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Pseudohypocalcemia With MR Imaging Contrast Agents

Pseudohypocalcemia With MR Imaging Contrast Agents

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02/21/2012

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 http://radiology.rsna.org/content/227/3/627.full
Pseudohypocalcemia with MR Imaging Contrast Agents: A Cautionary Tale
 
+ Author Affiliations
1.
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).
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 fourapproved gadolinium-based magnetic resonance (MR) imaging contrast agents, on thecolorimetric 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 willminimize the effect of this drug
laboratory test interaction.The most common method of measuring serum calcium levels in clinical laboratories is thecolorimetric assay. With this assay, the color-producing reagent binds to calcium andchanges color in relation to the calcium concentration. This calcium measurement method isrelatively inexpensive and is the most frequently used. Alternative assays include the ion-specific electrode method (ie, for measurement of ionized calcium) and atomic emissionspectroscopy. The false lowering of calcium levels occurs only with the colorimetric assayand only with use of gadodiamide (Omniscan; Nycomed Amersham, Princeton, NJ) orgadoversetamide (OptiMARK; Mallinckrodt, St Louis, Mo). The false measurements do notoccur with use of gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ) or gadoteridol(Prohance; Bracco Diagnostics, Princeton, NJ). Gadodiamide and gadoversetamide competewith 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 haveexcellent safety profiles, and, to our knowledge, no cases of actual hypocalcemia have beenreported in association with any of the gadolinium-based contrast agents.There is a direct relationship between the serum concentration of the contrast agent and thefalse 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), whohad compromised renal function, and in whom blood was drawn close to the time of the MRimaging 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 amanner not specified on the package insert
is legal, but it means that the local regulatoryagency, such as the U.S. Food and Drug Administration, has evaluated the safety andeffectiveness of the agent only when it is used in the conditions outlined in the productlabeling.Gadodiamide is approved in the United States for administration of a dose of 0.1 mmol perkilogram of body weight for central nervous system imaging in adult and pediatric patientsand for administration of an additional 0.2 mmol/kg for central nervous system applicationsperformed 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 availablein 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 renalinsufficiency” (package insert, Nycomed Amersham); however, specific guidelines for
dosemodifications are not provided.On the other hand, the gadodiamide package insert in Germany recommends limiting thedose to 0.1 mmol/kg in patients with impaired renal function (package insert, NycomedAmersham, Oslo, Norway). The common practice of performing MR angiography with higherdoses of contrast agent underscores the continuing disconnection between labeling policiesand 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 confirmedwith other methods; it is possible that some of the patients had actual hypocalcemia. Evenwith the assumption that most of the cases were spurious, which we consider to bereasonable, it is likely that patients who require repeated calcium measurements are notrepresentative of the general population. Additionally, because of the high percentage of MRangiographic examinations performed with double and triple doses of gadodiamide, as wellas the underlying diseases that lead to the MR angiographic examinations (eg, diabetes,hypertension, and atherosclerosis), it is likely that this population includes a particularly highproportion of patients who are susceptible to pseudohypocalcemia. Thus, the report thatapproximately 4% (42 of 1,049) of the gadodiamide-enhanced MR imaging examinationsyielded a significant decrease in measured serum calcium level probably represents anoverestimation of the general population that is examined with contrast material
enhancedMR 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 administeringgadodiamide in patients who undergo MR angiography”(
1)is too sweeping a statement to bemade on the basis of the described data. Many patients who undergo MR angiographyrequire 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 hypocalcemiaphenomenon is well understood by those treating the patients, then there should be littledanger.False hypocalcemia is not a new phenomenon. Although spurious hypocalcemia, orpseudohypocalcemia, as a consequence of gadodiamide or gadoversetamide administrationhas been described in the literature for many years, it is not as well known in clinicalpractice. 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 spurioushypocalcemia with colorimetric assays for many years. The U.S. gadoversetamide packageinsert includes a warning about interference with calcium determinations. NycomedAmersham, the manufacturer of gadodiamide, has recently added the following warning totheir U.S. package insert:OMNISCAN interferes with serum calcium measurements with some colorimetric(complexometric) methods commonly used in hospitals, resulting in serum calciumconcentrations lower than the true values. In patients with normal renal function, this effectlasts for 12
24 hours. In patients with decreased renal function, the interference withcalcium 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 majorityof outpatients who undergo MR imaging examinations, false hypocalcemia will never be aclinical issue. However, for those patients who require serum calcium determinations shortlyafter MR imaging, the following recommendations may be helpful:1. Radiologists should be aware of and read the package inserts that accompany thegadolinium-based contrast agents used in their practices and be familiar with the potentialspecific drug
laboratory test interactions.2. The method of calcium determination used in your clinical laboratory should beascertained.3. Hospital physicians, laboratories, and allied health professionals should be notified that
(a) 
 gadodiamide or gadoversematide may cause pseudohypocalcemia with the colorimetric assayand
(b) 
patients who receive double or triple doses of either of these contrast agents andwho 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 beused.6. Patients who are to have blood work subsequently to undergoing MR imaging should beinformed of the potential interference in standard calcium (ie, colorimetric assay)measurement.

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