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Original Research |
1 Department of Pathology and Immunology, Washington University School of
Medicine, 660 S Euclid Ave., Box 8118, St. Louis, MO 63110.
2 Mallinckrodt Institute of Radiology, Washington University School of Medicine,
St. Louis, MO.
3 Bayer HealthCare Pharmaceuticals, Wayne, NJ.
Received July 23, 2007;
accepted after revision September 7, 2007.
Address correspondence to M. G. Scott
(mscott{at}pathology.wustl.edu).
Abstract
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MATERIALS AND METHODS. Records of patients who received
gadoversetamide from June 24, 2006, to October 7, 2006, were reviewed to
determine if a routine calcium test had been performed after the injection.
Calcium values were repeated with an alternate method that is less susceptible
to gadoversetamide interference. If the difference was 
2.0 mg/dL or if
the initial test value was 
7.0 mg/dL, patient charts were reviewed for any
related treatment. Costs associated with this algorithm were tracked.
RESULTS. The initial calcium test was performed after
gadoversetamide in 766 of 3,439 instances. The alternate test was performed in
633 of 766. One hundred twenty-five of 633 (20%) showed a difference in
calcium values that was 0.7 mg/dL, with 16 showing differences of
1.6 mg/dL. Chart review for 56 instances revealed that calcium supplements
were administered in 22 of 56 around the time of gadoversetamide injection.
However, none appeared to be related to the spurious hypocalcemia. The total
additional cost (reagent and technologist) for following this algorithm for
just over 3 months was $6,807.
CONCLUSION. Approximately 20% of patients receiving gadoversetamide exhibited spurious hypocalcemia. No patients were identified who received inappropriate calcium because of this interference. This may be attributable to the quality assurance and physician education programs.
Keywords: calcium • gadolinium • interference
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Gadolinium chelates, unlike other contrast media, have a low incidence of nephrotoxicity [3–5] and an extremely low incidence of allergic reactions [6, 7]. Currently, there are five gadolinium-based contrast agents available commercially in the United States: gadodiamide (Omniscan, GE Healthcare), gadopentetate dimeglumine (Magnevist, Bayer HealthCare), gadoversetamide (OptiMARK, Mallinckrodt Imaging), gadoteridol (Pro-Hance, Bracco), and gadobenate dimeglumine (MultiHance, Bracco).
It has been suggested that two of these, gadodiamide and gadoversetamide, are less stable compared with the others, which, in vitro, leads to dechelation that interferes with common laboratory methods measuring total plasma or serum calcium [8]. This has been documented for gadodiamide and gadoversetamide in colorimetric calcium methods on the basis of the calcium-binding dyes o-cresolphthalein phosphate [8–12] and arsenazo III [9]. The extent of this negative interference is dependent on elapsed time after receiving the contrast agent and on renal function because the two agents are cleared by the kidney [13].
Normann et al. [9] and Wibble and Hynes [12] showed that gadolinium chelates do not affect calcium values that use ion-selective electrodes or atomic emission spectroscopy. We previously reported that the one o-cresolphthalein phosphate–based colorimetric method (Calcium/Flex Reagent, Dade Behring [now Siemens Healthcare Diagnostics]) for determining calcium value was far less affected by gadoversetamide interference compared with another o-cresolphthalein phosphate–based colorimetric method (Calcium, Roche Diagnostics)[13].
Incorrect diagnosis from spurious hypocalcemia has resulted in inappropriate treatment with either oral or IV calcium [10] and in unnecessary recalling of a patient to the hospital [14]. In response to these issues, a quality assurance program was instituted in November 2004 to identify and correct any falsely decreased calcium values due to gadoversetamide interference. In addition, a physician education program about this interference was done at the same time.
The economic consequences associated with the management of incorrect calcium values reported as a result of gadoversetamide interference have not been studied but could be of value in an increasingly cost-conscious health care environment that demands high quality and low cost. The objectives of this observational study were three-fold: first, to prospectively evaluate the incidence of serum calcium interference after gadoversetamide-enhanced MRI; second, to retrospectively determine the associated clinical outcomes in patients who may undergo additional tests or treatment because of erroneous calcium reporting; and third, to retrospectively assess the costs associated with managing and correcting erroneous calcium reporting because of this interference.
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Calcium Values and Protocol
Total calcium concentrations were determined by two different
o-cresolphthalein phosphate methods: one from Roche Diagnostics performed on
the Modular analyzer (Hitachi), which is the primary method at our
institution, and another performed on the Dimension analyzer (Dade Behring),
which is the backup method [13].
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1.5 mg/dL) after administration of gadoversetamide. The
different time periods were used because decreased glomerular filtration
prolongs the interfering effects of gadoversetamide
[12]. Samples were retrieved
from refrigerated storage and calcium values were repeated using the Dade
method for these patients.
If the difference between the Dade and Roche methods was < 0.7 mg/dL,
the original Roche calcium value was not updated in the patients' medical
record. If the difference between the Dade and Roche methods was 0.7
mg/dL, a patient's medical record was updated using the Dade calcium value.
The use of 0.7 mg/dL as a decision point in the algorithm is based on the
precision of the total calcium methods in the clinical laboratory, such that
if the difference in calcium values exceeds 0.7 mg/dL it is unlikely to be due
to assay imprecision with 95% confidence. Patient medical records were
reviewed for subsequent testing and treatment related to calcium interference
when the Dade calcium value minus the Roche calcium value exceeded 2.0 mg/dL
or if the initial Roche calcium value was < 7.0 mg/dL.
Patient Characteristics and Outcome Measures
Information on age; sex; and medical conditions including renal
insufficiency, cancer, seizure disorders, cardiac arrhythmia, and cardiac
contractility problems was collected for all patients. Outcomes measured
included the incidence of gadoversetamide-induced calcium interference and the
incidence of calcium values below 7 mg/dL after contrast administration. Other
outcomes measured were subsequent retesting (other than the protocol-driven
Dade method for calcium testing); treatment related to apparent hypocalcemia,
such as oral or IV calcium treatment; adverse outcomes, if any, as a result of
treatment; emergency and outpatient visits, if any; patient recall; and death,
if any.
Economic outcome measures included costs associated with the management of the calcium interference. This included the cost of staff time as provided by laboratory and radiology departmental administrators; test reagents; any treatment of hypocalcemia; and the subsequent clinical consequences including calcium supplementation (oral or IV), other medications, and other additional testing such as ECG.
Estimated Glomerular Filtration Rate
Glomerular filtration rate (GFR) in mL x minute–1
x (1.73 m)–2 was estimated by the simplified
Modification of Diet in Renal Disease (MDRD) equation
[15]:
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Model to Predict Falsely Decreased Calcium Values
Predicted differences between calcium values measured by the Roche and Dade
methods were computed as a function of estimated GFR and time since
administration of contrast medium using a previously described model in which
[13]
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Data from this study were used to calculate the specificities and
sensitivities of the model predictions to distinguish between calcium
differences of > 0.7 mg/dL and 0.7 mg/dL.
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1.5 mg/dL) after
administration of gadoversetamide in 766 instances in 730 individuals
(Table 1). However, repeat
calcium values using the Dade method were available in 633 instances, mainly
because of insufficient remaining blood sample in 97 instances as a result of
multiple tests being ordered and multiple aliquots being prepared by an
automated sample processor.
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Incidence of Spurious Hypocalcemia After Injection of Gadoversetamide
There were 125 instances (20% of 633) where there was a discrepancy between
Dade and Roche calcium values of at least 0.7 mg/dL after administration of
gadoversetamide (Fig. 3). The
majority of these discrepancies (n = 65) were between 0.7 and 0.9
mg/dL, but in 18, the discrepancy was 1.5 mg/dL including six instances
in which the difference was 2 mg/dL
(Table 2).
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Differences in Roche Calcium Values Before and After Gadoversetamide Injections
Calcium values within 48 hours before receiving the contrast agent were
available for 546 of the 633 instances. Of these, lower Roche calcium values
after gadoversetamide injections were observed in 386 (71%) instances, higher
Roche calcium values after gadoversetamide injections in 130 instances (24%),
and no change before and after gadoversetamide injection in 30 instances (5%)
(Fig. 3). The changes in
calcium values from before to after gadoversetamide injection ranged from
–4.2 to 2.4 mg/dL. Of the 386 instances with lower calcium values after
gadoversetamide injection, the decrease in calcium was < 1.2 mg/dL in 290
instances.
Of the 125 instances where there was a discrepancy of 0.7 mg/dL
between the Dade and Roche calcium values after gadoversetamide injection,
preinjection Roche calcium values were available in 115. Of these, 112 had
Roche calcium values after gadoversetamide injection that were lower than the
preinjection Roche calcium values. The median difference was a value after
gadoversetamide injection that was 1.4 mg/dL lower than the preinjection
value, with a range of 0.2 to 4.2 mg/dL.
Incidences with Evidence of Calcium Treatment
A calcium value of < 7 mg/dL was considered indicative of marked
hypocalcemia and a change of > 2 mg/dL might trigger physician
intervention. Patient charts were reviewed in these instances for subsequent
testing and treatment related to the calcium interference. Fifty-six charts
were reviewed; 50 in which calcium was < 7 mg/dL after gadoversetamide
injection and six in which the Dade minus Roche calcium value difference was
2 mg/dL. Five of these six had estimated GFRs of less than 40 mL/min/1.73
m2. Chart review to identify either oral or IV calcium
administration around the time of gadoversetamide injections revealed evidence
of calcium supplementation in 22 of 56. However, in 13 instances the patient
was receiving oral calcium before the gadoversetamide injection. In three
instances, oral calcium was administered 72 hours after the initial Roche
calcium value was obtained, by which time the calcium values would have been
updated using the Dade method.
In four other instances (three from one patient), calcium was administered IV as a part of a therapeutic plasmapheresis procedure in one patient and hemodialysis in another. In two of the 56 instances, oral calcium was administered within 12 hours of the gadoversetamide injection. In one case, the patient had osteomyelitis, and another patient was a 76-year-old woman with diabetes mellitus complicated with below-knee amputation and an infection. The patient was discharged on calcium and multivitamin supplements. No patients had evidence on additional laboratory testing (repeat calcium values, metabolic panels) related to the apparent hypocalcemia. Review of medical records for 7–30 days after administration of gadoversetamide revealed no evidence of any patient being recalled to the hospital as a result of spurious hypocalcemia.
Correlation Between Calcium Values and GFR and Time Since Administration of Gadoversetamide
The equation, calcium difference = 17.909–4.927 ln
(GFR) + 21.316/
Hr, from a previous model was used to
predict whether the difference in calcium values (Dade minus Roche) would be
0.7 or < 0.7 mg/dL in 633 instances
[12]. The model predicted this
difference with a sensitivity of 63.2% and specificity of 87.2%.
Economic Outcomes
Among patients with gadoversetamide-induced falsely decreased calcium
values, there were no incidences of patient recall or prolongation of the
current hospital stay during the study period. There was no evidence of
additional diagnostic testing related to this spurious hypocalcemia in any
patients during the study period. The total laboratory technologist time
logged for performing the protocol during the study period was approximately
85 hours. At a rate of $30 per hour including all benefits, this would
translate into a total technologist cost of $2,550. This amounts to one
full-time employee (FTE) for 10.625 working days (8 h/d) over the 14-week
study period (0.75 d/wk), costing an additional $26 per day. The cost of the
reagents for repeat testing of a single sample on the Dade machines was $0.76,
bringing the total reagent cost to $481 ($0.76 x 633). Thus the total
additional laboratory cost for following this algorithm during the study
period was $3,132. The total radiology technologist time logged was
approximately 105 hours. At the rate of $35 per hour including all benefits,
this would translate into a total technologist cost of $3,625, which
translates into one FTE for 13.125 working days over the study period. We did
not attempt to determine the cost of the physician education program in
2004.
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0.7 mg/dL was observed after
20% of gadoversetamide injections. One potential shortcoming of this study is
that the Dade colorimetric method, used here as the "control
method," is itself subject to a small degree of negative interference
from some gadolinium-containing contrast agents
[12]. Therefore, using the
Dade method as a control for the Roche method likely under-estimates the true
incidence and magnitude of spurious hypocalcemia caused by the interference of
gadoversetamide with the Roche method. These findings are consistent with
studies on such interference with another linear nonionic
gadolinium-containing MR contrast agent, gadodiamide
[9–13]. In a retrospective study analyzing the effect of gadolinium-chelates on calcium value, Prince et al. [10] found a decrease in measured serum calcium by more than 1 mg/dL in approximately 15% of the instances (157 of 1,049). None of these patients were noted to have exhibited symptoms of hypocalcemia; nevertheless, several received inappropriate treatment as a result of the spurious hypocalcemia: 11 patients were given oral calcium and seven were given IV calcium. None of these patients had adverse outcomes that were attributed to the calcium treatments, although the calcium administration complicated treatment in three of the patients, two with seizure disorders and one in a coma due to encephalitis [10]. An update on the data from 1993 to 2004 also found a similar rate of gadolinium interference with serum calcium value [15]. In other studies, findings of spurious hypocalcemia have resulted in patient recall [11] and urgent consultations [13].
On the basis of previous reports and local experience with gadoversetamide-induced spurious hypocalcemia, a QA procedure was instituted in November 2004 to minimize misdiagnosis of hypocalcemia and unnecessary treatment (Fig. 2). Following this algorithm, the QA technologist determines whether the total calcium value should be repeated using the alternative Dade method. The rollout of this procedure was accompanied by a laboratory medicine newsletter sent to more than 4,000 physicians alerting them to the possibility of spurious hypocalcemia after gadoversetamide injection. In addition, a short note about this phenomenon was included in the physician staff weekly newsletter.
In this study, medical record review of patients most likely to receive calcium treatment as a result of this laboratory interference revealed that calcium supplements were administered in 39% (22 of 56) of the instances. However, in the majority of such cases (16 of 22) calcium supplements were administered well before or at least 72 hours after gadoversetamide injections and there was no evidence of extra calcium supplementation after a reported falsely decreased Roche calcium value. Thus it was likely that these individuals received calcium supplements for a reason other than gadoversetamide-induced spurious hypocalcemia. In another four instances (three from a single patient undergoing therapeutic plasmapheresis and one from a patient undergoing hemodialysis), IV calcium administration was consistent with appropriate and justified use. In the two remaining cases in whom oral calcium was started within 12 hours of the reported decreased calcium value, one can speculate that this may have been related to the finding of spurious hypocalcemia. However, considering that both patients were elderly women (one with osteomyelitis and the other with diabetes mellitus and below-knee amputation who was discharged on calcium and multivitamins), it is also likely that oral calcium administration was started not as a result of the apparent hypocalcemia but as a justified supplementation for the patients' underlying disease.
Although in this study the observed incidence of gadoversetamide-induced spurious hypocalcemia is similar to other studies [10, 15, 16], it is likely that the nearly 2-year-old QA procedure and physician education program contributed to no apparent incidences of patients receiving inappropriate treatment for spurious hypocalcemia during the course of this study.
A mathematic model to predict whether the difference in calcium value after
gadoversetamide injection will be < 0.5 or 0.5 mg/dL was previously
developed [12]. Using this
model in the current study, the sensitivity of prediction for differences of
< 0.5 or 0.5 mg/dL compared with the actual observed values was 77.3%
and the specificity was 78.9%. However, when two calcium values from the same
sample differ by 0.7 mg/dL, they exceed the 95% CI range of the assay
such that the change in values is unlikely to be due to assay imprecision.
When we used the same model, the sensitivity of prediction for differences
0.7 or < 0.7 mg/dL was 63.2% whereas the specificity was 87.2%.
Reanalysis of the previous data to predict 0.7 or < 0.7 mg/dL resulted
in a sensitivity of 80.7% and a specificity of 92.9%. A QA protocol similar to
the one implemented in the current study would be expected to result in an
additional $0.76 of reagent cost per calcium test and an additional 50 min/d
of one laboratory FTE's time plus an additional 60 min/d of one radiology
FTE's time. Contrast this to the potentially fatal side effects of
inappropriate calcium treatment, and an additional QA protocol can be
justified for patient safety. Additional capital costs would be necessary in
institutions that do not have the instruments needed for less-affected total
calcium methods. We did not attempt to ascertain the costs of physician
education.
In smaller institutions where the additional QA may not be feasible or
where alternative calcium methods are not available, a mathematic model such
as the previously reported equation
[12] may be included in the
routine protocol to help prevent inappropriate calcium treatment after
contrast-induced spurious hypocalcemia. In the current study, only instances
in which the calcium values were obtained within 24–48 hours of the
gadoversetamide injection—when such discrepancies are likely to
occur—were included. However, there were no such restrictions in the
previous study [12], which may
explain the lower sensitivity and specificity for predicting the differences
of > 0.7 or 0.7 mg/dL in the current data. Other potentially more
effective measures include using more stable contrast agents that were shown
not to interfere with colorimetric calcium methods. However, institutions are
often part of large purchasing organizations or have long-term contracts,
making a change of agents difficult. Finally, it may not be possible to
readily change calcium testing methods for the above reasons and because
changing one test could necessitate changing an entire automated laboratory
platform that performs more than 40 other tests. Lastly, educating health care
professionals regarding possible calcium value interference with the two
contrast agents (gadodiamide and gadoversetamide) is a key element in
preventing inappropriate calcium supplementation.
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