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Contrast-Enhanced Ultrasound: What Is the Evidence and What Are the Obstacles?

¹ Department of Diagnostic Imaging, Foothills Medical Centre, 1403 29 St., NW, Calgary, AB T2N 2T9, Canada.
² The Hughes Center for Fetal Diagnostics, Winnie Palmer Hospital for Women & Babies, Orlando, FL.
³ Division of Ultrasound, Thomas Jefferson University Hospital, Philadelphia, PA.

Received February 9, 2009; accepted after revision March 23, 2009.

 
S. R. Wilson has an advisory role for ultrasound for Philips Healthcare and Siemens Medical Solutions and received a research grant from Lantheus Medical Imaging. L. D. Greenbaum performs premarket equipment evaluations for Philips Healthcare.

Address correspondence to S. R. Wilson (stephanie.wilson{at}albertahealthservices.ca).

FOR YOUR INFORMATION

A data supplement for this article can be viewed in the online version of the article at: www.ajronline.org.

Abstract

Top Abstract Introduction The Evidence The Obstacles References

 
OBJECTIVE. Although ultrasound contrast agents (UCAs) are popular and widely used in Europe and Asia, the U.S. Food and Drug Administration (FDA) has not approved a microbubble agent for radiology imaging in the United States. Herein, we discuss the evidence for and the obstacles to using UCAs for contrast-enhanced ultrasound (CEUS).

CONCLUSION. Despite the obstacles to the use of UCAs for CEUS including regulatory and practice patterns, the evidence indicates that radiologists and patients will be missing an effectual imaging option if we do not encourage the use of CEUS and strongly support the approval of UCAs by the FDA. The evidence outweighs the obstacles: CEUS is cost-effective; can be performed at the bedside; uses no ionizing radiation; has no nephrotoxicity; and, most importantly, can provide accurate diagnostic information comparable to CT and MRI.

Keywords: contrast-enhanced ultrasound • contrast media • FDA approval • radiology practice guidelines • ultrasound contrast agents

Introduction

Top Abstract Introduction The Evidence The Obstacles References

 
Contrast-enhanced ultrasound (CEUS) involves the use of microbubble contrast agents and specialized imaging techniques to show sensitive blood flow and tissue perfusion information. CEUS is a safe and easily performed technique with no requirement for ionizing radiation and no risk of nephrotoxicity. Although popular and widely used in Europe and Asia, the U.S. Food and Drug Administration (FDA) has not approved a microbubble agent for radiology imaging in the United States. Herein, we discuss the evidence and the obstacles.

The Evidence

Top Abstract Introduction The Evidence The Obstacles References

 
The role of conventional ultrasound for imaging many organs of the body is limited by the capabilities of conventional color and spectral Doppler imaging. Although Doppler imaging may provide valuable directional blood flow information, it is most effective for evaluating large blood vessels with fast-flowing blood such as the carotid arteries; leg veins; and major visceral vessels of the abdomen, including the portal veins and hepatic arteries. The ability of Doppler imaging to detect blood flow at the perfusion level is limited.

The remedy for this problem is to add microbubble contrast agents and specialized ultrasound imaging techniques. The former enhances the Doppler signal from blood, whereas the latter serves to suppress the signals from the background tissue while enhancing the sensitivity to the Doppler signals from the microbubbles within the blood pool. These additions allow ultrasound imaging of blood flow at the tissue perfusion level, thus enabling ultrasound to play a competitive role relative to CT and MRI in the evaluation of the solid and hollow organs of the abdomen and pelvis.

Contrast-enhanced ultrasound (CEUS) shows tissue perfusion analogous to that shown on contrast-enhanced CT and MRI in which patterns of enhancement in the arterial and portal venous phases predict diagnoses of focal liver lesions (Figs. 1A, 1B, 1C, 1D, 1E, and 1F). After the injection of microbubbles, maximum-intensity-projection (MIP) techniques may add the information between ultrasound frames, thereby tracking the course of the microbubbles and allowing superior depiction of vessel morphology on CEUS as compared with either CT or MRI, when performed with a similar venous injection of contrast agent [1] (Figs. 2A, 2B, 2C, 2D, 2E, and 2F).

View larger version (105K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Baseline transverse ultrasound image shows mixed echogenic mass in cirrhotic liver.

View larger version (85K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Arterial phase CEUS image shows hypervascular mass.

View larger version (109K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Portal venous phase CEUS image obtained at 150 seconds shows washout of lesion such that it is now less enhanced than adjacent liver.

View larger version (158K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1D —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Unenhanced CT image shows lesion is hypoattenuating.

View larger version (179K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1E —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Contrast-enhanced arterial phase CT image shows lesion is hypervascular.

View larger version (174K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1F —Hepatocellular carcinoma in 67-year-old woman with alcoholic cirrhosis. Analogous enhancement information is shown on contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT. Portal venous phase image shows lesion has washed out. Both CT and CEUS suggest hepatocellular carcinoma.

View larger version (127K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Baseline sagittal image shows bulbous expansion of tip of left lobe of liver.

View larger version (80K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

View larger version (94K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

View larger version (109K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2D —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

View larger version (119K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2E —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Sequential images obtained in arterial phase of CEUS show stellate vascularity, centrifugal filling, and homogeneous hypervascularity at peak enhancement (E).

View larger version (112K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2F —Focal nodular hyperplasia in asymptomatic 22-year-old woman. Arterial phase contrast-enhanced ultrasound (CEUS) images obtained with maximum-intensity-projection technique show superb vessel delineation. For video, see Figure S2 in supplemental data at www.ajronline.org. (Reprinted with permission from [35]) Image in portal venous phase at 3 minutes shows sustained contrast enhancement and central nonenhancing scar (arrow).

The actual performance of CEUS requires contrast-specific software on the ultrasound equipment that suppresses the signal from the background tissue leaving only the signal from the microbubbles. This is accomplished by various techniques, the most common of which is pulse inversion whereby two signals are sent down a single scan line and the second is a mirror image of the first. Echoes from both pulses are collected by the transducer and summed. Linear reflectors, such as normal tissue, produce no net signal. However, nonlinear reflectors, such as microbubbles, produce echoes that are asymmetric and do not sum to zero. The result is that echoes from bubbles are detected preferentially using this method, improving image contrast between tissue and microbubbles. If the sound is transmitted at a low mechanical index (MI), the microbubble population is preserved and long periods—up to several minutes—of observation are possible. Low-MI techniques comprise the standard imaging methods used today for CEUS. Conversely, if the sound is transmitted at a high MI, the bubbles may be destroyed in a single pulse. This facilitates a flash replenishment technique whereby the bubbles can be visualized refilling the liver or tumor after their destruction, which is optimal for visualization of vessel morphology in characterization studies.

Liver mass characterization is the most established and successful indication for the performance of CEUS [5-8]. Investigators have shown that simple algorithms allow diagnosis of most liver masses [9]. Reflective of many published studies reporting the success of CEUS for this indication, Ding et al. [6], in a study of 147 tumors using established and familiar diagnostic criteria, reported a high sensitivity of 96.3% and 97.5% specificity for the diagnosis of hemangioma and a very credible low of 92% sensitivity and 86.7% specificity for hepatocellular carcinoma. Therefore, CEUS can rapidly characterize incidentally detected masses found on conventional ultrasound or other techniques. Further, CEUS is valuable for the evaluation of nodules in the patient at risk for hepatocellular carcinoma [10, 11] and for the often-difficult differentiation between adenoma and focal nodular hyperplasia in asymptomatic young women [12-15].

Washout of contrast agent in the portal venous phase of liver mass evaluation with CEUS has been shown to have a high association with malignant histology [9], although benign lesions may also show washout. The timing of washout on CEUS adds further specificity in that metastases of any cell type generally show complete and rapid washout in the conventional time frame defined as the arterial phase [16, 17], whereas hepatocellular carcinoma often shows incomplete and slow washout [10].

Detection of liver masses is also greatly improved with CEUS in that more masses and smaller masses may be shown than can be seen on conventional ultrasound scans [18, 19] (Figs. 3A, 3B, and 3C). Albrecht et al. [19], in a description of 123 patients, showed the addition of CEUS improved sensitivity for the detection of individual metastases from 71% to 87% (p < 0.001). On a per-patient basis, sensitivity improved from 94% to 98% (p = 0.44) and specificity improved from 60% to 88% (p < 0.01).

View larger version (110K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A —Advantage of contrast-enhanced ultrasound (CEUS) for detection of liver metastases is shown in 72-year-old man with metastatic colon cancer. Baseline transverse sonogram shows gross steatosis and focal superficial mass in segment IV. Second tiny mass (arrow) may be present.

View larger version (100K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B —Advantage of contrast-enhanced ultrasound (CEUS) for detection of liver metastases is shown in 72-year-old man with metastatic colon cancer. Portal venous phase CEUS image of known mass shows typical complete washout so that mass is now more conspicuous, appearing black, relative to enhanced parenchyma. Second smaller mass (arrow) is confirmed.

View larger version (46K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3C —Advantage of contrast-enhanced ultrasound (CEUS) for detection of liver metastases is shown in 72-year-old man with metastatic colon cancer. Sweep through liver shows two additional metastases in segment VI that are obvious here but were unsuspected on baseline scan (A).

The impact of the introduction of CEUS on an ultrasound practice is addressed in two retrospective reviews of more than 1,000 patients each in which CEUS was performed for liver mass characterization using two different second-generation contrast agents [28, 29]. In both studies, the accuracy of diagnosis of CEUS in patients with pathology confirmation was identical at 89%. Both also document a similar reduction in time to diagnosis; reduction in referral for CT, MRI, or both; and a positive contribution to patient management in 17.5% and 15.6%, respectively. The negative impact from CEUS was very low in both studies at 0.8% and 1.7%, respectively.

The Obstacles

Top Abstract Introduction The Evidence The Obstacles References

 
With such compelling evidence of the efficacy of CEUS and with the extensive use of microbubble contrast agents throughout Europe and Asia, why are ultrasound contrast agents (UCAs) rarely used for body imaging in the United States? The answers fall into two categories: regulatory and practice patterns. The regulatory issues involve the FDA.

There are three major manufacturers of UCAs: Bracco Imaging (Milano, Italy), GE Healthcare (Little Chalfont, United Kingdom), and Lantheus Medical Imaging (North Billerica, MA). Two second-generation perfluorocarbon contrast agents, perflutren protein-type A microspheres for injection (Optison, GE Healthcare) and perflutren lipid microsphere injectable suspension (Definity, Lantheus Medical Imaging), have been approved by the FDA for left ventricular opacification. However, no agent has been approved for a noncardiac use in the United States. By 2005, this approval process had come to a standstill because of safety concerns of the FDA and the extent and type of information requested by the FDA in the design of suggested clinical trials (Greenbaum L, personal communication with FDA, Bracco Imaging, GE Healthcare, and Bristol-Myers Squibb). The safety issue was primarily with one agent; during its after-marketing surveillance, three deaths were reported.

The information issues include a requirement in previous clinical trials conducted in the United States to use contrast-enhanced CT, contrast-enhanced MRI, or both as the reference standard. Furthermore, there are also cross-platform problems because previous clinical trials performed in the hope of gaining a radiology approval have shown great inconsistencies in the performance of CEUS depending on the type of ultrasound equipment used. The American Institute of Ultrasound in Medicine (AIUM) was concerned about this standstill and formed a task force to address the problem in 2005.

As a result of efforts from the AIUM task force, there were several meetings with the FDA during 2005 and 2006, including an extensive educational session presented by the AIUM to the FDA staff in March 2006. At that time, the FDA asked the AIUM to write a protocol for the performance of a clinical trial using UCAs to image the liver. This protocol was accepted by the FDA later that year and was subsequently published [30]. Key issues addressed were appropriate end points, examination procedures, equipment criteria, safety, and training. Perhaps the most significant recommendation for a possible trial was that the comparison should be CEUS versus non-CEUS and not CEUS versus contrast-enhanced CT or MRI.

Unfortunately, as the AIUM initiative was moving forward, all progress came to an abrupt halt on October 10, 2007, when the FDA issued a "black box warning" on the labeling for the two approved UCAs in the United States, Definity and Optison [31]. The warning greatly expanded the list of contraindications for using these agents and also mandated a 30-minute monitoring period after their use in all patients. This significantly affected the cardiology community because the new contraindications for use restricted cardiologists from using Definity or Optison on the very patients who benefited most from contrast-enhanced echocardiography [32, 33]. Further, the warning was another impediment to the use of UCAs by radiologists who were already burdened by the lack of an approved radiology indication.

A grassroots action started in response with a letter to the FDA signed by 161 physicians from the United States and the international community. Many radiologists in the United States participated. A group of cardiologists subsequently met with the FDA in December 2007 to present their objections to the black box warning, present additional safety information, and request the convening of an advisory panel (Feinstein SB, personal communication). Based on the new safety information, on May 13, 2008, the FDA modified the black box warning by rescinding the new contraindications and requiring monitoring only in patients with pulmonary hypertension or unstable cardiopulmonary conditions [34].

There have been ongoing interactions with the FDA, including testimony on June 24, 2008, at the FDA Cardiovascular and Renal Drugs Advisory Committee meeting titled "Safety Considerations in the Development of Ultrasound Contrast Agents." However, there still is no FDA-approved radiology indication for the use of UCAs. Although there has been off-label use by radiologists, there is no reimbursement for the use of UCAs. Despite this obstacle, the future looks promising. In September 2008, Bracco announced that it would initiate an American clinical trial based on the AIUM protocol for the characterization of focal liver lesions using CEUS (Bokor D, Bracco, personal communication). In addition, in response to the actions of the FDA, a group of radiologists and cardiologists joined forces to form the International Contrast Ultrasound Society to promote the use of UCAs, respond to regulatory agencies, and educate the medical community and public about the benefits of UCAs.

The other obstacle for radiologists using CEUS has to do with practice patterns. For the purposes of this discussion, we will limit the use of CEUS to imaging of the liver, the most common noncardiac use worldwide. Liver imaging in the United States is performed almost exclusively by radiologists, and they primarily use CT and MRI. Obtaining CT or MR studies is dependent on radiologic technologists following established protocols for all examinations. These technologists are highly skilled but little, if any, "art" is required. Although performing occasional examinations may require specialized imaging, for the most part, the radiologist can sit at his or her PACS station and wait for the examination to be placed on the work list. By comparison, CEUS is a dynamic examination that depends on the skill of the sonographer and requires the active participation of the sonologist. Therefore, it cannot compete with CT or MRI from an efficiency and productivity point of view. Add to this the differences in reimbursement based on relative value units between ultrasound and CT or MRI (Encoder Pro, Ingenix) and the fact that CEUS is currently not reimbursable. Therefore, radiologists have little incentive to use CEUS other than intellectual curiosity. However, recent concerns about excess ionizing radiation from CT and renal toxicity from MRI contrast agents have opened a window of opportunity for CEUS.

Despite all these obstacles, radiologists and patients will be missing an effectual imaging option if we do not encourage the use of CEUS and strongly support the approval of UCAs by the FDA. CEUS is cost-effective; can be performed at the bedside; uses no ionizing radiation; has no nephrotoxicity; and, most importantly, can provide accurate diagnostic information comparable to CT and MRI: The evidence outweighs the obstacles.

References

Top Abstract Introduction The Evidence The Obstacles References

 

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This Article Abstract Figures Only Full Text (PDF) VIDEO Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wilson, S. R. Articles by Goldberg, B. B. PubMed PubMed Citation Articles by Wilson, S. R. Articles by Goldberg, B. B. Social Bookmarking                      What's this? Hotlight (NEW!) What's Hotlight?