The United States is way behind the rest of the world in the use of contrast-enhanced ultrasound, but new efforts to redefine the pathway to approval may modernize its use and catch the US up.

Barry B. Goldberg, MD

The United States may be a world power, but when it comes to the use of ultrasound contrast agents, it’s a third-world country. In much of the rest of the world, including Europe, Asia, and Latin America, contrast-enhanced ultrasound (CEUS) has been approved for use in many of the body’s organ systems.

But the situation in America presents a striking contrast.

“Here in the United States, the only approvals occurred more than a decade ago and that was for use in the evaluation of the cardiac chambers of the heart,” said Barry B. Goldberg, MD, director of the Division of Diagnostic Ultrasound in the Department of Radiology at Thomas Jefferson University Hospital in Philadelphia. This was in part because of the pathway created for approvals and in part due to legitimate safety concerns.

But with more than 2 million doses administered throughout the world, some in the medical community are pushing to revisit these concerns and enable new uses. Organizations, such as the International Contrast Ultrasound Society (ICUS) and the American Institute of Ultrasound in Medicine (AIUM), have opened discussions within the industry as well as with the FDA.

Topics addressed have included appropriate endpoints for contrast agent clinical trials, ultrasound equipment selection, contrast agent safety, and training guidelines for those performing related clinical trials and evaluating associated images. A tremendous amount of research is needed, particularly as companies must seek approval—and provide the data—for each use in each organ system.

Even so, some companies are likely to take advantage of new pathways, should they be agreed upon, to expand the use of CEUS in the United States. “We are not presently in a dialogue with the FDA regarding that, but we may be by the end of the year. We’re assessing which area would be the best one for a discussion with the FDA regarding how it would become approved in the United States,” said Mark Hibberd, MD, PhD, senior medical director of Global Medical Affairs for Lantheus Medical Imaging, headquartered in North Billerica, Mass.

The Road Less Traveled

The previous pathway to approval of CEUS hinged on its comparison to the established gold standard, CT, rather than a comparison to non-contrast-enhanced ultrasound. “If you look at how contrast has been approved for CT or MR, you find that they compared the usefulness of contrast with not using contrast. So you would have an MR exam without contrast compared to MR with contrast,” said Goldberg.

Having to compete with the CT gold standard proved a disadvantage for ultrasound since the gold standard was never considered wrong. When differences occurred in results between CEUS and contrast CT, CT was assumed to be correct and ultrasound incorrect. “If ultrasound saw, with contrast, a mass in the liver, and it was not seen on CT with contrast, then obviously ultrasound must be wrong. If ultrasound saw a mass and CT saw a mass but the difference in location was more than a few centimeters, it was assumed that ultrasound was wrong, because it had to be a different lesion and not the same lesion,” Goldberg said.

Companies, therefore, pulled out of trying to get approvals in the United States. “All [the FDA] wanted was for ultrasound to be equal to CT, but it could never be,” Goldberg said.

In the past few years, however, associations have begun to revisit the pathway with the FDA, presenting research results from around the globe. A committee of the AIUM developed recommendations for a new approach. “The committee included the concept of comparing the differences between ultrasound without contrast and with contrast. What are the improvements when you add contrast to ultrasound?” said Goldberg, who sat on the committee.

Additional suggestions looked at how to produce uniformity between equipment with standard settings, training, and use among multiple centers. Safety is also an issue but one that is more readily addressed with legitimate, agreed-upon data. The details are typically established in discussions between individual companies and the FDA, but they must address the safety organization’s concerns.

“[The FDA] was concerned about a couple of things: the interaction of ultrasound and bubbles and the potential for anaphylaxis. Even though the numbers of adverse events have been small, they still need to look carefully,” said Kathy Ferrara, PhD, a professor at UC Davis in California.

Why Ultrasound?

Concern with already approved contrast agents led to a black box warning that, though modified, still highlights the risk in patients with pulmonary hypertension or unstable cardiopulmonary conditions. Global use, though, has established the diagnostic value of CEUS, finding it both safe and efficacious.

For instance, Kim, Jang, and Wilson cite an extremely low adverse event rate of 0.13% found in the largest European study.1 Picardi et al concluded that harmonic compound ultrasound with contrast enhancement was more sensitive in the characterization of possible nodules than CT or FDG PET in the detection of splenic involvement by Hodgkin lymphoma.2

“With a contrast agent in ultrasound and with the right hardware and software, it is possible to quantify blood flow or flow rate or vascular volume in ways and with a sensitivity that you can’t do with ultrasound otherwise. So it opens up whole new opportunities,” said Ferrara.

Ultrasound bubbles travel easily through the bloodstream but are too large to move into tissues, making them ideal for studying vascular structures, both big (veins and arteries) and small (such as the tiny vessels that grow around tumors). “One large application of these agents might be in that area. There are certainly a significant number of peer-reviewed academic publications that attest to the value of using bubble contrast agents for differentiating tumor types,” said Hibberd. CEUS could therefore help to diagnose malignant versus nonmalignant tumors noninvasively, requiring only the injection of contrast.

Similarly, the modality can be used to determine how tumor treatment is progressing. “Whether it’s through heating a tumor to try to kill it or through chemotherapy, you’re able to quite easily determine how effective the treatment is by the use of contrast agents, which tell you whether all of the tumor has been effectively treated,” said Goldberg.

CEUS also can be used for more direct treatments, such as interventional radiology, where its practical capabilities (portability, size, etc) make it more useful than CT or MR. “You can do [CEUS] just before the operation; you can do it during the operation; you can do it just after the operation. As a result, you can be very sure that you’re doing the operation in the right place and getting all of the tumor resected or ablated in a way that would be more difficult to do, in fact, not really possible to do, any other way,” said Hibberd. The principles generally apply to all organ systems. The liver, breasts, and kidneys may be most common, but Goldberg notes work is being done in the pancreas, thyroid, scrotum, and musculoskeletal system. Kim et al also cite the aorta, prostate, spleen, bowel, and pelvic organs.1 “In most of the applications that we look at, it is possible to implement a fairly broad range of pulsing sequences and therefore to measure accumulation and blood flow rate in a manner that is pretty similar across organ systems,” said Ferrara.

The left photo shows an unenhanced apical view of cardiology ultrasound; the right is the view enhanced with Definity.

Ultrasound Assets

Although comparison to CT and MR has proved challenging for ultrasound outside of the heart, it does offer benefits in regard to safety and cost. “Therefore, it can be used in a patient population where you might not want to use frequent CT or MR contrast exams,” said Ferrara.

Contrast CT carries the risk of ionizing radiation, and contrast MR has health risks depending on the agent and the patient. “In certain cases with gadolinium, you can have renal toxicity—that’s not been shown in ultrasound,” said Goldberg.

Ultrasound has also been shown to be less expensive, although this is certainly not a concern of the FDA. “The FDA isn’t usually concerned with the cost-efficacy argument, although certainly the third-party payors, insurance companies, and others that govern the costs of medicines and billing codes associated with certain procedures are extremely interested in such information,” said Hibberd.

Unfortunately, there is not much direct comparison of the costs and benefits associated with these agents. “However, if you just look at [the modalities] individually, ultrasound exams are less expensive and use cheaper equipment; they’re portable and more readily accessible to patients on a wide-scale basis than are CT or MR scanners; and the contrast agents themselves for ultrasound are inexpensive,” said Hibberd.

The ultrasound workflow also can help to reduce costs. Now, when a patient undergoing an ultrasound exam has a mass identified, he is referred for a CT or MR exam for characterization. “The patient has to come back another day and undergo another full procedure,” said Goldberg, noting this means both a non-contrast and a contrast-enhanced exam.

Approval of CEUS would mean that instead of rescheduling and returning, the patient could undergo a CEUS exam immediately and often have the diagnosis made during one visit. “This cuts down on hospitalization time, outpatient work loss, and cost,” Goldberg said.

Ultimate Ultrasound

Goldberg predicts that CEUS will be used more and more as an initial triage tool, with more expensive procedures saved for follow-up exams when needed for an appropriate diagnosis. “I think it will fit into the health care policies we are seeing evolve in Washington to lower costs and do the most appropriate studies at the least cost,” said Goldberg.

With the medical community and Washington taking a closer look at medical costs, the push toward effective but less expensive ways to deliver high-quality health care may result in new processes. “I think looking more carefully at opportunities that are less expensive and more widely available to populations that might not be served by other diagnostic modalities is the right thing for everybody, including regulators, at this point. Even if not as absolutely perfect as CT and MR for certain applications, the value of ultrasound may still be great to the community in simply providing a cost-effective solution for a variety of health care diagnostic issues,” Hibberd said.

Cost pressures may help in the development of new pathways for approval with the FDA. Companies and physicians are both interested in seeing CEUS become a possibility outside of cardiology. “It’s well recognized by many radiologists that these microbubble contrast agents would be valuable to them, and frankly, they are a little frustrated with the fact that there hasn’t been any approval for any product in this area to date,” Hibberd said.

As a result, once a pathway is approved, more companies are likely to seek approval for their contrast agents. “I think if there is an approved radiology application and the new systems that are being developed to quantify various vascular parameters in radiology applications actually develop and become commercially available, then I would expect to see more widespread use of these agents,” said Ferrara.

There is already one in the immediate pipeline. Bracco Diagnostic Inc, based in Princeton, NJ, reopened its discussions with the FDA for approval of the use of an ultrasound contrast agent for liver mass characterization. The company’s proposal was based on the concept put forth by the AIUM, and the FDA has agreed to a phase three trial (phases one and two were completed years ago, according to Goldberg). “So hopefully, in the next year or two, this will be marketed in the United States,” said Goldberg.

Lantheus may also enter the pipeline once it reopens discussions with the FDA. “We have tried to get Definity on the market for radiology applications previously unsuccessfully, but times have changed and the evidence base has changed, so it may be time for further discussions about that,” said Hibberd.

If those discussions are fruitful and ultrasound contrast agents are approved in the United States, then we can leave our “third-world” status behind. “Maybe, finally, we’ll really catch up to the rest of the world in this one area where the rest of the globe is using it, making diagnoses, and most likely saving lives that we haven’t been able to do here in the United States,” said Goldberg.

Renee Diiulio is a contributing writer for Axis Imaging News.


  1. Kim TK, Jang HJ, Wilson SR. Microbubble contrast agents for ultrasound imaging—safety and efficacy in abdominal and vascular imaging. Lantheus Medical Imaging/Touch Briefing. 2008. Available at: Accessed on June 2, 2009.
  2. Picardi M, Soricelli A, Pane F, et al. Contrast-enhanced harmonic compound US of the spleen to increase staging accuracy in patients with Hodgkin lymphoma. Radiology. 2009;251:574-582.