FDA Orders Boxed Warning on Gadolinium

When two scientists filed a patent application for “contrast enhancement” in nuclear magnetic resonance imaging more than 20 years ago, they cited the “reduced burden of toxic contrast material” as an unprecedented advantage for the new and improved compounds. One of them was gadolinium. Now, however, the very agent that inspired so much optimism back then is the subject of a boxed warning by the U.S. Food and Drug Administration. Gadolinium-based contrast agents have been linked with a rare but tragic side effect — nephrogenic systemic fibrosis — when used in MRIs for patients with acute or chronic severe renal insufficiency, renal insufficiency due to hepato-renal syndrome, and in liver transplant patients in the perioperative period. However, “gado,” as radiologists call it, is only one imaging agent to make headlines recently. In the past few months, findings linked a possible heightened cancer risk to radiation dosing for CT, results that were published in November in the New England Journal of Medicine (2007;357:2277), and reports that iodinated contrast agents used in CT cause more allergic reactions than those utilized for MRI. Other accounts ranged from an investigation on how much contrast media gets into breast milk (not much) to whether patients who get hives from shellfish are likely to react to contrast media (an urban legend, according to one author). All this may have the unanticipated effect of bringing together two specialties that have had a rather notorious history of turf battles: radiology and emergency medicine. How notorious? Ten years ago, at Yale-New Haven Hospital in Connecticut, when emergency physicians started doing ultrasound scans, a group of sleuth radiologists began to document the results carefully. In the first 30 cases, they found “numerous errors,” and, not surprisingly, the data meant a return of all ultrasound exams to diagnostic radiology. (Radiology 1998;209[2]:330.) Then, five years ago, a survey of practice patterns in emergency radiology in Canada revealed that radiologists were timely, on-the-spot diagnosticians in many urgent care settings, but that their availability dropped off after normal business hours. (Can Assoc Radiol J 2007;6:160.)Figure: Dr. James RobertsScreen for Renal Dysfunction Now, in the wake of the gadolinium-based contrast media warnings, emergency physicians are being urged to reach out to radiologists, and some physicians in both specialties seem eager to see that happen. “When a patient with renal compromise is in need of an imaging study, then a direct consultation with a radiologist should be initiated,” said John Ferretti, MD, the chair of radiology at the State University of New York, Stony Brook. “There may be other modalities which may give the answer.” There are even cases in which “it is determined that the MRI needs to done with the agent gadolinium,” he pointed out. “There are protocols for dealing with this patient, which include post-imaging dialysis.” The FDA asked that all patients be screened for renal dysfunction either by obtaining laboratory results or checking patient history, which poses a challenge in urgent care settings. In fact, an FDA spokesperson suggested that asking a patient whether he has kidney disease would be consistent with prescribing instructions. In the emergency department, however, this is often a moot point, observed Peter Viccellio, MD, a clinical professor of emergency medicine at SUNY and a colleague of Dr. Ferretti's. As the clinical director of SUNY's emergency department, Dr. Viccellio said the warning about gadolinium didn't strike him as “a seismic earthquake,” primarily because renal function will be known prior to the possible use of the contrast agent.Figure: Dr. Peter ViccellioHe noted, though, that it didn't surprise him there is some concern among emergency physicians who had been relying on the contrast agent. “It was something that we thought was perfectly safe,” he said. Now, however, it has been shown to cause fibrosis in some patients, and although this is an “extraordinarily rare” side effect, “it is one that justifiably requires greater care in balancing the risks and benefits of the use of the agent in selected patients.” Haloperidol Warning The FDA also issued a warning to physicians about haloperidol, saying it can cause cardiac arrhythmias in relatively high doses or when administered intravenously. Most emergency physicians say this is not a cause for alarm, even though Torsades de Pointes and QT prolongation have been observed in patients receiving haloperidol. There are ways to calm agitated patients that don't involve high doses of the drug, said Dr. Viccellio. Compared with gadolinium, haloperidol is a pretty straightforward issue. Reducing reliance on it may mean altering old habits, but such changes aren't likely to have a high impact on patient care, he suggested. Patient agitation can be treated by using the drug in combination with another medication, by using it only in moderate doses, or by administering another agent just as effective, though the substitute is much more expensive, Dr. Viccellio noted. “It is the ‘super-therapeutic’ dose where case reports have raised a concern,” he stressed. “Overall, [haloperidol] has had an extraordinarily good risk-benefit ratio over the years. Although the reported cases are of concern, one should not forget that thousands of doses of this drug have been used without serious consequences in the ED setting.” Reactions Rare Most emergency physicians will never see a serious gadolinium or haloperidol reaction during their entire careers, said James R. Roberts, MD, the chairman of emergency medicine and the director of toxicology of Mercy Health Systems in Philadelphia. “I have not seen a single such reaction in 35 years, and I use both almost daily,” he said. “Both have clearly stood the test of time. However, if you give enough patients anything, even OTC aspirin or Benadryl, or even vitamins — consider thiamine and vitamin K — someone somewhere will have an untoward reaction.” Dr. Roberts, also a professor of emergency medicine and toxicology at Drexel University College of Medicine, said often the use is coincidental and only related in time, especially when unstable patients are extremely sick and receive multiple interventions. “Nonetheless, reports of this nature, even if unproven, get one's attention, but they don't always change practice,” he said. “These reports should be noted, and it's probably best to avoid high-dose IV Haldol and gadolinium in the presence of renal failure, but neither agent should be banned, or fodder for frivolous litigation, the latter being only a pipedream these days.”

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