Improving Gadolinium-based Contrast Safety

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It is clear that gadolinium-based contrast agents (GBCA) for MRI improve detection (sensitivity), characterization (specificity), disease staging, and diagnostic confidence levels. It has also become clear that nephrogenic systemic fibrosis (NSF) is associated with their use in patients with preexisting kidney disease. For radiology, the challenge is to minimize the risk of NSF while retaining, when appropriate, the advantages of GBCA use. GBCA Characteristics GBCAs consist of an active element (gadolinium chelate), an added safety measure (an extra chelating agent) in some products, and a solvent (water). GBCAs increase reliability and may decrease examination times; this is particularly true in MR angiography. Increased signal (enhancement) on T1-weighted images is the result of GBCA’s ability to shorten the T1 relaxation time of nearby water protons. GBCAs are administered intravenously at an injection rate of 1 to 5 mL per second, with the dose depending on the specific application, but typically 0.1 mmol/kg. This total dose of 15 to 30 mL is sometimes increased for MR angiography, for multiple examinations, or for imaging patients with brain metastases or multiple sclerosis. On administration, GBCAs initially circulate in intravascular spaces, but they quickly leak through pores of vessels into extracellular spaces. They do not cross the normal blood-brain barrier. They are excreted primarily through the kidneys by glomerular filtration and have a half-life of about two hours in patients who have normal renal function; most are eliminated completely within a day. GBCAs were commonly used in patients with kidney problems because they are less harmful to the kidneys (at standard doses) than the iodinated contrast used for CT. Patients in this category include those with renal insufficiency, diabetes, or vasculopathies, as well as the elderly (and, of course, dialysis patients). In the United States, none of the GBCAs on the market have been approved for use in imaging the heart, breast, or musculoskeletal system, nor are they approved for intra-articular use, CT, or angiography (whether MR or conventional). Off-label use is permitted, as usual, if there are no explicit warnings or contraindications associated with the intended use and if that use meets the community standard of care. The NSF Connection NSF is a systemic disorder first recognized in 1997. Through skin swelling and tightening, NSF limits motion, leading to contractures and resulting in falls (with fractures and clotting complications). Burning, itching, and severe pain are among the symptoms, and the lungs, heart, muscles, and other tissues may become involved. Several deaths have been reported, and no effective therapy has been documented. The disease may develop over a protracted period, but about 5% of patients experience rapid progression. As of May 2007, more than 250 cases of NSF had been reported to the FDA; by October 2007, 262 cases had been reported to the International NSF Registry at Yale University. The worldwide total of known cases is approximately 500. It is important to bear in mind, when considering these figures, that millions of contrast-enhanced MRI procedures have been performed. In 2005, for example, about a third of the 31 million MRI procedures that were performed used GBCAs. It appears that the individuals who experience NSF have serious kidney disease before they undergo imaging using GBCAs. Approximately 2% to 5% of patients with severe or end-stage renal disease who have received GBCAs have developed NSF, by most estimates (with one recent report1 indicating a much higher percentage). NSF has not been shown to be related to the cause or duration of patients’ serious kidney disease. Almost all patients who have developed NSF have been exposed to high doses or repeated doses of GBCAs. The disorder appears to be distributed worldwide, with no incidence differences based on sex or race. Patients have ranged in age from 8 to 87 years. To date, six pediatric cases have been reported, although there have been no reports of NSF in neonates or infants. In May 2007, an FDA request for a boxed warning to appear on GBCAs was issued to manufacturers. The agency noted that no cases of NSF had been reported in patients without serious underlying kidney disorders. The warning states that GBCAs should be avoided in imaging patients with estimated glomerular filtration rates (eGFRs) of less than 30 mL/minute/1.73 m2, with acute renal insufficiency due to hepatorenal syndrome, or in the perioperative liver-transplantation period, unless the diagnostic information is essential and is unavailable using MRI without contrast enhancement. The warning also asks users to screen all patients for renal dysfunction by obtaining a history and/or laboratory tests, to avoid exceeding the recommended dose, and to allow a sufficient period of time for elimination of the agent from the body to elapse prior to any readministration of GBCAs. Decreasing Risk Beyond the FDA’s recommendations, what can be done to minimize the risk of NSF? Education and communication are the primary means of increasing awareness in radiology and in the broader medical community. Changes in the processes used before, during, and after contrast-enhanced MRI are also called for; they include screening for patients at risk for NSF due to dialysis or chronic kidney disease. In patients with eGFRs of less than 30, GBCAs should be used only if they are clearly necessary, and if no good alternative becomes apparent when alternative imaging algorithms are applied. In 2006, the chief of staff and the Legal & Risk Services Department of Yale New Haven Hospital issued a letter on gadolinium and NSF as part of a comprehensive education and communications plan. Conference calls with affiliates and grand rounds and other meetings for house staff and attending physicians were accompanied by initial and update meetings with all radiologists and all MRI staff. The radiology and hospital information systems were modified to prevent scheduling of contrast-enhanced MRI examinations for high-risk inpatients without a nephrologist’s approval. High-risk outpatients have been harder to identify, although schedulers ask them screening questions and require a nephrology consultation as indicated. Unfortunately, kidney disorders are common, and many patients are unaware that they have chronic kidney disease, even at its severe stages. Patients are also questioned immediately before their MRI examinations. If a high risk level is suspected, imaging may be delayed while laboratory confirmation of kidney function is obtained through stat serum creatinine testing and eGFR. If the decision is made to administer GBCAs, informed consent explaining the risk of NSF is obtained. An explicit order for intravenous contrast is signed by a radiologist (not a referring physician) stating the amount and specific type of agent to be administered for a specific MRI examination. Precise measures covering the procedure and post-MRI patient observation have been implemented, and emphasis is placed on keeping the contrast dose as low as possible (and avoiding or delaying repeated procedures). Patients are given a checklist of potential symptoms to report, although every effort is being made to ensure that they will never need to do so.