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Original Research |
1 Mallinckrodt Institute of Radiology, Washington University, St. Louis,
MO.
2 Covidien/Mallinckrodt Imaging, PO Box 5840, 675 McDonnell Blvd., Saint Louis,
MO 63134.
Received April 24, 2007;
accepted after revision June 24, 2007.
This study was designed and funded by Covidien/Mallinckrodt. J. J. Brown is
an investigator at the clinical site and a paid consultant of
Covidien/Mallinckrodt. J. H. Wible and M. R. Hynes are employees of
Covidien/Mallinckrodt.
Abstract
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SUBJECTS AND METHODS. After providing informed consent, 12 healthy adult volunteers (mean age, 38.6 ± 13.6 [SD] years) received IV injections of gadoversetamide, gadodiamide, gadopentetate dimeglumine, and gadoteridol at a dose of 0.1 mmol/kg. Blood samples were obtained before contrast administration and 5, 10, 15, 30, 60, 90, 120, 180, and 240 minutes after contrast injection. Serum calcium levels were measured with an orthocresolphthalein complexone method, an arsenazo III method, and inductively coupled plasma mass spectrometry (ICP-MS). Analyses of variance coupled with a Dunnett test were used to compare baseline serum calcium measurements with values at the different time points after injection.
RESULTS. Administration of gadoversetamide or gadodiamide caused no significant change in serum calcium concentration measured with the arsenazo III and ICP-MS analytic methods. However, the orthocresolphthalein assay showed a transient decrease in serum calcium concentration after injection of gadoversetamide or gadodiamide. Injection of gadopentetate or gadoteridol produced no significant change in serum calcium values measured with the orthocresolphthalein, arsenazo III, and ICP-MS methods.
CONCLUSION. Administration of gadoversetamide or gadodiamide caused no significant effect on serum calcium concentration. Neither gadoversetamide nor gadodiamide interfered with measurement of serum calcium with the arsenazo III or ICP-MS method. However, the orthocresolphthalein method of measuring serum calcium produced a transient hypocalcemia artifact in the presence of gadoversetamide or gadodiamide.
Keywords: calcium assay • contrast agents • gadolinium • gadoversetamide • MRI
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Results of previous studies [6, 7] indicated that some gadolinium chelates can interfere with colorimetric assays of serum calcium. Severe hypocalcemia can be life-threatening if not promptly and properly managed, making early detection critical [8]. However, managing an erroneously low calcium level with IV or oral calcium comes with the risk of hypercalcemia, which can result in muscle weakness, coma, hypertension, and cardiac arrhythmia [9]. The literature provides reports on in vitro [6, 10–14] and retrospective in vivo [14, 15] studies and case reports [16–18], but there is a dearth of information on prospective in vivo studies of different methods and the time course of the gadolinium interference.
A study with dogs [19] showed that gadoversetamide and gadodiamide produced a transient decrease in serum calcium concentration measured with an orthocresolphthalein assay system. However, when the arsenazo III and inductively coupled plasma mass spectrometry (ICP-MS) methods of measuring serum calcium were used, these gadolinium chelates were not found to interfere. In this study, we explored the effects on human volunteers and defined the duration and magnitude of the analytic artifact in subjects with normal renal function.
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Subjects
Adult healthy volunteers (n = 28) were enrolled for MRI of the
abdomen to evaluate the time course of contrast enhancement with four
extracellular gadolinium contrast agents. Physical examination and a history
interview were performed to determine the health status of each subject. The
first 12 subjects (five men, seven women; age, 32–64 years) who
completed all four dosing cycles also participated in the pharmacokinetic
portion of the study. Subjects were excluded from the study if they withdrew
informed consent or met any of the following conditions: had received any
investigational drug within 30 days of participation; were pregnant or
lactating; had a condition that was a contraindication to MRI (e.g., presence
of cardiac pacemaker, epicardial pacing leads, cochlear implant, or
ferromagnetic aneurysm clip) or other condition that precluded safe proximity
to a strong external magnetic field; had undergone any contrast-enhanced
imaging examination within 7 days before participation; had a history of
hemolytic anemia, sickle cell anemia, or other hemoglobinopathy; had a history
of hypersensitivity or adverse reaction to any radiologic contrast agent; or
had a history of marked claustrophobia.
Contrast Agents
All of the gadolinium chelates were supplied as commercial materials at a
concentration of 0.5 mmol/mL. Gadoversetamide (Optimark, Mallinckrodt Imaging)
is a nonionic gadolinium chelate of diethylenetriamine pentaacetic acid
bismethoxyethylamide. Gadodiamide (Omniscan, GE Healthcare) is a nonionic
formulation of a gadolinium complex of diethylenetriamine pentaacetic acid
bismethylamide. Gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma
AG) is an ionic N-methylglucamine salt of the gadolinium complex of
diethylenetriamine pentaacetic acid gadopentetate. Gadoteridol (Pro-Hance,
Bracco) is a nonionic formulation of the gadolinium complex
10-(2-hydroxypropyl)-1,4,7,10 tetraazacyclododecane-1,4,7-triacetic acid. All
gadolinium-based contrast agents approved for human use in the United States
at the time of the study were included in this investigation. A fifth agent,
gadobenate dimeglumine, was approved after initiation of the study.
Procedures
Each subject received 0.1-mmol/kg (0.2 mL/kg) IV injections of
gadoversetamide, gadodiamide, gadopentetate dimeglumine, and gadoteridol at
separate imaging sessions. Contrast agents were administered IV in an
appropriate arm vein by power injection at a rate of 2 mL/s. The order of
administration of the contrast agents was assigned with a Latin square design.
A period of at least 6 days and a maximum of 5 weeks elapsed between
administrations of the contrast agents.
Blood specimens (2 mL) were collected from each subject before (within 2 hours) and after injection of each gadolinium chelate. The collection times were 5, 10, 15, 30, 60, 90, 120, 180, and 240 minutes after injection. Blood samples were collected from the arm opposite the site of contrast injection. The catheter system used to obtain the blood samples was flushed with normal saline solution before collection and after each sampling to ensure a fresh specimen. Each specimen was centrifuged for 20 minutes to separate the serum, which was transferred to a storage tube and frozen at approximately –20°C until analyzed.
Analytic Measurements
Analysis of serum calcium and serum gadolinium concentrations was performed
at MedTox Laboratories. The serum calcium level of each sample was measured
with the orthocresolphthalein, arsenazo III, and ICP-MS methods. The
gadolinium concentration of each sample was measured with ICP-MS.
A chemistry analyzer (Aeroset, Abbott Laboratories) was used for assessment of serum calcium concentrations with the orthocresolphthalein and arsenazo III methods. The orthocresolphthalein method was performed with reagents manufactured by Roche Diagnostics. With this analytic kit, a reaction takes place between orthocresolphthalein dye and calcium in the presence of 8-hydroxyquinoline under acidic conditions to produce a purple solution measured at a wavelength of 604 nm. The orthocresolphthalein method produced a maximum intraassay coefficient of variation of 1.8% with a maximum interassay coefficient of variation of 1.8%. The lower limit of detection was 1.3 mg/dL (0.3 mmol/L) with a linear range up to 19.4 mg/dL (4.9 mmol/L). The arsenazo III method was performed with kit reagents from Abbott Laboratories. A reaction takes place between the arsenazo III dye and calcium under acidic conditions to produce a blue–purple complex. The colored solution was measured spectro-photometrically and had a wavelength of 660 nm. Under these conditions, the assay system had intraassay and interassay coefficients of variation of 1.9%. The lower limit of detection was 2.0 mg/dL (0.5 mmol/L) with a linear range up to 13.0 mg/dL (3.2 mmol/L).
Both serum calcium and serum gadolinium concentrations were measured with a validated ICP-MS system (Elan 6000 ICP-MS, Perkins-Elmer). For serum calcium measurements, this method had an intraassay coefficient of variation of 4.7% and an interassay coefficient of variation of 6.0%. The lower limit of detection was 0.5 mg/dL with a linear range of 60.0 mg/dL. For serum gadolinium concentration, the ICP-MS technique had an intraassay coefficient of variation of 5.2% and an interassay coefficient of variation of 8.9%. The lower limit of detection was 0.2 µg/mL with a linear range up to 40.0 µg/mL.
Pharmacokinetic Analysis
The pharmacokinetic characteristics of the gadolinium chelates were based
on serum gadolinium measurements. The pharmacokinetic parameters of
elimination half-life (t
), area under the plasma
concentration curve to time of the last collected blood sample
(AUC0–t), steady-state volume of distribution
(VDSS), and total clearance (CLT) were calculated with
standard pharmacokinetic noncompartmental methods (WinNonlin, v1.1, Pharsight)
based on the following equations: t = ln(2)/kel
where kel is the slope from the regressed log-transformed
concentration with respect to time;
 |
 |
= 
Ci/kel2
and AUC = Ci/kel (AUMC = area
under the first moment curve);
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Statistical Analysis
Serum calcium and serum gadolinium concentrations were summarized with the
mean ± SD for each gadolinium chelate and time point. Analyses of
variance coupled with the Dunnett test were used to compare serum calcium
concentrations at the different collection time points after contrast
injection with the baseline values. Pharmacokinetic parameters of the
gadolinium chelates were compared by use of a two-way mixed model analysis of
variance and analysis of covariance. Pharmacokinetic and statistical analyses
were conducted with SAS for Windows version 9 (SAS Institute). The criterion
for statistical significance was set at p < 0.05.
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IV administration of gadodiamide produced no significant change in serum calcium values measured with the arsenazo III and ICP-MS techniques (Fig. 2). Serum calcium values measured with the orthocresolphthalein method decreased significantly (p < 0.05) 5, 10, 15, 30, 60, and 90 minutes after injection of gadodiamide. The calcium concentration reached the lowest value approximately 15 minutes after injection and returned to baseline within 120 minutes of gadodiamide administration. After injection of gadodiamide, the arsenazo III method of measuring serum calcium showed a significant (p < 0.05) increase 5 minutes after injection.
IV administration of gadopentetate dimeglumine and gadoteridol caused no significant change in serum calcium values measured with the orthocresolphthalein, arsenazo III, and ICP-MS analytic techniques (Figs. 3A and 3B).
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, AUC0-t, VDSS, and CLT
showed no significant differences between the four gadolinium chelates
(Table 1). Results of
pharmacokinetic analysis indicated that the elimination t
for the gadolinium chelates ranged from 93 minutes for gadoversetamide to 119
minutes for gadoteridol. The pharmacokinetic results also showed that the
gadolinium chelates were distributed throughout the extracellular space with a
VDSS between 214 and 243 mL/kg. In addition, the gadolinium
chelates cleared the plasma at similar rates with a range of 1.5–1.7
mL/min/kg.
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Our data confirm that IV gadoversetamide administration has no significant effect on true serum calcium level. Measured with either the arsenazo III or the ICP-MS method, serum calcium values remained constant after IV injection of each of the four gadolinium chelates tested in this study; however, the orthocresolphthalein technique showed transient artificially low calcium values after injection of gadoversetamide and gadodiamide. Injection of gadopentetate dimeglumine and gadoteridol did not interfere with the orthocresolphthalein method of measuring serum calcium. These observations in healthy volunteers are similar to those previously described in dogs [19].
Modified linear chelates of diethylenetriaminepentaacetic acid, such as gadoversetamide and gadodiamide, have similar high affinity constants for gadolinium [22, 23]. Under the conditions of the orthocresolphthalein assay, however, the orthocresolphthalein dye has a higher affinity for gadolinium than does gadoversetamide or gadodiamide [6, 10]. Once it binds to gadolinium, the orthocresolphthalein dye can no longer interact with calcium to produce the appropriate color change indicating the amount of calcium present.
It is important to recognize this interference so that patients are not needlessly treated for what appears to be hypocalcemia [14, 15]. Severe hypocalcemia can be life-threatening if not promptly and properly controlled, making early detection critical [8]. However, managing spurious hypocalcemia with IV or oral calcium comes with the risk of hypercalcemia [9]. Thus it is important for practitioners to recognize the timing of spurious hypocalcemia associated with the administration of gadolinium chelates. The timing of the orthocresolphthalein-caused artifact is directly related to the elimination of the gadolinium chelate from the body. When the orthocresolphthalein technique was used, serum calcium values returned to baseline within 90 minutes of gadoversetamide injection and within 120 minutes of gadodiamide injection. The pharmacokinetic analysis showed similar characteristics for the different gadolinium agents with equivalent half-lives, volumes of distribution, and rates of clearance. These gadolinium chelates are small molecules that exhibit little plasma protein binding and are eliminated by glomerular filtration. Under normal conditions, gadolinium chelates are quickly removed from the body. This rapid elimination accounts for the transient nature of the orthocresolphthalein-caused artifact in the calcium determination.
Study Limitations
The absence of subjects with impaired renal function was a limitation of
this study. Gadolinium contrast agents are eliminated from the body by the
kidneys. In patients with poor renal function, gadolinium contrast agents
remain in the body for a longer period than in those with normal renal
function
[24–26].
Thus as renal function decreases, the duration of the orthocresolphthalein
artifact is prolonged [11].
However, administration of gadolinium contrast agents has been associated with
the development of nephrogenic systemic fibrosis in patients with end-stage
renal disease, severe chronic renal disease (estimated glomerular filtration
rate < 30 mL/min/1.73 m2), and acute renal injury due to
hepatorenal syndrome and in those in the perioperative period of liver
transplantation [4,
5]. The U.S. Food and Drug
Administration has required new labeling for all approved gadolinium contrast
agents. The labels suggest avoidance of gadolinium contrast agents in the
renally at-risk patient population unless the diagnostic information is
essential and not available with noncontrast-enhanced MRI (Food and Drug
Administration alert 5–23-07). A second limitation of this study was the
use of only one dose of gadolinium, 0.1 mmol/kg. Data from studies with dogs
[19] show that an increase in
the dose of gadolinium increases both the magnitude and the duration of
orthocresolphthalein artifact for serum calcium concentration.
Practical Applications
Although gadoversetamide and gadodiamide caused a transient, spurious
decrease in serum calcium concentration measured with the orthocresolphthalein
method, the effect diminished as the gadolinium chelate was eliminated from
the body. None of the gadolinium chelates studied caused a false serum calcium
measurement in healthy patients 2 hours after contrast material was
administered regardless of the analytic method used.
The orthocresolphthalein artifact is unlikely to cause clinical problems for most patients undergoing MRI with a gadolinium-based contrast agent [27]. However, it is important for radiologists to know the types of MRI contrast agents and serum calcium assays used at their facilities. According to a survey conducted by the College of American Pathologists [28], 46% of responding laboratories use the arsenazo III method and 54% use the orthocresolphthalein technique. It is relatively simple for laboratories to change techniques by replacing one modular analytic package with another. Changing the analytic method to a technique not influenced by the presence of any gadolinium chelate is a practical and consistent approach to assuring accurate measurement of serum calcium.
If the potential for erroneous serum calcium measurement exists, referring physicians and laboratory personnel should be informed and precautions undertaken to avoid misdiagnosis and inappropriate treatment. In patients who need close monitoring of serum calcium concentration, blood samples should be obtained before administration of gadoversetamide or gadodiamide. In patients with normal renal function, a reliable serum calcium level can be obtained 2 hours after administration of the contrast agent. In patients with decreased renal function, the time frame for a reliable serum calcium level after contrast administration is likely to be prolonged. The same is true of patients who receive a contrast dose greater than the standard 0.1 mmol/kg. If a spurious serum calcium concentration is suspected, most laboratories have the ability to retest the blood sample with an assay that is not susceptible to spurious measurements. If this retesting cannot be done, a second blood sample should be obtained.
In conclusion, the orthocresolphthalein method of measuring serum calcium produces an analytic artifact in the presence of gadoversetamide or gadodiamide. This artifact is transient in nature, peaking 5–15 minutes after contrast administration and returning to baseline within 2 hours of injection in patients with normal renal function. If serum calcium assessments are needed for patient monitoring, blood samples should be collected either before or more than 2 hours after injection of a gadolinium-based contrast agent. Installation of an analytic method, such as arsenazo III or ICP-MS, not influenced by the presence of a gadolinium contrast agent also is a practical approach to ensuring accurate measurement of serum calcium.
Acknowledgments
We thank Karen M. Coulson for efforts in the preparation of this manuscript
and Jennifer C. Lee for statistical analysis of the data.
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