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Editorials |
1 From the Diagnostic Radiology Department, National Institutes of Health, 10 Center Dr, MSC 1182, Bldg 10, Rm 1C660, Bethesda, MD 20892-1182 (P.L.C.); and Department of Radiology, Ohio State University College of Medicine & Public Health, Columbus, Ohio (M.V.K.). Received March 3, 2002; accepted March 6. Address correspondence to P.L.C. (e-mail: pchoyke@nih.gov).
Index terms: Calcium • Contrast media • Contrast media, effects • Editorials • Magnetic resonance (MR), contrast media, **.121432
Prince et al (1) have done the imaging community a service by bringing to light the previously underappreciated effects of gadodiamide and gadoversetamide, two of the four approved gadolinium-based magnetic resonance (MR) imaging contrast agents, on the colorimetric measurement of serum calcium. The Prince et al article (1) vividly points out how pseudohypocalcemia—that is, spurious hypocalcemia—can lead to unnecessary treatment, diagnostic confusion, and expense. Informing radiologists about this potential pitfall will minimize the effect of this drug–laboratory test interaction.
The most common method of measuring serum calcium levels in clinical laboratories is the colorimetric assay. With this assay, the color-producing reagent binds to calcium and changes color in relation to the calcium concentration. This calcium measurement method is relatively inexpensive and is the most frequently used. Alternative assays include the ion-specific electrode method (ie, for measurement of ionized calcium) and atomic emission spectroscopy. The false lowering of calcium levels occurs only with the colorimetric assay and only with use of gadodiamide (Omniscan; Nycomed Amersham, Princeton, NJ) or gadoversetamide (OptiMARK; Mallinckrodt, St Louis, Mo). The false measurements do not occur with use of gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ) or gadoteridol (Prohance; Bracco Diagnostics, Princeton, NJ). Gadodiamide and gadoversetamide compete with calcium for the colorimetric reagent, but they do not affect other assays. Thus, if a calcium measurement obtained after MR imaging is thought to be in error, then the patient’s serum can be retested with another method, typically the ionized calcium assay.
It cannot be overemphasized that these contrast agents do not cause actual hypocalcemia, but rather they cause spurious hypocalcemia. In fact, all of the gadolinium chelates have excellent safety profiles, and, to our knowledge, no cases of actual hypocalcemia have been reported in association with any of the gadolinium-based contrast agents.
There is a direct relationship between the serum concentration of the contrast agent and the false lowering of serum calcium measurements. Predictably, the patients in the Prince et al study (1) who received double or triple doses of gadolinium chelate (0.2–0.3 mmol/kg), who had compromised renal function, and in whom blood was drawn close to the time of the MR imaging examination had more pronounced hypocalcemia readings in the colorimetric assay.
Prince et al (1) do not mention that the use of double or triple doses of gadodiamide for MR angiography is an "off-label" use of the agent. Off-label use—that is, the use of a drug in a manner not specified on the package insert—is legal, but it means that the local regulatory agency, such as the U.S. Food and Drug Administration, has evaluated the safety and effectiveness of the agent only when it is used in the conditions outlined in the product labeling.
Gadodiamide is approved in the United States for administration of a dose of 0.1 mmol per kilogram of body weight for central nervous system imaging in adult and pediatric patients and for administration of an additional 0.2 mmol/kg for central nervous system applications performed within the first 20 minutes after the first dose. For most body regions, the label "recommends 0.1 mmol/kg" (package insert, Nycomed Amersham) and the use of only 0.05 mmol/kg for the kidney. None of the MR imaging contrast agents that are currently available in the United States is actually approved for use in MR angiography. Additionally, the label for gadodiamide includes the caveat that "caution should be exercised in patients with renal insufficiency" (package insert, Nycomed Amersham); however, specific guidelines for dose modifications are not provided.
On the other hand, the gadodiamide package insert in Germany recommends limiting the dose to 0.1 mmol/kg in patients with impaired renal function (package insert, Nycomed Amersham, Oslo, Norway). The common practice of performing MR angiography with higher doses of contrast agent underscores the continuing disconnection between labeling policies and clinical reality (2).
Caution is warranted when interpreting the results described by Prince et al (1). First, it should be noted that the spurious results reported in the article were not actually confirmed with other methods; it is possible that some of the patients had actual hypocalcemia. Even with the assumption that most of the cases were spurious, which we consider to be reasonable, it is likely that patients who require repeated calcium measurements are not representative of the general population. Additionally, because of the high percentage of MR angiographic examinations performed with double and triple doses of gadodiamide, as well as the underlying diseases that lead to the MR angiographic examinations (eg, diabetes, hypertension, and atherosclerosis), it is likely that this population includes a particularly high proportion of patients who are susceptible to pseudohypocalcemia. Thus, the report that approximately 4% (42 of 1,049) of the gadodiamide-enhanced MR imaging examinations yielded a significant decrease in measured serum calcium level probably represents an overestimation of the general population that is examined with contrast material–enhanced MR imaging.
Although we agree with most of the findings reported in the Prince et al article, there is one statement that we believe may not be warranted: "We prefer to avoid administering gadodiamide in patients who undergo MR angiography" (1) is too sweeping a statement to be made on the basis of the described data. Many patients who undergo MR angiography require only a single dose of contrast agent, have normal renal function, and may not require immediate blood work after MR angiography. Moreover, if the false hypocalcemia phenomenon is well understood by those treating the patients, then there should be little danger.
False hypocalcemia is not a new phenomenon. Although spurious hypocalcemia, or pseudohypocalcemia, as a consequence of gadodiamide or gadoversetamide administration has been described in the literature for many years, it is not as well known in clinical practice. Normann et al (3) in 1995 and Lin et al (4) in 1999 described this interference effect. The European package insert for gadodiamide has included a warning about spurious hypocalcemia with colorimetric assays for many years. The U.S. gadoversetamide package insert includes a warning about interference with calcium determinations. Nycomed Amersham, the manufacturer of gadodiamide, has recently added the following warning to their U.S. package insert:
OMNISCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12–24 hours. In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN. After patients receive OMNISCAN, careful attention should be used in selecting the type of method used to measure calcium.
If your facility uses gadodiamide or gadoversetamide, what should you do? For the majority of outpatients who undergo MR imaging examinations, false hypocalcemia will never be a clinical issue. However, for those patients who require serum calcium determinations shortly after MR imaging, the following recommendations may be helpful:
1. Radiologists should be aware of and read the package inserts that accompany the gadolinium-based contrast agents used in their practices and be familiar with the potential specific drug–laboratory test interactions.
2. The method of calcium determination used in your clinical laboratory should be ascertained.
3. Hospital physicians, laboratories, and allied health professionals should be notified that (a) gadodiamide or gadoversematide may cause pseudohypocalcemia with the colorimetric assay and (b) patients who receive double or triple doses of either of these contrast agents and who have renal dysfunction are at the highest risk of having the more elevated and long-lasting false calcium values.
4. If possible, serum calcium levels should be measured either before or more than 24 hours after MR imaging, depending on the patient’s renal function.
5. If serum calcium determinations cannot be delayed, the ionized calcium assay should be used.
6. Patients who are to have blood work subsequently to undergoing MR imaging should be informed of the potential interference in standard calcium (ie, colorimetric assay) measurement.
Since their introduction more than 15 years ago, gadolinium chelates have been associated with high standards of safety and patient acceptance. The finding of pseudohypocalcemia following the administration of either of two gadolinium chelates does not alter this important conclusion. By following a few common-sense guidelines, one can avoid most of the problems associated with spurious hypocalcemia after gadodiamide or gadoversetamide administration.
FOOTNOTES
See also the article by Prince et al in this issue.
REFERENCES
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  J. J. Brown, M. R. Hynes, and J. H. Wible Jr. Measurement of Serum Calcium Concentration After Administration of Four Gadolinium-Based Contrast Agents to Human Volunteers Am. J. Roentgenol., December 1, 2007; 189(6): 1539 - 1544. [Abstract] [Full Text] [PDF]
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 J. H. Wible Jr and M. R. Hynes Measurement of Serum Calcium Concentration after Administration of Gadoversetamide in Dogs Radiology, October 1, 2004; 233(1): 158 - 164. [Abstract] [Full Text] [PDF]
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 M. R. Prince, P. L. Choyke, M. V. Knopp, C. J. Doorenbos, K. Koster, and M. van Wijnen More on Pseudohypocalcemia and Gadolinium-Enhanced MRI N. Engl. J. Med., January 1, 2004; 350(1): 87 - 88. [Full Text] [PDF]
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