U.S. patients miss benefits of ultrasound contrast media

Contrast-enhanced ultrasound for abdominal applications in radiology was first approved in Canada in 2001. Although reimbursement issues have prevented its general dissemination and adoption, ample publications describe the benefits and applications of this exciting and robust technique.^1-16

CEUS is widely used in many countries in Europe and Asia.^17-25 We believe that its adoption in the North American ultrasound community is overdue.

Ultrasound using a microbubble contrast agent is performed on systems with contrast-specific software. When injected as a small bolus in an antecubital vein, the agent rapidly disseminates through the vascular system. The agent is nontoxic, and most patients are unaffected by its injection. The adverse event rate is low. The largest study in Europe showed 29 adverse events in 23,988 examinations (0.13%), including serious adverse reaction in two patients (0.0086%).²⁶

CEUS is noninvasive and easily performed. It provides vascular information at a level not possible with conventional ultrasound with Doppler. The major established application is characterization of focal liver lesions. Enhancement of a lesion relative to the liver may be assessed in both the arterial and portal venous phases, analogous to the enhancement information obtained with a contrast-enhanced CT or MR examination.

Our assessment of this information suggests that CEUS is capable of accurate diagnosis of commonly encountered liver masses (Figure 1).¹³ Unique to CEUS, however, is the ability to show lesional vascularity more akin to that shown on angiography.¹⁵ This detailed vessel information shows vessel morphology and direction of lesional filling with special information for the characterization of some lesions, especially focal nodular hyperplasia and adenoma (Figure 2).⁷

The detection of a liver mass as an incidental observation on any cross-sectional modality performed for any reason is a special circumstance in which CEUS is particularly valuable. Its performance at the time of detection of the mass leads to reduced time to diagnosis, reduced patient anxiety, and a reduction in referral for other imaging examinations (Figure 3).⁹

The challenging problem of detection and diagnosis of hepatocellular carcinoma in patients at high risk is a highlight of CEUS investigations (Figure 4). The long-held belief that these tumors always show arterial phase hypervascularity and portal venous phase wash-out has been shown by the authors and others to be an incomplete truth.⁵ We now recognize that there are many variations of enhancement for these interesting tumors.

Further, we recognize the valuable contribution of CEUS when used in conjunction with contrast-enhanced CT and MRI in this difficult situation. In fact, the importance of CEUS is recognized by the American Association for the Study of Liver Diseases, and the technique has been included in practice guidelines for the management of small nodules detected in the surveillance for hepatocellular carcinoma.²⁷

REAL-TIME ASSESSMENT

Contrast agents for ultrasound allow for a dynamic real-time assessment of blood flow in any organ or region amenable to satisfactory ultrasound study (Figure 5), including the liver, pancreas, gallbladder, spleen, kidneys, gut (Figure 6), or pelvic organs, with demonstration of flow regardless of its timing, intensity, or duration. Since the agents are not nephrotoxic, they can be administered to patients with elevated creatinine or even frank renal failure. Utilization of ultrasound rather than CT also offers an immeasurable benefit in terms of diminished risk of exposure to ionizing radiation.

CEUS plays an integral role in the characterization of liver masses at our institutions. It is a key component to the monitoring of radiofrequency ablation of liver tumors (Figure 7)³ and has proved useful in detecting endoleak after an aortic stent-graft procedure.²⁸ We believe that similar benefits will be confirmed in the future for CEUS imaging of the pancreas, spleen, kidneys, and abdominal great vessels.

As a nontoxic, easily performed technique that does not use ionizing radiation, CEUS offers advantages to Canadian patients that are denied to U.S. patients, as there is no FDA approval for use of these agents in the U.S. We firmly believe that this should change in the near future and that U.S. patients should enjoy similar benefit from the use of CEUS as do their Canadian neighbors.

References

1. Burns PN, Wilson SR. Focal liver masses: enhancement patterns on contrast-enhanced images-concordance of US scans with CT scans and MR images. Radiology 2006.
2. Burns PN, Wilson SR. Microbubble contrast for radiological imaging: 1. Principles. Ultrasound Q 2006;22:5-13.
3. Dill-Macky MJ, Asch M, Burns P, Wilson S. Radiofrequency ablation of hepatocellular carcinoma: predicting success using contrast-enhanced sonography. AJR 2006;186:S287-S295.
4. Dill-Macky MJ, Burns PN, Khalili K, Wilson SRal hepatic masses: enhancement patterns with SH U 508A and pulse-inversion US. Radiology 2002;222:95-102.
5. Jang HJ, Kim TK, Burns PN, Wilson SR. Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. Radiology 2007;244:898-906.
6. Jang HJ, Kim TK, Wilson SR. Imaging of malignant liver masses: characterization and detection. Ultrasound Q 2006;22:19-29.
7. Kim TK, Jang HJ, Burns PN, et al. Focal nodular hyperplasia and hepatic adenoma: differentiation with low-mechanical-index contrast-enhanced sonography. AJR 2008; 190:58-66.
8. Kim TK, Jang HJ, Wilson SR. Benign liver masses: imaging with microbubble contrast agents. Ultrasound Q 2006;22:31-39.
9. Lanka B, Jang HJ, Kim TK, et al. Impact of contrast-enhanced ultrasonography in a tertiary clinical practice. J Ultrasound Med 2007;26:1703-1714.
10. Murphy-Lavallee J, Jang HJ, Kim TK, et al. Are metastases really hypovascular in the arterial phase? The perspective based on contrast-enhanced ultrasonography. J Ultrasound Med 2007;26:1545-1556.
11. Wilson SR, Burns PN. Liver mass evaluation with ultrasound: the impact of microbubble contrast agents and pulse inversion imaging. Semin Liver Dis 2001;21:147-159.
12. Wilson SR, Burns PN. Microbubble contrast for radiological imaging: 2. Applications. Ultrasound Q 2006;22:15-18.
13. Wilson SR, Burns PN. An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography. AJR 2006;186:1401-1412.
14. Wilson SR, Jang HJ, Kim TK, Burns PN. Diagnosis of focal liver masses on ultrasonography: comparison of unenhanced and contrast-enhanced scans. J Ultrasound Med 2007;26:775-787; quiz 788-790.
15. Wilson SR, Jang HJ, Kim TK, et al. Real-time temporal maximum-intensity-projection imaging of hepatic lesions with contrast-enhanced sonography. AJR 2008;190:691-695.
16. Wilson SR, Kim TK, Jang HJ, Burns PN. Enhancement patterns of focal liver masses: discordance between contrast-enhanced sonography and contrast-enhanced CT and MRI. AJR 2007;189:W7-W12.
17. Albrecht T, Blomley M, Bolondi L, et al. Guidelines for the use of contrast agents in ultrasound. January 2004. Ultraschall Med 2004;25:249-256.
18. Albrecht T, Overberg A, Hoffmann CW, et al. Characterization of focal liver lesions with phase inversion ultrasound during the late liver-specific phase of Levovist. Acad Radiol 2002;9 Suppl 2:S375.
19. Blomley MJ, Cooke JC, Unger EC, et al. Microbubble contrast agents: a new era in ultrasound. BMJ 2001; 322:1222-1225.
20. Choi BI, Kim TK, Han JK, et al. Vascularity of hepatocellular carcinoma: assessment with contrast-enhanced second-harmonic versus conventional power Doppler US. Radiology 2000;214:381-386.
21. Cosgrove D, Blomley M. Liver tumors: evaluation with contrast-enhanced ultrasound. Abdom Imaging 2004; 29:446-454.
22. Nicolau C, Catala V, Vilana R, et al. Evaluation of hepatocellular carcinoma using SonoVue, a second generation ultrasound contrast agent: correlation with cellular differentiation. Eur Radiol 2004;14:1092-1099.
23. Nicolau C, Vilana R, Catala V, et al. Importance of evaluating all vascular phases on contrast-enhanced sonography in the differentiation of benign from malignant focal liver lesions. AJR 2006;186:158-167.
24. Quaia E, Calliada F, Bertolotto M, et al. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 2004; 232:420-430.
25. Kudo M. New sonographic techniques for the diagnosis and treatment of hepatocellular carcinoma. Hepatol Res 2007;37 Suppl 2:S193-S199.
26. Piscaglia F, Bolondi L. The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol 2006;32:1369-1375.
27. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208-1236.
28. Dill-Macky MJ. Aortic endografts: detecting endoleaks using contrast-enhanced ultrasound. Ultrasound Q 2006;22:49-52.

Dr. Kim is an associate professor of radiology and Dr. Jang is an assistant professor of radiology, both at the University of Toronto. Both are radiologists in the department of medical imaging at Toronto General Hospital, University of Toronto, in Ontario. Dr. Wilson is a professor of radiology at the University of Calgary and a radiologist in the department of diagnostic imaging at Foothills Medical Centre, University of Calgary, in Alberta.