuration of a stricture, but sometimes the configuration alone does not allow reliable diagnosis of the cause of the stricture. Trying to clarify the cause of biliary obstruction, we use a combination of endocavitary and intravenous administration. This combined technique appears to enable a new quality of diagnostic US imaging: bile duct 75
€ MULLER ET AL
FIGURE 8. Oral eCEUS in a normal subject. Swallowed sulfur hexafluoride diluted in 50 ml of water highlights the gastric cardia (arrow) and the stomach (S). Patency of the lower esophageal sphincter can be proven, but details of neither gastric wall structures nor the posterior wall can be assessed.
FIGURE 7. A 53-year-old woman presenting jaundice without pain. Biliary eCEUS was performed, followed by intravenous CEUS. (A) After placement of a nasobiliary tube, diluted USCM is administered through the tube. A common bile duct’s stenosis is displayed on eCEUS (arrows). (B) Zoomed view: a hypoechoic tumor (arrows) thickening the bile duct wall and causing the stenosis can be seen. GB, gallbladder. (C) Intravenous CEUS performed after aspiration of the USCM and flushing of the drain with saline solution (arterial phase shown) shows the common bile duct as anechoic. The tumor shows high arterial USCM uptake (arrows), and later, a washout was seen, making carcinoma highly probable. Bile duct carcinoma was proven after surgery.
tumors, which have always proved extremely difficult to reveal, were visualized with precision (Figure 7A–7C).17 Gastrointestinal Applications. Gastrointestinal US is useful in diagnosing changes in wall diameter in cases of tumor or inflammation and 76
in observing motility. Hydrosonography uses water or polyethylene glycol solution as a hypoechoic or anechoic contrast medium,42,43 which depicts the bowel wall structure precisely. Distension of the bowel appears to be more significant than changes in contrast, however, as unfolding improves the visualization of the bowel wall. An Italian group has published the largest trial of hydrosonography for the diagnosis of small-bowel lesions in Crohn’s disease. They used 500–800 ml of polyethylene glycol solution as the USCM in 102 patients who had previously undergone fluoroscopic and endoscopic examinations. The sensitivity of hydrosonography in detecting inflammatory lesions was 96.1%, and for strictures, it was 89%.34 Other investigators combined oral administration of rice and soya powder dissolved in water and intravenous CEUS to assess gastric lesions. This seems to be another strategy that might improve bowel wall diagnostic imaging over that of gray-scale US.33,44–47 However, at present, gastroscopy, CT, and endoscopic US remain the gold standard in tumor characterization and staging. A number of reports have been published on the use of hydrosonography in the diagnosis of colonic polyps.43 We doubt that this method will ever achieve the sensitivity of endoscopy, and it can definitely not be used to exclude colonic malignancies. So far, there have been no controlled trials of hyperechoic USCMs. We perform gastrointestinal eCEUS by mixing 0.1 ml of sulfur hexafluoride with 50 ml of distilled water for diagnostic investigations in the esophagus and stomach. Once swallowed, the bubbles can easily be detected at several predefined points, such as the upper esophagus, the lower esophagus or cardia (Figure 8), all regions of the stomach, and all three parts of the duodenum. JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND
FIGURE 10. A 38-year-old man with a history of reflux disease who presented with severe upper abdominal pain. Gray-scale ultrasound performed initially revealed a pleural effusion of unknown origin. With a tentative diagnosis of lower esophageal perforation, the patient was asked to swallow 50 ml of diluted sulfur hexafluoride. We were able to see the effusion of bubbles (thick arrow) from the esophagus (E) to the pleural cavity (PC), and their spreading. An esophageal ulcer due to peptic esophagitis was confirmed later the same day by endoscopy, and the patient was referred for surgery. D, diaphragm.
FIGURE 9. An 80-year-old woman with carcinoma of the pylorus, treated with a self-expanding metal stent, who presented because of frequent vomiting. (A) Oral eCEUS reveals a blockage at the duodenal end of the stent (arrow). (B) Zoomed view: the distal end is pressed up against the duodenal wall. Subsequent endoscopy confirmed the diagnosis. Endoscopic repositioning was successful.
To depict lower parts of the small bowel, up to 500 ml of water is needed, but it does not seem to be necessary to increase the amount of USCM. Placement of a nasogastric or nasojejunal tube in advance may be helpful. Correct placement of feeding tubes can then be immediately confirmed by eCEUS. Visualization of the entire length of the small intestine is not really practicable and can only be achieved with large amounts of solution. After oral administration of diluted sulfur hexafluoride, we observed no passage to the portal venous system. USCM bubbles can be depicted in the bowel for up to 30 minutes Distinguishing intestinal air from USCM bubbles can occasionally prove difficult because both are highly echogenic. In this case, bubble destruction is again useful, as this will cause the bubbles to vanish transiently, while the intestinal air remains. Unfortunately, meticulous assessment of the bowel wall layers is not really possible due to the bubbles’ strong echoes, which cause blooming. For the same reason, the posterior wall is invisible (Figure 8). Although gastrointestinal eCEUS using hyperechoic USCMs seems a rather weak tool VOL. 43, NO. 2, FEBRUARY 2015
for examining the bowel wall, we found it very helpful in detecting disruptions of the continuity of the gastrointestinal tract, whether due to obstruction or leakage. Obstruction causes a stoppage in the passage of the bubbles down the intestine that can be well depicted (Figure 9A and 9B). Leakages, especially, can be diagnosed by the observation of bubbles where no bubbles should be,17 as shown in Figure 10. Gastrointestinal eCEUS appears promising for this indication–and, unlike fluoroscopic examinations, it can be done at the bedside. Urological Applications. Assessment of vesicoureteral reflux was one of the first endocavitary applications of USCMs, shortly after their approval for intravenous use. Avoiding ionizing radiation is particularly crucial in children,4 and the preparation of galactose, palmitic acid, and air (Levovist) that was formerly used is no longer available. To administer sulfur hexafluoride, the empty bladder is slowly filled with saline solution up to one-third of the predicted bladder volume. Then 1 ml of sulfur hexafluoride can be injected through the bladder catheter.48 To assess vesicoureteral reflux, the transurethral catheter must be removed and the patient asked to urinate. The US examination should focus on the orifice of the ureter. Here, reflux may be confirmed by the observation of USCM bubbles ascending the ureter. If this occurs, the renal pelvis should be inspected to grade the reflux. 77
€ MULLER ET AL
be sufficiently well established to become the gold standard itself.
CONCLUSIONS
FIGURE 11. A 64-year-old man referred to our department with renal failure and suspected ascites after colonic surgery due to diverticulitis. A small bladder leak (arrows) resulting in a large volume of intraabdominal urine mistaken for ascites was confirmed by administering a few milliliters of diluted sulfur hexafluoride to the bladder through a transurethral catheter.
A prospective trial comprising 228 patients and assessing voiding urosonography with sulfur hexafluoride against voiding cystourography reported a sensitivity of 92% versus 64%.48 For the diagnosis of bladder diverticula or fistulae, whether inflammatory (eg, in Crohn’s disease) or malignant (eg, carcinoma of the colon in the pelvis), the bladder is filled as for voiding urosonography. Diverticula appear as protrusions of the bladder wall. Fistulae and leakages can be detected, and the distribution of USCM bubbles often reveals their origin (Figure 11). As in anterograde imaging of the biliary system, eCEUS can also be performed in the urinary tract to facilitate placement of a nephrostomy catheter. Correct placement of, first, the Chiba needle and, later, the drain, can be confirmed.35 Localization of ureteric obstruction is then possible because the dilated ureter is clearly visible when filled by diluted USCM. The cause of an obstruction (tumor, stone, stricture) can be identified in the gray-scale image. Gynecological Applications. In diagnosing tubal patency, fluoroscopic transvaginal hysterosalpingography and HyCoSy are carried out concurrently with the gold-standard techniques of laparoscopy and chromopertubation (“lap and dye”). HyCoSy requires a blocked cervical balloon catheter. Spreading of the USCM bubbles is monitored by vaginal US; the balloon is expected to prevent vaginal efflux. Usually 0.1 ml of sulfur hexafluoride is diluted in 10 ml saline solution. In fertility testing, HyCoSy using sulfur hexafluoride showed concordance with the standard method (lap and dye) in up to 90–94% of the patients.9,12 Thus, this method would appear to 78
The current state of knowledge suggests that endocavitary administration of diluted USCMs (eCEUS) provides a new diagnostic tool without side effects. In voiding urosonography and HyCoSy, it has already been investigated in controlled trials against fluoroscopic or laparoscopic standards and proved to be at least equivalent. Because it additionally avoids radiation exposure, eCEUS might become the “new” gold standard. It is likely that eCEUS in time will find a role in percutaneous US-guided treatment of abscesses and fluid collections in various locations. Important information on complications can be gained with eCEUS that cannot be obtained with conventional gray-scale US. eCEUS of the gastrointestinal tract using echogenic USCMs appears to be a very dependable tool for detecting perforations and fistulae. In the biliary tract, diagnostic eCEUS may be equivalent to fluoroscopy in detecting stenosis, but offers no advantage in this application apart from avoiding radiation exposure. The combination of endocavitary and intravenous administration of USCM seems to be superior to endoscopic retrograde cholangiography in depicting bile duct malignancies. In the detection of colonic polyps and intestinal inflammation, the diagnostic benefit offered by eCEUS over endoscopy is questionable, whereas details of bowel wall can be much better depicted by hydrosonography. We have presented findings based on our own observations. However, with the exception of HyCoSy and voiding contrast urosonography, controlled trials that include the various standard diagnostic methods are needed to demonstrate the diagnostic value of eCEUS.
ACKNOWLEDGMENT The authors are grateful to Kersti Wagstaff for language assistance.
REFERENCES 1. Bracco Imaging S.p.A. Available at: http:// www.braccoimaging.com/sites/braccoimaging.com/ files/technica_sheet_pdf/Fachinformation%20Sono Vue%20Mai%202014.pdf; accessed August 23, 2014. JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND 2. Schneider M. SonoVue, a new ultrasound contrast agent. Eur Radiol 1999;9:S347. 3. Albrecht T, Blomley M, Bolondi L, et al. Guidelines for the use of contrast agents in ultrasound. Ultraschall Med 2004;25:249. 4. Darge K. Voiding urosonography with ultrasound contrast agents for the diagnosis of vesicoureteric reflux in children. Pediatr Radiol 2008;38:40. 5. Galloy MA, Guillemin F, Couture A, et al. Voiding ultrasonography: evaluation of the detection of vesicoureteral reflux based on the review of digital ultrasound clips. Ultraschall Med 2008;29:53. 6. McEwing RL, Anderson NG, Hellewell S, et al. Comparison of echo-enhanced ultrasound with fluoroscopic MCU for the detection of vesicoureteral reflux in neonates. Pediatr Radiol 2002;32:853. 7. Valentini AL, De Gaetano AM, Destito C, et al. The accuracy of voiding urosonography in detecting vesico-ureteral reflux: a summary of existing data. Eur J Pediatr 2002;161:380. 8. Boudghene FP, Bazot M, Robert Y, et al. Assessment of Fallopian tube patency by HyCoSy: comparison of a positive contrast agent with saline solution. Ultrasound Obstet Gynecol 2001;18:525. 9. Exacoustos C, Zupi E, Szabolcs B, et al. Contrasttuned imaging and second-generation contrast agent SonoVue: a new ultrasound approach to evaluation of tubal patency. J Minim Invasive Gynecol 2009;16:437. 10. Lanzani C, Savasi V, Leone FP, et al. Two-dimensional HyCoSy with contrast tuned imaging technology and a second-generation contrast media for the assessment of tubal patency in an infertility program. Fertil Steril 2009;92:1158. 11. Tamasi F, Weidner A, Domokos N, et al. ECHOVIST-200 enhanced hystero-sonography: a new technique in the assessment of infertility. Eur J Obstet Gynecol Reprod Biol 2005;121:186. 12. Zhou L, Zhang X, Chen X, et al. Value of threedimensional hystero-salpingo-contrast sonography with SonoVue in the assessment of tubal patency. Ultrasound Obstet Gynecol 2012;40:93. 13. H€opfner M, Weskott H. Intracavitary contrastenhanced sonography in liver abscesses–-a tool relevant in diagnosis and therapy [Abstract, in German]. Ultraschall Med 2009;30:S28. 14. Girlich C, B€ uttner R, Schacherer D, et al. Contrast-enhanced sonographic drainage control: a feasibility study. Z Gastroenterol 2011;49:1470. 15. Puls R, Gebauer B, Hildebrandt B, et al. Intraperitoneal distribution of ultrasound contrast medium imaged with B-mode ultrasound and colourstimulated acoustic emission imaging. Eur Radiol 2003;13:695. 16. Heinzmann A, Blank W, M€ uller T, et al. New applications of contrast enhanced ultrasound (CEUS): via drains, retrogradely by ERCP, biliary tubes or orally [Abstract, in German]. Ultraschall Med 2010;31:S29. 17. Heinzmann A, M€ uller T, Leitlein J, et al. Endocavitary contrast enhanced ultrasound (CEUS)–-work in progress. Ultraschall Med 2012;33:76. VOL. 43, NO. 2, FEBRUARY 2015
18. Ignee A, Baum U, Schuessler G, et al. Contrastenhanced ultrasound-guided percutaneous cholangiography and cholangiodrainage (CEUSPTCD). Endoscopy 2009;41:725. 19. Luyao Z, Xiaoyan X, Huixiong X, et al. Percutaneous ultrasound-guided cholangiography using microbubbles to evaluate the dilated biliary tract: initial experience. Eur Radiol 2012;22:371. 20. Mao R, Xu EJ, Li K, et al. Usefulness of contrastenhanced ultrasound in the diagnosis of biliary leakage following T-tube removal. J Clin Ultrasound 2010;38:38. 21. Xu E, Zheng R, Su Z, et al. Intra-biliary contrastenhanced ultrasound for evaluating biliary obstruction during percutaneous transhepatic biliary drainage: a preliminary study. Eur J Radiol 2012;81:3846. 22. Zheng R, Chen G, Xu E, et al. Evaluating biliary anatomy and variations in living liver donors by a new technique: three-dimensional contrastenhanced ultrasonic cholangiography. Ultrasound Med Biol 2010;36:1282. 23. Zuber-Jerger I, Endlicher E, Sch€olmerich J, et al. Endoscopic retrograde cholangiography with contrast ultrasonography. Endoscopy 2008;40(Suppl 2):E202. 24. Foschi FG, Piscaglia F, Pompili M, et al. Real-time contrast-enhanced ultrasound–-a new simple tool for detection of peritoneal-pleural communications in hepatic hydrothorax. Ultraschall Med 2008;29: 538. 25. Matono T, Koda M, Murawaki Y. Right diaphragmatic defect in hepatic hydrothorax exposed by contrast-enhanced ultrasonography after radiofrequency ablation. Hepatology 2012;56:784. 26. Tamano M, Hashimoto T, Kojima K, et al. Diagnosis of hepatic hydrothorax using contrastenhanced ultrasonography with intraperitoneal injection of Sonazoid. J Gastroenterol Hepatol 2010;25:383. 27. Chew SS, Yang JL, Newstead GL, et al. Anal fistula: Levovist-enhanced endoanal ultrasound: a pilot study. Dis Colon Rectum 2003;46:377. 28. Henrich W, Meckies J, Friedmann W. Demonstration of a recto-vaginal fistula with the ultrasound contrast medium Echovist. Ultrasound Obstet Gynecol 2000;15:148. 29. Volkmer BG, Neßlauer T, K€ ufer R, et al. Diagnosis of vesico-intestinal fistulas using contrast medium enhanced 3-D ultrasound. Ultraschall Med 2001; 22:81. 30. Antypa E, Cokkinos DD, Kalogeropoulos I, et al. Ultrasound contrast agent delivered per os first diagnoses pharyngoesopgageal tumour. JBR-BTR 2013;96:69. 31. Weskott HP, H€opfner M. Display of gastric, duodenal and colonic lumen by endoluminal contrast agent application. A feasibility study [Abstract, in German] Ultraschall Med 2010;31:S30. 32. Badea R, Ciobanu L, Gomotirceanu A, et al. Contrast ultrasonography of the digestive tract lumen.
79
€ MULLER ET AL
33.
34.
35.
36.
37.
38.
39.
40.
80
Review of the literature and personal experience. Med Ultrason 2010;12:52. Badea R, Ciobanu L, Gomotirceanu A, et al. Contrast ultrasonography–-a necessary procedure for a better characterization of digestive tract pathology. Med Ultrason 2010;12:73. Parente F, Greco S, Molteni M, et al. Oral contrast enhanced bowel ultrasonography in the assessment of small intestine Crohn’s disease. A prospective comparison with conventional ultrasound, x ray studies, and ileocolonoscopy. Gut 2004;53:1652. Dietrich CF, Cui XW, Barreiros AP, et al. EFSUMB guidelines 2011: comment on emergent indications and visions. Ultraschall Med 2012;33:S39. Zengel P, Berghaus A, Weiler C, et al. Intraductally applied contrast-enhanced ultrasound (IACEUS) for evaluating obstructive disease and secretory dysfunction of the salivary glands. Eur Radiol 2011;21:1339. Piscaglia F, Nolsøe C, Dietrich CF, et al. The EFSUMB Guidelines and Recommendations on the Clinical Practice of Contrast Enhanced Ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall Med 2011;33:33. Piscaglia F, Bolondi L. The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol 2006; 32:1369. Dijkmans PA, Visser CA, Kamp O. Adverse reactions to ultrasound contrast agents: is the risk worth the benefit? Eur J Echocardiogr 2005;6:363. Geleijnse ML, Nemes A, Vletter WB, et al. Adverse reactions after the use of sulphur hexafluoride
41.
42.
43.
44.
45.
46.
47.
48.
(SonoVue) echo contrast agent. J Cardiovasc Med 2009;10:75. Miller DL, Averkiou MA, Brayman AA. Bioeffects considerations for diagnostic ultrasound contrast agents. J Ultrasound Med 2008;27:611. Castiglione F, Bucci L, Pesce G, et al. Oral contrast-enhanced sonography for the diagnosis and grading of postsurgical recurrence of Crohn’s disease. Inflamm Bowel Dis 2008;14:1240. Maconi G, Radice E, Bareggi E, et al. Hydrosonography of the gastrointestinal tract. AJR Am J Roentgenol 2009;193:700. Badea R, Neciu C, Iancu C, et al. The role of i.v. and oral contrast enhanced ultrasonography in the characterization of gastric tumors. A preliminary study. Med Ultrason 2012;14:197. Huang P, Li S, Aronow WS, et al. Double contrastenhanced ultrasonography evaluation of preoperative Lauren classification of advanced gastric carcinoma. Arch Med Sci 2011;7:287. Zheng Z, Yu Y, Lu M, et al. Double contrast– enhanced ultrasonography for the preoperative evaluation of gastric cancer: a comparison to endoscopic ultrasonography with respect to histopathology. Am J Surg 2011;202:605. Shi H, Yu XH, Guo XZ, et al. Double contrastenhanced two-dimensional and three-dimensional ultrasonography for evaluation of gastric lesions. World J Gastroenterol 2012;18:4136. Papadopoulou F, Anthopoulou A, Siomou E, et al. Harmonic voiding urosonography with a secondgeneration contrast agent for the diagnosis of vesicoureteral reflux. Pediatr Radiol 2009;39:239.
JOURNAL OF CLINICAL ULTRASOUND
Endocavitary Contrast-Enhanced Ultrasound: A Technique Whose Time Has Come? Thomas M€ uller, MD, Wolfgang Blank, MD, Jens Leitlein, MD, Stefan Kubicka, MDx, Alexander Heinzmann, MD Klinikum am Steinenberg, Medizinische Klinik I, Reutlingen, Germany Received 24 May 2013; accepted 7 September 2014
ABSTRACT: Endocavitary use of contrast agents in sonography (US) is a relatively new method in diagnostic imaging, competing against gray-scale US, fluoroscopy, and endoscopy. This article describes established indications, demonstrates the techniques of evolving applications, and discusses their potential benefits. These benefits include the ability to obtain precise information about the placement of drains and the extent of fluid collections, and to accurately identify the location and features of strictures in various organs, and those of complications of fluid collections or abscesses, without resorting to ionizing C radiation. V 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:71–80, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ jcu.22250 Keywords: contrast-enhanced ultrasound; ultrasoundguided intervention; endocavitary; ultrasonography
INTRODUCTION
T
he first sonography (US) contrast media (USCMs), introduced in the 1980s, improved the sonographic visibility of heart cavities, blood vessels, blood flow, and pathologic entities such as arteriovenous shunts. During the 1990s, several first-generation USCMs were approved for intravenous administration. A second-generation USCM, sulfur hexafluoride (SonoVue; Bracco Imaging S.p.A., Milan,
Wolfgang Blank received financial support from Bracco (travel grants, lectures). The other authors declare no conflict of interest. Correspondence to: T. M€ uller C 2014 Wiley Periodicals, Inc. V
VOL. 43, NO. 2, FEBRUARY 2015
Italy), was approved in Europe in 2001 solely for intravenous use in adults.1,2 Second-generation USCMs permit continuous visualization when using a low mechanical index, thus enabling real-time imaging of perfusion patterns.3 Almost immediately, however, the search began for additional applications of this new tool in diagnostic US. Shortly after its approval, a preparation of galactose, palmitic acid, and air (Levovist; Schering AG, Berlin, Germany) was administered into the bladder to detect vesicoureteral reflux in voiding urosonography in a child, thus avoiding the use of ionizing radiation. Hysterosalpingo-contrast-sonography (HyCoSy) using various USCMs has been successfully performed and evaluated against fluoroscopic or laparoscopic procedures in controlled trials.4–12 In the assessment of other diseases or organs, however, the situation is very different. Various possible indications for endocavitary contrastenhanced US (eCEUS) have been proposed in case reports, abstracts, or feasibility studies from Europe and Asia, but in most cases reliable dosage recommendations are not available and the method is not well-established compared with standard methods such as fluoroscopic imaging or the administration of saline solution under US guidance. Proposed indications for eCEUS include locating tubes and drains in body cavities, abscesses, or collections13,14; estimating the dimensions and detecting the communications of fluid collections13,15–17; percutaneous, transpapillary, or intraoperative visualization of the biliary system16–23; demonstrating thoracoabdominal communication in cases of suspected hepatic hydrothorax24–26; detecting and quantifying fistulae in various locations27–29; assessing the 71
€ MULLER ET AL
digestive tract after oral or colonic administration of USCMs17,30–34; confirming correct placement of a percutaneous nephrostomy35; and evaluating obstructive disease of the salivary glands.36 Endocavitary administration of USCMs has recently been included in guidelines from the European Federation of Societies for Ultrasound in Medicine and Biology, which emphasize that no well-established indications exist at present but recommend considering the use of eCEUS if alternatives (eg, fluoroscopy, need to transport critically ill patients) may carry a higher risk for the patient.37 Against the background of this miscellany of publications, it seems useful to try to attain clarity about where eCEUS is rewarding and where it may be superfluous. Some advantages are obvious. eCEUS can be done at the bedside, without radiation, and is minimally invasive. When performing several examinations successively, the costs of sulfur hexafluoride are relatively low: a multidose vial of SonoVue contains 5 ml sulfur hexafluoride, and each examination requires only 1 drop. Other USCMs like perflutren lipid microspheres (Definity Injectable Solution; Lantheus Medical Imaging, North Billerica, MA) are marketed for single use only, and the costs may be significantly higher. To justify its use, eCEUS must be diagnostically equivalent to standard procedures, provide additional information, or avoid possible risks of other methods. In our US department we do more than 12,000 US examinations and around 600 USguided interventions per year and frequently perform eCEUS in various settings preliminarily described by Heinzmann et al,17 in an attempt to gain information beyond that provided by gray-scale US or to reduce patient risk to less than that associated with fluoroscopic imaging or endoscopy. In this article, we provide examples of eCEUS from our own investigations, discuss possible benefits, and point out where eCEUS seems to be unnecessary. For well-established indications, we provide data from recent studies.
MATERIALS AND METHODS
All of our studies were performed using sulfur hexafluoride (SonoVue) and an Acuson Sequoia 512 US machine (Siemens Medical Solutions USA, Inc., Malvern, PA) with cadence contrast pulse sequencing technology using the low 72
mechanical-index mode. A convex array multifrequency transducer (4C1, Acuson Siemens) was used for all examinations. Unless otherwise stated, the dosages given below relate to sulfur hexafluoride. One milliliter of SonoVue contains approximately 8 ml of sulfur hexafluoride as microbubbles in a phospholipid shell.1 All eCEUS applications have in common the use of a solvent (eg, 0.9% saline) to which a small amount of USCM is added. The resulting solution is shaken vigorously and administered directly into a body cavity through a drain, catheter, or cannula. When imaging the gastrointestinal tract, we use tap water at room temperature as the solvent. Specific preparations are described together with the indications below. Because our studies were performed in daily practice, each based on an individual decision rather than forming part of a clinical trial, they were not subject to the Declaration of Helsinki. Oral informed consent was obtained from each patient. Risks and Possible Side Effects of eCEUS Endocavitary administration of USCM is a relatively new method. Trials involving its use in voiding urosonography, HyCoSy, or biliary imaging mention no adverse reactions except for localized pain during injection, which probably was due to distension rather than to the USCM itself.5,8–12,19,21 A postmarketing multicenter analysis claims a fairly low rate of adverse reactions seen after intravenous administration of sulfur hexafluoride in 23,188 investigations: major complications seemed to occur at a rate between 0.0086% and 0.012%. The vast majority of these complications were direct allergic reactions, including allergic shock syndrome and spastic bronchial reactions. These allergies appear to be related to the bubbles’ polyethylene glycol sheath. Fatalities are rare: among more than 150,000 administrations, three deaths were reported (0.002%), and causality could not be proved. All three of the patients involved had severe cardiac disease.38,39 A smaller singlecenter analysis of cardiac indications for the use of sulfur hexafluoride in 352 consecutive patients reported a much higher rate of severe allergic reactions, 0.9%.40 Local cytotoxic effects are related to a high mechanical index of the US beam and are not expected to appear when the low mechanical index mode is used.41 Nevertheless, contraindications for intravenous administration (hypersensitivity to any of the components of the product, right-to-left-shunt, pulmonary or untreated JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND
FIGURE 2. An 82-year-old woman with pancreatic carcinoma and fever. A hepatic abscess (A) was diagnosed on gray-scale US. After the instillation of 15 ml of diluted USCM into an abscess drainage catheter, USCM bubbles also appeared in the dilated bile ducts (BD) and in a hepatic vein (arrows). The connection of the abscess with the biliary system had not been detectable on gray-scale US alone. The appearance of USCM bubbles in the hepatic vein indicates a complication of catheter placement. One of the catheter’s holes must have been placed in a vein close to the abscess. The catheter was repositioned because of this finding.
Resuscitation equipment should be available nearby and especially trained personnel available to take care of adverse events. The administration of USCMs other than intravenously is currently an off-label use, so we recommend obtaining the patient’s informed consent. Patients must be informed about the method itself, potential risks (eg, allergic reactions), possible benefits, and alternatives. Possible Indications for eCEUS
FIGURE 1. A 76-year-old man with fever and shivering. (A) Gray-scale US imaging shows a hypoechoic liver lesion with ill-defined margins (1 1). (B) Intravenous CEUS performed in the expectation of finding liver abscesses. The lesion remains anechoic, although the size and shape of the abscess are well depicted. Pus was aspirated. (C) A pigtail drain (arrow) was inserted into the abscess under ultrasound guidance. After injection of diluted USCM (1 drop of sulfur hexafluoride in 10 ml saline solution), the abscess can be depicted for a long time. In eCEUS, the margins appear irregular compared with those on the CEUS image (B) and depict more precisely the extent and shape of the cavity containing liquid pus.
systemic hypertension, acute dyspnea, and pregnancy or lactation)1 should be taken into consideration when delivering diluted USCMs to body cavities. VOL. 43, NO. 2, FEBRUARY 2015
Fluid Collections. Fluid collections such as abscesses and effusions can be diagnosed by gray-scale US (Figure 1A), but detecting complications such as fistulae, communications, or loculations can be a challenge. Drains can be placed under US guidance, but a misplaced drain tip is sometimes hard to detect with grayscale US alone. For eCEUS, after insertion of the drain, depending on the estimated volume of the collection, 10–20 ml of 0.9% saline solution with the addition of 0.1 ml of sulfur hexafluoride is administered via the tube. This concentration of USCM seems sufficient for most purposes in the abdominal and retroperitoneal space. When searching for communicating fluid collections (eg, in the case of loculated ascites or ascites with concomitant pleural effusion [hepatic hydrothorax]), a larger amount of saline solution may be useful. It is rarely necessary to increase the amount of USCM in the solution. 73
€ MULLER ET AL
FIGURE 3. A 72-year-old man suffering weight loss, fever, and nightly sweats. (A) A complex structure of 9 cm diameter (1 1) showing probable air within a cavity is seen in the gray-scale image of the spleen. It was suspected to be a splenic abscess. (B) After drain placement, eCEUS of the abscess (arrowheads) was performed. The distribution of diluted sulfur hexafluoride in the abscess cavity is shown here. (C) Surprisingly, USCM bubbles appeared in the left colonic flexure simultaneously. They are distinguished from colonic air (arrow) by bubble destruction (not shown). (D) In this case, eCEUS allows detection of a fistula (arrow) between the splenic abscess (arrowheads) and the colonic flexure. Subsequent colonoscopy depicted the fistula orifice. At surgery, a splenic lymphoma with a fistula to the colon proved to be the origin of the abscess.
FIGURE 4. A chest tube (arrow) has been placed in a 77-year-old man with pneumonia and loculated pleural empyema. Dual images obtained in contrast mode (left) and gray-scale (right). eCEUS shows poor distribution of the bubbles within the effusion. Forceful injection does not lead to wider distribution of bubbles in the pleural cavity. The patient’s treatment was supplemented with urokinase instillation.
Intravenous CEUS facilitates the identification and sizing of abscesses (Figure 1B) and hence the placement of tubes. Performing 74
eCEUS also allows more precise estimation of the cavities’ shape and the size of the fluid collections (Figure 1C). This information could perhaps be useful in treatment monitoring. However, in our experience, the most important advantage of eCEUS compared with saline instillation alone is that it will dependably detect fistulae, both those occurring as complications and those indicating the origin of an abscess (Figure 2, Figure 3A–3D).17 In some cases, this information will lead to important changes in management (eg, from antibiotic treatment and drainage to surgery). In the thorax, too, the instillation of USCM via drains can be useful to confirm correct tube placement. If dislodgment occurs, it can be correctly diagnosed.17 In gray-scale US, inadequate drainage can be suspected when septa are seen in a pleural effusion. eCEUS can prove loculation (Figure 4), and the patient’s management can be changed. JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND
FIGURE 5. A 68-year-old woman with carcinoma of the common bile duct with a nasobiliary tube in place. Because of biliary sepsis with renal failure, she was being treated in the intensive care unit. Because of interruption of bile flow in the drain, the nasobiliary tube is believed to have become displaced. Bedside eCEUS via the tube (arrowheads) was performed. USCM bubbles appear in the whole biliary system, thus confirming correct tube placement. After flushing the tube carefully with another 10 ml of saline solution, bile flow recurred.
As in abdominal cavities, USCM in the pleural space is visible for up to 20 minutes, much longer than after intravenous administration. Biliary Applications. For biliary applications, we use 0.1 ml of sulfur hexafluoride diluted in 10–20 ml of saline solution. Injection is performed slowly under constant US visualization. The patient is supine when the nasobiliary tube is used, and in the left lateral position during endoscopic retrograde cholangiography. Tubes and Chiba needles can be detected sufficiently well in gray-scale owing to the high differences in impedance between their material and the surrounding tissue, but visualizing the tip is often difficult. When injected slowly, USCM shows the lumen of the drain as a thread, and the point where the bubbles disperse shows the tip of the drain. Placement of a percutaneous transhepatic cholangiography (PTC) catheter can be made more easily because the correct position of the tip can thus be established. The position of the drain tip can also be monitored during treatment (eg, if draining is interrupted) to elucidate the cause.17,18,21 eCEUS–PTC may also be useful to confirm passage of a drain into the small bowel or patency of the cystic duct. In cases of concurrent aerobilia, it can be useful to destroy bubbles by means of a high-energy US impulse (bubble destruction) to distinguish refluxed air from USCM. Injecting the whole content of the syringe allows the biliary system to be visualized in its VOL. 43, NO. 2, FEBRUARY 2015
FIGURE 6. A 69-year-old man who had undergone Whipple resection 1 year earlier presented with jaundice. (A) A stenosis (arrow) in the region of the bilioenteric anastomosis is visualized on percutaneous cholangio-eCEUS. DHC, common bile duct. (B) Fluoroscopic view of the same stenosis (arrow). The two imaging modalities provide equivalent diagnostic information.
entirety (Figure 5). Gallstones in the bile duct are seen only as poor negative contrast; they can be identified more precisely on gray-scale US.17 In our experience, stenoses are adequately shown by eCEUS (Figure 6A and 6B), but more subtle alterations of the bile ducts (eg, in primary sclerosing cholangitis) are not depicted satisfactorily. This agrees with the results of two single-center studies from China comparing eCEUS–PTC and fluoroscopic PTC. The authors of those studies report rates of more than 90% for locating stenoses and determining their grade with eCEUS–PTC.19,21 One of those studies was blinded; it comprised 58 patients, and the accuracy of biliary eCEUS in determining the cause of obstruction was reported to be 93.1% (PTC, 79.3%).19 Contrast fluoroscopy and eCEUS both allow precise imaging of the configuration of a stricture, but sometimes the configuration alone does not allow reliable diagnosis of the cause of the stricture. Trying to clarify the cause of biliary obstruction, we use a combination of endocavitary and intravenous administration. This combined technique appears to enable a new quality of diagnostic US imaging: bile duct 75
€ MULLER ET AL
FIGURE 8. Oral eCEUS in a normal subject. Swallowed sulfur hexafluoride diluted in 50 ml of water highlights the gastric cardia (arrow) and the stomach (S). Patency of the lower esophageal sphincter can be proven, but details of neither gastric wall structures nor the posterior wall can be assessed.
FIGURE 7. A 53-year-old woman presenting jaundice without pain. Biliary eCEUS was performed, followed by intravenous CEUS. (A) After placement of a nasobiliary tube, diluted USCM is administered through the tube. A common bile duct’s stenosis is displayed on eCEUS (arrows). (B) Zoomed view: a hypoechoic tumor (arrows) thickening the bile duct wall and causing the stenosis can be seen. GB, gallbladder. (C) Intravenous CEUS performed after aspiration of the USCM and flushing of the drain with saline solution (arterial phase shown) shows the common bile duct as anechoic. The tumor shows high arterial USCM uptake (arrows), and later, a washout was seen, making carcinoma highly probable. Bile duct carcinoma was proven after surgery.
tumors, which have always proved extremely difficult to reveal, were visualized with precision (Figure 7A–7C).17 Gastrointestinal Applications. Gastrointestinal US is useful in diagnosing changes in wall diameter in cases of tumor or inflammation and 76
in observing motility. Hydrosonography uses water or polyethylene glycol solution as a hypoechoic or anechoic contrast medium,42,43 which depicts the bowel wall structure precisely. Distension of the bowel appears to be more significant than changes in contrast, however, as unfolding improves the visualization of the bowel wall. An Italian group has published the largest trial of hydrosonography for the diagnosis of small-bowel lesions in Crohn’s disease. They used 500–800 ml of polyethylene glycol solution as the USCM in 102 patients who had previously undergone fluoroscopic and endoscopic examinations. The sensitivity of hydrosonography in detecting inflammatory lesions was 96.1%, and for strictures, it was 89%.34 Other investigators combined oral administration of rice and soya powder dissolved in water and intravenous CEUS to assess gastric lesions. This seems to be another strategy that might improve bowel wall diagnostic imaging over that of gray-scale US.33,44–47 However, at present, gastroscopy, CT, and endoscopic US remain the gold standard in tumor characterization and staging. A number of reports have been published on the use of hydrosonography in the diagnosis of colonic polyps.43 We doubt that this method will ever achieve the sensitivity of endoscopy, and it can definitely not be used to exclude colonic malignancies. So far, there have been no controlled trials of hyperechoic USCMs. We perform gastrointestinal eCEUS by mixing 0.1 ml of sulfur hexafluoride with 50 ml of distilled water for diagnostic investigations in the esophagus and stomach. Once swallowed, the bubbles can easily be detected at several predefined points, such as the upper esophagus, the lower esophagus or cardia (Figure 8), all regions of the stomach, and all three parts of the duodenum. JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND
FIGURE 10. A 38-year-old man with a history of reflux disease who presented with severe upper abdominal pain. Gray-scale ultrasound performed initially revealed a pleural effusion of unknown origin. With a tentative diagnosis of lower esophageal perforation, the patient was asked to swallow 50 ml of diluted sulfur hexafluoride. We were able to see the effusion of bubbles (thick arrow) from the esophagus (E) to the pleural cavity (PC), and their spreading. An esophageal ulcer due to peptic esophagitis was confirmed later the same day by endoscopy, and the patient was referred for surgery. D, diaphragm.
FIGURE 9. An 80-year-old woman with carcinoma of the pylorus, treated with a self-expanding metal stent, who presented because of frequent vomiting. (A) Oral eCEUS reveals a blockage at the duodenal end of the stent (arrow). (B) Zoomed view: the distal end is pressed up against the duodenal wall. Subsequent endoscopy confirmed the diagnosis. Endoscopic repositioning was successful.
To depict lower parts of the small bowel, up to 500 ml of water is needed, but it does not seem to be necessary to increase the amount of USCM. Placement of a nasogastric or nasojejunal tube in advance may be helpful. Correct placement of feeding tubes can then be immediately confirmed by eCEUS. Visualization of the entire length of the small intestine is not really practicable and can only be achieved with large amounts of solution. After oral administration of diluted sulfur hexafluoride, we observed no passage to the portal venous system. USCM bubbles can be depicted in the bowel for up to 30 minutes Distinguishing intestinal air from USCM bubbles can occasionally prove difficult because both are highly echogenic. In this case, bubble destruction is again useful, as this will cause the bubbles to vanish transiently, while the intestinal air remains. Unfortunately, meticulous assessment of the bowel wall layers is not really possible due to the bubbles’ strong echoes, which cause blooming. For the same reason, the posterior wall is invisible (Figure 8). Although gastrointestinal eCEUS using hyperechoic USCMs seems a rather weak tool VOL. 43, NO. 2, FEBRUARY 2015
for examining the bowel wall, we found it very helpful in detecting disruptions of the continuity of the gastrointestinal tract, whether due to obstruction or leakage. Obstruction causes a stoppage in the passage of the bubbles down the intestine that can be well depicted (Figure 9A and 9B). Leakages, especially, can be diagnosed by the observation of bubbles where no bubbles should be,17 as shown in Figure 10. Gastrointestinal eCEUS appears promising for this indication–and, unlike fluoroscopic examinations, it can be done at the bedside. Urological Applications. Assessment of vesicoureteral reflux was one of the first endocavitary applications of USCMs, shortly after their approval for intravenous use. Avoiding ionizing radiation is particularly crucial in children,4 and the preparation of galactose, palmitic acid, and air (Levovist) that was formerly used is no longer available. To administer sulfur hexafluoride, the empty bladder is slowly filled with saline solution up to one-third of the predicted bladder volume. Then 1 ml of sulfur hexafluoride can be injected through the bladder catheter.48 To assess vesicoureteral reflux, the transurethral catheter must be removed and the patient asked to urinate. The US examination should focus on the orifice of the ureter. Here, reflux may be confirmed by the observation of USCM bubbles ascending the ureter. If this occurs, the renal pelvis should be inspected to grade the reflux. 77
€ MULLER ET AL
be sufficiently well established to become the gold standard itself.
CONCLUSIONS
FIGURE 11. A 64-year-old man referred to our department with renal failure and suspected ascites after colonic surgery due to diverticulitis. A small bladder leak (arrows) resulting in a large volume of intraabdominal urine mistaken for ascites was confirmed by administering a few milliliters of diluted sulfur hexafluoride to the bladder through a transurethral catheter.
A prospective trial comprising 228 patients and assessing voiding urosonography with sulfur hexafluoride against voiding cystourography reported a sensitivity of 92% versus 64%.48 For the diagnosis of bladder diverticula or fistulae, whether inflammatory (eg, in Crohn’s disease) or malignant (eg, carcinoma of the colon in the pelvis), the bladder is filled as for voiding urosonography. Diverticula appear as protrusions of the bladder wall. Fistulae and leakages can be detected, and the distribution of USCM bubbles often reveals their origin (Figure 11). As in anterograde imaging of the biliary system, eCEUS can also be performed in the urinary tract to facilitate placement of a nephrostomy catheter. Correct placement of, first, the Chiba needle and, later, the drain, can be confirmed.35 Localization of ureteric obstruction is then possible because the dilated ureter is clearly visible when filled by diluted USCM. The cause of an obstruction (tumor, stone, stricture) can be identified in the gray-scale image. Gynecological Applications. In diagnosing tubal patency, fluoroscopic transvaginal hysterosalpingography and HyCoSy are carried out concurrently with the gold-standard techniques of laparoscopy and chromopertubation (“lap and dye”). HyCoSy requires a blocked cervical balloon catheter. Spreading of the USCM bubbles is monitored by vaginal US; the balloon is expected to prevent vaginal efflux. Usually 0.1 ml of sulfur hexafluoride is diluted in 10 ml saline solution. In fertility testing, HyCoSy using sulfur hexafluoride showed concordance with the standard method (lap and dye) in up to 90–94% of the patients.9,12 Thus, this method would appear to 78
The current state of knowledge suggests that endocavitary administration of diluted USCMs (eCEUS) provides a new diagnostic tool without side effects. In voiding urosonography and HyCoSy, it has already been investigated in controlled trials against fluoroscopic or laparoscopic standards and proved to be at least equivalent. Because it additionally avoids radiation exposure, eCEUS might become the “new” gold standard. It is likely that eCEUS in time will find a role in percutaneous US-guided treatment of abscesses and fluid collections in various locations. Important information on complications can be gained with eCEUS that cannot be obtained with conventional gray-scale US. eCEUS of the gastrointestinal tract using echogenic USCMs appears to be a very dependable tool for detecting perforations and fistulae. In the biliary tract, diagnostic eCEUS may be equivalent to fluoroscopy in detecting stenosis, but offers no advantage in this application apart from avoiding radiation exposure. The combination of endocavitary and intravenous administration of USCM seems to be superior to endoscopic retrograde cholangiography in depicting bile duct malignancies. In the detection of colonic polyps and intestinal inflammation, the diagnostic benefit offered by eCEUS over endoscopy is questionable, whereas details of bowel wall can be much better depicted by hydrosonography. We have presented findings based on our own observations. However, with the exception of HyCoSy and voiding contrast urosonography, controlled trials that include the various standard diagnostic methods are needed to demonstrate the diagnostic value of eCEUS.
ACKNOWLEDGMENT The authors are grateful to Kersti Wagstaff for language assistance.
REFERENCES 1. Bracco Imaging S.p.A. Available at: http:// www.braccoimaging.com/sites/braccoimaging.com/ files/technica_sheet_pdf/Fachinformation%20Sono Vue%20Mai%202014.pdf; accessed August 23, 2014. JOURNAL OF CLINICAL ULTRASOUND
ENDOCAVITARY CONTRAST-ENHANCED ULTRASOUND 2. Schneider M. SonoVue, a new ultrasound contrast agent. Eur Radiol 1999;9:S347. 3. Albrecht T, Blomley M, Bolondi L, et al. Guidelines for the use of contrast agents in ultrasound. Ultraschall Med 2004;25:249. 4. Darge K. Voiding urosonography with ultrasound contrast agents for the diagnosis of vesicoureteric reflux in children. Pediatr Radiol 2008;38:40. 5. Galloy MA, Guillemin F, Couture A, et al. Voiding ultrasonography: evaluation of the detection of vesicoureteral reflux based on the review of digital ultrasound clips. Ultraschall Med 2008;29:53. 6. McEwing RL, Anderson NG, Hellewell S, et al. Comparison of echo-enhanced ultrasound with fluoroscopic MCU for the detection of vesicoureteral reflux in neonates. Pediatr Radiol 2002;32:853. 7. Valentini AL, De Gaetano AM, Destito C, et al. The accuracy of voiding urosonography in detecting vesico-ureteral reflux: a summary of existing data. Eur J Pediatr 2002;161:380. 8. Boudghene FP, Bazot M, Robert Y, et al. Assessment of Fallopian tube patency by HyCoSy: comparison of a positive contrast agent with saline solution. Ultrasound Obstet Gynecol 2001;18:525. 9. Exacoustos C, Zupi E, Szabolcs B, et al. Contrasttuned imaging and second-generation contrast agent SonoVue: a new ultrasound approach to evaluation of tubal patency. J Minim Invasive Gynecol 2009;16:437. 10. Lanzani C, Savasi V, Leone FP, et al. Two-dimensional HyCoSy with contrast tuned imaging technology and a second-generation contrast media for the assessment of tubal patency in an infertility program. Fertil Steril 2009;92:1158. 11. Tamasi F, Weidner A, Domokos N, et al. ECHOVIST-200 enhanced hystero-sonography: a new technique in the assessment of infertility. Eur J Obstet Gynecol Reprod Biol 2005;121:186. 12. Zhou L, Zhang X, Chen X, et al. Value of threedimensional hystero-salpingo-contrast sonography with SonoVue in the assessment of tubal patency. Ultrasound Obstet Gynecol 2012;40:93. 13. H€opfner M, Weskott H. Intracavitary contrastenhanced sonography in liver abscesses–-a tool relevant in diagnosis and therapy [Abstract, in German]. Ultraschall Med 2009;30:S28. 14. Girlich C, B€ uttner R, Schacherer D, et al. Contrast-enhanced sonographic drainage control: a feasibility study. Z Gastroenterol 2011;49:1470. 15. Puls R, Gebauer B, Hildebrandt B, et al. Intraperitoneal distribution of ultrasound contrast medium imaged with B-mode ultrasound and colourstimulated acoustic emission imaging. Eur Radiol 2003;13:695. 16. Heinzmann A, Blank W, M€ uller T, et al. New applications of contrast enhanced ultrasound (CEUS): via drains, retrogradely by ERCP, biliary tubes or orally [Abstract, in German]. Ultraschall Med 2010;31:S29. 17. Heinzmann A, M€ uller T, Leitlein J, et al. Endocavitary contrast enhanced ultrasound (CEUS)–-work in progress. Ultraschall Med 2012;33:76. VOL. 43, NO. 2, FEBRUARY 2015
18. Ignee A, Baum U, Schuessler G, et al. Contrastenhanced ultrasound-guided percutaneous cholangiography and cholangiodrainage (CEUSPTCD). Endoscopy 2009;41:725. 19. Luyao Z, Xiaoyan X, Huixiong X, et al. Percutaneous ultrasound-guided cholangiography using microbubbles to evaluate the dilated biliary tract: initial experience. Eur Radiol 2012;22:371. 20. Mao R, Xu EJ, Li K, et al. Usefulness of contrastenhanced ultrasound in the diagnosis of biliary leakage following T-tube removal. J Clin Ultrasound 2010;38:38. 21. Xu E, Zheng R, Su Z, et al. Intra-biliary contrastenhanced ultrasound for evaluating biliary obstruction during percutaneous transhepatic biliary drainage: a preliminary study. Eur J Radiol 2012;81:3846. 22. Zheng R, Chen G, Xu E, et al. Evaluating biliary anatomy and variations in living liver donors by a new technique: three-dimensional contrastenhanced ultrasonic cholangiography. Ultrasound Med Biol 2010;36:1282. 23. Zuber-Jerger I, Endlicher E, Sch€olmerich J, et al. Endoscopic retrograde cholangiography with contrast ultrasonography. Endoscopy 2008;40(Suppl 2):E202. 24. Foschi FG, Piscaglia F, Pompili M, et al. Real-time contrast-enhanced ultrasound–-a new simple tool for detection of peritoneal-pleural communications in hepatic hydrothorax. Ultraschall Med 2008;29: 538. 25. Matono T, Koda M, Murawaki Y. Right diaphragmatic defect in hepatic hydrothorax exposed by contrast-enhanced ultrasonography after radiofrequency ablation. Hepatology 2012;56:784. 26. Tamano M, Hashimoto T, Kojima K, et al. Diagnosis of hepatic hydrothorax using contrastenhanced ultrasonography with intraperitoneal injection of Sonazoid. J Gastroenterol Hepatol 2010;25:383. 27. Chew SS, Yang JL, Newstead GL, et al. Anal fistula: Levovist-enhanced endoanal ultrasound: a pilot study. Dis Colon Rectum 2003;46:377. 28. Henrich W, Meckies J, Friedmann W. Demonstration of a recto-vaginal fistula with the ultrasound contrast medium Echovist. Ultrasound Obstet Gynecol 2000;15:148. 29. Volkmer BG, Neßlauer T, K€ ufer R, et al. Diagnosis of vesico-intestinal fistulas using contrast medium enhanced 3-D ultrasound. Ultraschall Med 2001; 22:81. 30. Antypa E, Cokkinos DD, Kalogeropoulos I, et al. Ultrasound contrast agent delivered per os first diagnoses pharyngoesopgageal tumour. JBR-BTR 2013;96:69. 31. Weskott HP, H€opfner M. Display of gastric, duodenal and colonic lumen by endoluminal contrast agent application. A feasibility study [Abstract, in German] Ultraschall Med 2010;31:S30. 32. Badea R, Ciobanu L, Gomotirceanu A, et al. Contrast ultrasonography of the digestive tract lumen.
79
€ MULLER ET AL
33.
34.
35.
36.
37.
38.
39.
40.
80
Review of the literature and personal experience. Med Ultrason 2010;12:52. Badea R, Ciobanu L, Gomotirceanu A, et al. Contrast ultrasonography–-a necessary procedure for a better characterization of digestive tract pathology. Med Ultrason 2010;12:73. Parente F, Greco S, Molteni M, et al. Oral contrast enhanced bowel ultrasonography in the assessment of small intestine Crohn’s disease. A prospective comparison with conventional ultrasound, x ray studies, and ileocolonoscopy. Gut 2004;53:1652. Dietrich CF, Cui XW, Barreiros AP, et al. EFSUMB guidelines 2011: comment on emergent indications and visions. Ultraschall Med 2012;33:S39. Zengel P, Berghaus A, Weiler C, et al. Intraductally applied contrast-enhanced ultrasound (IACEUS) for evaluating obstructive disease and secretory dysfunction of the salivary glands. Eur Radiol 2011;21:1339. Piscaglia F, Nolsøe C, Dietrich CF, et al. The EFSUMB Guidelines and Recommendations on the Clinical Practice of Contrast Enhanced Ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall Med 2011;33:33. Piscaglia F, Bolondi L. The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol 2006; 32:1369. Dijkmans PA, Visser CA, Kamp O. Adverse reactions to ultrasound contrast agents: is the risk worth the benefit? Eur J Echocardiogr 2005;6:363. Geleijnse ML, Nemes A, Vletter WB, et al. Adverse reactions after the use of sulphur hexafluoride
41.
42.
43.
44.
45.
46.
47.
48.
(SonoVue) echo contrast agent. J Cardiovasc Med 2009;10:75. Miller DL, Averkiou MA, Brayman AA. Bioeffects considerations for diagnostic ultrasound contrast agents. J Ultrasound Med 2008;27:611. Castiglione F, Bucci L, Pesce G, et al. Oral contrast-enhanced sonography for the diagnosis and grading of postsurgical recurrence of Crohn’s disease. Inflamm Bowel Dis 2008;14:1240. Maconi G, Radice E, Bareggi E, et al. Hydrosonography of the gastrointestinal tract. AJR Am J Roentgenol 2009;193:700. Badea R, Neciu C, Iancu C, et al. The role of i.v. and oral contrast enhanced ultrasonography in the characterization of gastric tumors. A preliminary study. Med Ultrason 2012;14:197. Huang P, Li S, Aronow WS, et al. Double contrastenhanced ultrasonography evaluation of preoperative Lauren classification of advanced gastric carcinoma. Arch Med Sci 2011;7:287. Zheng Z, Yu Y, Lu M, et al. Double contrast– enhanced ultrasonography for the preoperative evaluation of gastric cancer: a comparison to endoscopic ultrasonography with respect to histopathology. Am J Surg 2011;202:605. Shi H, Yu XH, Guo XZ, et al. Double contrastenhanced two-dimensional and three-dimensional ultrasonography for evaluation of gastric lesions. World J Gastroenterol 2012;18:4136. Papadopoulou F, Anthopoulou A, Siomou E, et al. Harmonic voiding urosonography with a secondgeneration contrast agent for the diagnosis of vesicoureteral reflux. Pediatr Radiol 2009;39:239.
JOURNAL OF CLINICAL ULTRASOUND
