Recently, there has been good news as well as disturbing news when it comes to contrast agents. If you’ve been hearing contrasting stories, learn what the latest studies have to say.

On the one hand, veteran gadolinium-based compounds and micro-bubble contrast agents are getting new black box warnings. On the other hand, blueberry juice, noncontrast MR techniques, and a developing crop of nanoparticle-based contrast agents show promise.

Contrast agents have been in the news lately—a lot. With recent FDA black box warnings being placed on two types of compounds, one on gadolinium-based agents and another on micro-bubble contrast agents, radiologists are having to be more careful than ever about assessing patients before administering these two commonly used imaging enhancement tools. At the same time, manufacturers continue to find innovative ways to develop new contrast agents, and perhaps even replace them entirely.

Warnings in Contrast

Widely used FDA-approved contrast agents for MRI and ultrasound have been around for years, effectively enhancing images for diagnosis, albeit with known side effects. However, recent concerns have developed over two well-known contrast agents: gadolinium-based compounds used for MR studies and micro-bubble contrast agents used for echocardiograms. As a result of these concerns, the FDA asked manufacturers to update package inserts.

• Micro-bubble Warning
In October 2007, the FDA received reports of serious cardiopulmonary reactions, including a total of 11 deaths, following the administration of ultrasound micro-bubble contrast agents used in echocardiography. As a result, the FDA requested that a black box warning be added to the labeling for Definity (Perflutren Lipid Microsphere) Injectable Suspension from Bristol-Myers Squibb, New York, and Optison (Perflutren Protein-Type A Micro-spheres for Injection) from Amersham Health Inc, Piscataway, NJ, a division of GE Healthcare.¹

(Ten of the 11 deaths reported were from patients using Definity. As of this writing in mid October, the new labeling has been approved only for Definity, but the FDA's Web site said that the new Optison labeling will be approved in the near future.)

Most of the reported deaths were patients with severe underlying cardiac conditions and occurred 1 to 12 hours following administration of the contrast agents. The FDA also received approximately 200 reports of serious nonfatal reactions following the administration of the micro-bubble compounds.

In its warning, the FDA advises physicians who administer echocardiographic micro-bubble contrast agents to assess all patients for the presence of several cardiac conditions, including clinically unstable or recent worsening congestive heart failure, acute myocardial infarction, serious ventricular arrhythmias, or high risk for arrhythmias due to QT prolongation, as well as other conditions. In addition, physicians are to monitor all patients for serious cardiopulmonary reactions during the infusion and for 30 minutes following completion of administration.

The packaging also now mentions several contraindications, especially using the agents in patients with known cardiac shunts, as well as other cardiac conditions.¹

Additionally, physicians are asked to report any abnormalities to the FDA's MedWatch reporting system (www.fda.gov/medwatch/report.htm or 800-FDA-1088). Manufacturers have also agreed to conduct a postmarketing safety study to further assess the risks of serious cardiovascular reactions.

For complete information on the FDA's warning, go to: www.fda.gov/cder/drug/InfoSheets/HCP/microbubbleHCP.htm

• Gadolinium Black Box Approved
Gadolinium concerns have been known for some time, but the black box warning has only recently been approved in September 2007.² The FDA's investigation of gadolinium agents began in 2006 when it learned of 25 cases of nephrogenic systemic fibrosis (NSF) (sometimes referred to as nephrogenic fibrosing dermopathy) in patients with kidney failure who received gadolinium contrast agents.

NSF risks were identified with five gadolinium-based contrast agents, including Magnevist, Bayer HealthCare Pharmaceuticals Inc, Montville, NJ; MultiHance and ProHance from Bracco Diagnostics Inc, Princeton, NJ; Omniscan from GE Healthcare, Princeton, NJ; and OptiMARK from Mallinckrodt Inc, Commerce, Calif.

The new black box wording specifically cautions that gadolinium-based agents increase the risk of NSF in patients with:

• Acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m²), or
• Acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period.

In addition, the label advises health care professionals to screen all patients for renal dysfunction, to not exceed the recommended doses, and to allow for sufficient time for eliminating the agent from the body.

For more complete information on the final labeling, go to the FDA's Web site at www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html.

Alternatives to Gadolinium

The FDA notes that while the previous gadolinium-based compounds have been approved for MRI, they have never been specifically approved for MR angiography (MRA).³ Nevertheless, many radiologists have used gadolinium-based contrast agents for MRA because of its ability to improve images of blood vessels, especially in renal studies.

Currently, there are few FDA-approved MRI contrast agent alternatives to gadolinium-based compounds—and there are no contrast agents specifically approved for MRA.

The two other FDA-approved MRI contrast agents are Feridex I.V., a superparamagnetic iron oxide nanoparticle negative contrast agent from Bayer Healthcare, which is FDA-approved for MR studies to enhance liver lesions. The second approved MRI contrast agent is Teslascan, a manganese-containing injectable solution developed by GE Healthcare Biosciences that is, again, FDA-approved only for the evaluation of lesions of the liver.

One can be sure that manufacturers are working on alternatives to gadolinium and on different methods for improving its safety, but it is unknown whether any new products will be made available in the near future. There is, however, the possibility that older European brands that have already applied for FDA clearance may be available sooner.

Claire Corot, PharmD, is the research vice president for Guerbet Group, Villepinte, France. Guerbet is best known in America for its x-ray contrast agent, Oxilan, but it is also a manufacturer of other contrast media approved in Europe. One of the company's EU-approved contrast agents is Doterem, an ionic symmetric macrocyclic gadolinium-based compound that has been available in Europe for more than 20 years. According to Corot, there have been no confirmed cases of NSF associated with Doterem, and she said that the company is in discussions with the FDA for approval.

Noncontrast MRA Techniques

Though gadolinium-enhanced studies have been used most often for MRA in the past 10 years, there are noncontrast MRA methods as well. The most common noncontrast methods are "time-of-flight" and "phase contrast" techniques. While these well-known methods can effectively enhance MRA images, they can also be subject to artifact, such as Venetian blind artifact and flow-related artifact.

Aside from time of flight and phase contrast, there are also three relatively recent proprietary noncontrast procedures that were developed by Toshiba America Medical Systems, Tustin, Calif. The techniques are available through most of Toshiba's MR product line, including its current Vantage systems. The three methods are known as "fresh blood imaging" (FBI), "contrast-free improved angiography" (CIA), and the company's latest method, "Time-SLIP."

FBI is a 3D, fast spin echo, half Fourier gated technique that was introduced in 1998, and has the advantage of Toshiba MRs being able to image arteries and veins at the same time, yet display them separately. CIA is a further developed version of FBI that enables the MRs to more effectively image small vessels.

Time-SLIP, introduced in 2001, is an entirely different technique from the first two. The company describes Time-SLIP as an arterial spin labeling technique. Mark Totina, RT, R-MR, CT, a product manager for MR at Toshiba, explained that Time-SLIP electronically labels the blood molecules with an electronic pulse and then lets the molecules flow to particular parts of the body. At that time, the scanner takes a picture of molecules that were labeled.

Totina said, "You can use this technique all over the body and in complex circulations." He also points out that Time-SLIP provides enhancements for MRA renal studies without the kidney's "blushing," an effect normally seen in gadolinium contrast-enhanced MRAs.

Contrast Juice for MRCP?

For those looking for the truly alternative—as in going all natural—some radiologists are looking again at blueberry juice and pineapple juice for MR cholangiopancreatography (MRCP) imaging. MRCP images can often be fettered by gastric secretions in the stomach and duodenum that create high fluid signals, which can sometimes obscure the bile ducts.

However, research published years ago in Radiology suggests that certain manganese-rich drinkable liquids, such as blueberry juice, can eliminate this high signal.⁴

Wayne Patola, MRI technologist and supervisor at St Paul's Hospital, Vancouver, British Columbia, has been using this technique for more than 6 months. He said, "The manganese causes an alteration in the magnetic field nearby, like when you stick a piece of iron in a magnetic field and all the field lines move toward it. By causing that alteration, we then change the signal intensity we receive from any fluid that's in the direct vicinity of those manganese molecules, and that allows us to remove the brightness of the fluid from the stomach and duodenum."

If blueberry juice is not available at the local grocery store, try pineapple juice. A 2004 study in the British Journal of Radiology found that pineapple juice (PJ) has a "naturally occurring manganese containing agent that has desirable effects as an oral contrast agent for abdominal MR imaging in patients with inflammatory bowel disease." The study concluded that "PJ may be used as a negative oral contrast agent that significantly improves the quality of MRCP imaging. Visualization of the pancreatic duct, in whole and part, is significantly improved following PJ if imaged at 15 minutes or 30 minutes post-ingestion."⁵

New Contrasts on the Horizon

Despite the disconcerting news in contrast, there is still much potential for enhancing images.

Contrast agents that incorporate nanoparticles, in particular, are generating a great deal of research. Nano-particle formulas are seen as beneficial in early cancer detection because of their ability to latch on to targeted tissues and identify very small lesions that might otherwise be missed in early cancer screenings.

Bayer's Feridex I.V. is one of the first generations of iron oxide nanoparticle contrast agents for the liver to be approved by the FDA, but there are more on the way:

• Guerbet is developing a new ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle compound with AMAG Pharmaceuticals, Cambridge, Mass, marketed under the name of Combidex in the United States and Sinerem in Europe. According to the company's Web site, Combidex has "demonstrated in clinical studies that Combidex only accumulates in normal lymph node tissue and can therefore facilitate differentiation between cancerous nodes and normal nodes." It is still working toward final FDA approval for marketing in the United States.
• Another superparamagnetic iron oxide nanoparticle contrast agent for the liver that is available in Europe and awaiting FDA approval in the United States is Resovist from Schering AG, Berlin, Germany. Resovist has specially coated nanoparticles that are accumulated by phagocytosis in cells of the reticuloendothelial system of the liver. The resulting accumulation creates a decrease of the signal intensity of normal liver parenchyma on both T2 and T1 weighted images and enhances tumors.
• South Korean researchers have developed an MRI contrast agent for anatomical brain imaging. The study appears in the journal, Angewandte Chemie. The researchers report that the newly developed nanoparticles are able to produce images of the anatomic structures of mouse brains that are as clear as those obtained by histological examination.⁶
• In CT nanoparticle news, the May 2007 issue of the journal Nature Medicine published a study where researchers demonstrated that multidetector CT utilizing a new nanoparticle agent can detect high-risk plaque that would eventually lead to a heart attack and stroke. The clinicians used an animal model to test an iodinated nanoparticulate contrast agent called N1177 from NanoScan Imaging, LLC, Lansdale, Pa, for the detection of macrophages using 64-slice CT. High-risk plaque in the animal model contained high levels of macrophages, which are similar in size and content to human coronary plaques.⁷

These are but a few of the latest studies in contrast media. Given the ever-increasing demand for enhanced image quality in MR and all modalities, there is no doubt that unique contrast agents will continue to be a dynamic and important tool for radiology, whether in the form of iron oxide nanoparticles or in blueberry juice.

Tor Valenza is a staff writer for  Imaging Economics. For more information, contact .

References

1. Micro-bubble contrast agents (marketed as Definity (Perflutren Lipid Microsphere) Injectable Suspension and Optison (Perflutren Protein-Type A Microspheres) for Injection). www.fda.gov/cder/drug/InfoSheets/HCP/microbubbleHCP.htm. Accessed on October 15, 2007.
2. FDA requests boxed warning for contrast agents used to improve MRI images. www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html. Accessed on October 15, 2007.
3. Questions and answers on gadolinium-based contrast agents. www.fda.gov/cder/drug/infopage/gcca/qa_200705.htm. Accessed on October 15, 2007.
4. Hiraishi K, Narabayashi I, Fujita O, et al. Blueberry juice: preliminary evaluation as an oral contrast agent in gastrointestinal MR imaging. Radiology. 1995;194:119-123.
5. Riordan RD, Khonsari M, Jeffries J, Maskell GF, Cook PG. Pineapple juice as a negative oral contrast agent in magnetic resonance cholangiopancreatography. Br J Radiol. 2004;77:991-999.
6. Na HB, Lee JH, An K, et al. Development of a T1 contrast agent for magnetic resonance imaging using MnO nanoparticles. Angewandte Chemie International Edition. 2007;46(28):5397-5401.
7. Hyafil F, Cornily JC, Feig JE, et al. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med. 2007;13:636-41. DOI:10.1038/nm1571. Available at: www.nature.com/nm/index.html.