Dose Of Gadodiamide Research Articles

The effect of iron status on gadolinium deposition in the rat brain: mechanistic implications.

Introduction: Sites associated with gadolinium (Gd) deposition in the brain (e.g., the globus pallidus) are known to contain high concentrations of ferric iron. There is considerable debate over the mechanism of Gd deposition in the brain. The role of iron transport mechanisms in Gd deposition has not been determined. Thus, we seek to identify if Gd deposition can be controlled by modifying iron exposure. Methods: Female Sprague-Dawley rats were given diets with controlled iron levels at 2-6ppm, 6ppt (20g/kg Fe carbonyl) or 48ppm for 3weeks to induce iron deficiency, overload or normalcy. They were kept on those diets while receiving a cumulative 10mmol/kg dose of gadodiamide intravenously over 2weeks, then left to washout gadodiamide for 3days or 3weeks before tissues were harvested. Gd concentrations in tissues were analyzed by ICP-MS. Results: There were no significant effect of dietary iron and total Gd concentrations in the organs, but there was a significant effect of iron status on Gd distribution in the brain. For the 3-week washout cohort, there was a non-significant trend of increasing total brain deposition and decreasing dietary iron, and about 4-fold more Gd in the olfactory bulbs of the low iron group compared to the other groups. Significant brain accumulation was observed in the low iron group total brain Gd in the 3-week washout group relative to the 3-day washout group and no accumulation was observed in other tissues. There was a strong negative correlation between femur Gd concentrations and concentrations in other organs when stratifying by dietary iron. Discussion: Gd brain deposition from linear Gd-based contrast agents (GBCAs) are dependent upon iron status, likely through variable transferrin saturation. This iron dependence appears to be associated with redistribution of peripheral deposited Gd (e.g., in the bone) into the brain.

Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T2 Mapping and Intraperitoneal Administration.

Currently, the gadolinium retention in the brain after the use of contrast agents is studied by T1 -weighted magnetic resonance imaging (MRI) (T1 w) and T1 mapping. The former does not provide easily quantifiable data and the latter requires prolonged scanning and is sensitive to motion. T2 mapping may provide an alternative approach. Animal studies of gadolinium retention are complicated by repeated intravenous (IV) dosing, whereas intraperitoneal (IP) injections might be sufficient. T2 mapping will detect the changes in the rat brain due to gadolinium retention, and IP administration is equivalent to IV for long-term studies. Prospective longitudinal. A total of 31 Sprague-Dawley rats administered gadodiamide IV (N=8) or IP (N=8), or saline IV (N=6) or IP (N=9) 4 days per week for 5 weeks. A 7 T, T1 w, and T2 mapping. T2 relaxation and image intensities in the deep cerebellar nuclei were measured pre-treatment and weekly for 5 weeks. Then brains were assessed for neuropathology (N=4) or gadolinium content using inductively coupled plasma mass spectrometry (ICP-MS, N=12). Repeated measures analysis of variance with post hoc Student-Newman-Keuls tests and Hedges' effect size. Gadolinium was detected by both approaches; however, T2 mapping was more sensitive (effect size 2.32 for T2 vs. 0.95 for T1 w), and earlier detection (week 3 for T2 vs. week 4 for T1 w). ICP-MS confirmed the presence of gadolinium (3.076 ± 0.909 nmol/g in the IV group and 3.948 ± 0.806 nmol/g in the IP group). There was no significant difference between IP and IV groups (ICP-MS, P=0.109; MRI, P=0.696). No histopathological abnormalities were detected in any studied animal. T2 relaxometry detects gadolinium retention in the rat brain after multiple doses of gadodiamide irrespective of the route of administration. 1 TECHNICAL EFFICACY: Stage 1.

Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure

Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16–72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.

Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats.

The aim of this study was to determine potential metabolism and histological modifications due to gadolinium retention within deep cerebellar nuclei (DCN) after linear gadolinium-based contrast agent injection (gadodiamide) in rats at 1 year after the last injection. Twenty female rats received 20 doses of gadodiamide (0.6 mmol of gadolinium per kilogram each) over 5 weeks. They were followed at 1 week (M0), 6 weeks (M1), and 54 to 55 weeks (M13) postinjections to evaluate hypersignal on unenhanced T1-weighted magnetic resonance imaging and metabolic alterations by H magnetic resonance spectroscopy (H-MRS). At 1 year postinjections, brains were sampled to determine the localization of gadolinium within cerebellum by laser ablation inductively coupled mass spectroscopy and to evaluate morphological changes by semiquantitative immunofluorescence analysis. There is a significant increase of the ratio DCN/brainstem for the gadodiamide group at M0 (+7.2% vs control group = 0.989 ± 0.01), M1 (+7.6% vs control group = 1.002 ± 0.018), and it lasted up to M13 (+4.7% vs control group = 0.9862 ± 0.008). No variation among metabolic markers (cellular homeostasis [creatine, choline, taurine], excitatory neurotransmitter [glutamate], and metabolites specific to a cellular compartment [N-acetyl aspartate for neurons and myo-inositol for glial cells]) were detected by H-MRS between gadodiamide and saline groups at M0, M1, and M13. At M13, laser ablation inductively coupled mass spectroscopy demonstrated that long-term gadolinium retention occurred preferentially in DCN. No histological abnormalities (including analysis of astrocytes, neurons, and microglial cells) were found in the rostral part of DCN. Repeated administration of gadodiamide lead to a retention of gadolinium preferentially within DCN at 1 year postinjections. This retention did not lead to any detectable changes of the measured metabolic biomarkers nor histological alterations.

Signal intensity increases in dentate nucleus/globus pallidus/pulvinar on unenhanced T1WI MR images after multiple examinations with gadodiamide.

Elevated signal intensity (SI) in the dentate nucleus (DN), globus pallidus (GP) and pulvinar (PUL) was reportedly observed on unenhanced T1-weighted (T1WI) magnetic resonance (MR) images in patients receiving multiple enhanced MR examinations. We aimed to clarify whether this phenomenon influences the long-term neurological status of patients. We studied 196 radiosurgically treated patients undergoing ≥10 MR examinations using a single dose of gadodiamide and the same 1.5 Tesla MR unit. SI ratios were calculated by referencing the brainstem (BS) for the DN and the thalamus (TH) for the GP and PUL. We compared the SI ratios at the first, fifth, and 10th, and at the most recent examinations. The neurological symptoms of all 196 patients were assessed at each MR examination by one of the authors (MY). The DN/BS and GP/TH SI ratios were significantly increased at the fifth examination ( p < .0001, p = 0.0094) and, thereafter, gradually increased. Although the PUL/TH SI ratio was not significantly increased at the fifth examination ( p = 0.2515), a significant increase was noted at the 10th examination ( p < .0001). There were no significant predictive factors for DN/BS SI increases. Younger age, no brain metastasis, and normal estimated glomerular filtration rate were related to GP/TH SI ratio increases ( p = 0.0308, p = 0.0001, p = 0.0306). Higher age and total bilirubin level were related to an increased PUL/TH SI ratio ( p = 0.0276, p = 0.0097). No patients experienced gadodiamide-related health problems. Although the SI ratios rose as numbers of gadodiamide administrations increased, no adverse health effects have developed to date.

Impact of chelation timing on gadolinium deposition in rats after contrast administration

ObjectiveTo determine if gadolinium (Gd) can be rechelated once released from Gd-based contrast agents (GBCAs) and deposited in vivo. Despite extensive research comparing GBCAs and GBCA formulations as well as the ongoing debate about their risks of deposition and the role of Gd release, it remains unknown if retained Gd can be eliminated by administering chelating agents. Materials and methodsRats were injected intravenously with 10 doses of 1 mmol/kg gadodiamide and treated with intravenous Zn-DTPA (30 μmol/kg) concomitantly or 1, 4 or 8 h after GBCA administration (N = 3 rats per group). After euthanization, tissues were harvested three days after the last dose of gadodiamide and tissue Gd concentrations were assessed by ICP-MS. Additionally, a simulation of a single 0.1 mmol/kg gadopentetate dose with 30 μmol/kg DTPA given either concomitantly or within the first 24 h after GBCA was run; simulated tissue Gd concentrations were compared with those observed in rats to determine if simulated trends were accurate. ResultsConcomitant DTPA did not produce a significant reduction in Gd concentration in any organ for rats. There was a time-dependent trend in liver Gd reduction. The 1 h timepoint was associated with a non-significant increase in kidney, brain and femur Gd relative to untreated controls. There were no significant deviations from the model-predicted Gd changes. DiscussionBoth the simulation and rat study did not identify major benefits for chelation at the doses given, despite the simulation assuming all Gd deposited in tissues is unchelated. The potential redistribution in the rat study provide a compelling result that may impact the clinical relevance of further work investigating rechelation of Gd. Future work should further describe the three-dimensional dose-time-response relationship for preventing Gd deposition, and how that relates to long-term Gd toxicities.

Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.

Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

A comparison of inner ear imaging features at different time points of sudden sensorineural hearing loss with three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging.

It has been reported that about half of patients with sudden sensorineural hearing loss (SSNHL) show high signals in the affected inner ear on three-dimensional, fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI). These signals may reflect minor hemorrhage or an increased concentration of protein in the inner ear, which has passed through blood vessels with increased permeability. Our objective was to compare the positive ratio of the high signal in affected inner ears at different time points to determine the suitable imaging time point for 3D-FLAIR MRI in SSNHL. 3D-FLAIR MRI images were taken at three times, precontrast and approximately 10 min and 4 h after intravenous injection of a single dose of gadodiamide (Gd) (0.1 mmol/kg), in 46 patients with SNHL. We compared the positive findings of the high signals in the inner ear of patients with SNHL as well as the signal intensity ratio (SIR) between the affected cochleae and unaffected cochleae at three time points. The positive ratios of the high signals in the affected inner ear at the time points of precontrast and 10 min and 4 h after the intravenous Gd injection were 26.1, 32.6, and 41.3%, respectively. The high signal intensity ratios of affected inner ears at the three time points were 1.28, 1.31, and 1.48, respectively. The difference between the positive ratios precontrast and at 10 min after the intravenous Gd injection was statistically significant (P = 0.006); the differences between the positive ratios at 4 h after the intravenous Gd injection and precontrast and between the ratios at 4 h and 10 min after the intravenous Gd injection were not statistically significant. The time effects of the median value of SIR were not significant (P = 0.064). We do not recommend 4 h after intravenous Gd injection as a time point to image the inner ear in SNHL. We believe that imaging precontrast and at 10 min after the intravenous Gd injection are suitable time points.

Evidence for bilateral endolymphatic hydrops in ipsilateral delayed endolymphatic hydrops: preliminary results from examination of five cases

Conclusion: After the administration of a standard dose of gadodiamide, an intravenous gadolinium-based contrast agent (GBCA), magnetic resonance imaging (MRI) evaluation of endolymphatic hydrops (EH) became possible in patients with ipsilateral delayed endolymphatic hydrops (DEH). We found that patients with ipsilateral DEH may also have bilateral EH. Objective: MRI evaluation contributes to understanding of the pathological conditions in patients with EH. However, double or triple the standard dose of GBCA is often required to obtain images of high quality. We attempted to examine EH bilaterally in patients with ipsilateral DEH after routine administration of an intravenous GBCA. Methods: GBCA (gadodiamide, 0.2 ml/kg) was administered intravenously to five patients with ipsilateral DEH. Three-dimensional fluid attenuated inversion recovery (3D-FLAIR) MRI was performed with a 3-T MRI scanner 4 h after GBCA administration. Results: In all five patients, EH was observed in the affected vestibules. Moreover, EH was observed bilaterally in four (80%) of five patients with ipsilateral DEH. The region of the deaf ear affected by EH was considerably larger compared with the normal ear in three patients. However, observed regions of EH were of approximately the same size in both ears in patients 4 and 5.

Time-resolved and high-resolution MRA in a rabbit model of pulmonary embolism at 7 T: preliminary results

Evaluate feasibility of using time-resolved and high-resolution, contrast-enhanced magnetic resonance angiography (MRA) at 7 T for characterization of an animal model of pulmonary embolism. MRAs were performed in five rabbits using a 7-T MR scanner. Preceding the MR studies, each rabbit underwent a pulmonary artery catheterization with balloon placement. Two doses of gadodiamide were injected: first during a time-resolved MRA, immediately followed by a high-resolution acquisition. Balloon was then deflated, permitting reperfusion for 5 min. A second dose was then injected and another high-resolution MRA acquired. Measurements of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and vessel cross-sections down to fourth-order branches were made, among other parameters. Occlusion was detected in all rabbits. Despite a TE of 0.58 ms for the time-resolved MRA, regions of nonuniform enhancement attributed to susceptibility effects at the 7-T field were observed in perfused lung. Mean SNR=7.5+/-3.3 and 134.2+/-46.5 for the lung and aorta, respectively, and mean CNR=126.7+/-46.4 for aorta versus lung were obtained. Diameters of vessels in lung that was never occluded were not statistically different from those in reperfused lung. Results show that time-resolved and high-resolution MRA of the lung are feasible at 7 T and provide high SNR, CNR and resolution, but TEs smaller than 0.58 ms are required to avoid susceptibility artifacts in time-resolved MRAs.

Effects of gadolinium contrast agents in naïve and nephrectomized rats: Relevance to nephrogenic systemic fibrosis

Human nephrogenic systemic fibrosis (NSF) is a rare condition reported in patients with severe renal insufficiency exposed to a gadolinium (Gd)-based contrast agent. An animal model of NSF could help to investigate its mechanisms and lead to prevention and treatment. To evaluate a possible animal model of NSF using naive and partially nephrectomized rats to induce conditions similar to those in patients at risk of NSF. Naive rats received intravenous doses of 5 or 10 mmol/kg Omniscan; 5 mmol/kg Magnevist; 1 mmol/kg caldiamide; 1, 2.5, or 5 mmol/kg gadodiamide; 25 micromol/kg GdCl(3); or 25 micromol/kg Gd citrate. Partially nephrectomized rats received 5 mmol/kg Omniscan; 5 mmol/kg Magnevist; 1 mmol/kg caldiamide; 1 mmol/kg gadodiamide; 25 micromol/kg GdCl(3); or 25 micromol/kg Gd citrate. There were three or four animals per group. Clinical signs were recorded during treatment. At termination, clinical biochemistry, histopathology, and tissue Gd and Zn concentrations were investigated. Similar responses to treatment were seen in naive and nephrectomized rats. High doses of gadodiamide were toxic, necessitating early termination of the affected animals. Skin lesions appeared in naive and nephrectomized groups treated with gadodiamide or Omniscan, coinciding with the onset of signs of pruritus, i.e., intensive scratching. The histomorphological features of the skin lesions were also consistent with superficial physical trauma. Dermal fibrosis was not a feature of these skin lesions in any of the groups, i.e., no increased collagen density, CD34+ cells, or increased fibroblasts. This was supported by skinfold measurements that demonstrated no increased skin thickness. Treatment with the gadolinium-based contrast agents and Gd salts resulted in increased Gd content of several tissues. The Gd salts were mainly taken up by the liver and spleen, possibly reflecting formation of insoluble particles and macrophage uptake. Zn tissue concentrations were normal or increased. Other major treatment-related changes included increased serum rat C-reactive protein and histamine; mineralization affecting the dermis, stomach, and blood vessels; and renal proximal tubule vacuolation. The visible skin lesions seen in this study appeared to be caused by excessive scratching in response to pruritus. As there was no evidence of dermal fibrosis, the cardinal feature of human NSF, this did not appear to be a model of human NSF.

Gadolinium-enhanced MR Imaging and Nephrogenic Systemic Fibrosis: Retrospective Study of a Renal Replacement Therapy Cohort

To retrospectively compare the frequency of administration and cumulative dose of gadolinium-based contrast agent in dialysis-dependent patients who did and those who did not develop nephrogenic systemic fibrosis. The ethics committees granted exempt status for this study and also waived the need for informed consent. A retrospective analysis was performed of all adult patients undergoing dialysis in the west of Scotland between January 1, 2000, and July 1, 2006. Diagnoses of nephrogenic systemic fibrosis, episodes of gadolinium-enhanced magnetic resonance (MR) imaging, and cumulative doses of gadolinium-based contrast agent were recorded. Outcomes were analyzed by means of parametric and nonparametric testing. Fourteen of 1826 patients had a diagnosis of nephrogenic systemic fibrosis. Mortality was similar for affected and nonaffected patients. Thirteen (93%) of 14 patients with nephrogenic systemic fibrosis had undergone gadolinium-enhanced MR imaging compared with 408 (22.5%) of 1812 nonaffected patients (P<.001). Patients with nephrogenic systemic fibrosis received a higher median cumulative dose of gadodiamide (0.39 vs 0.23 mmol per kilogram of body weight, P=.008) and underwent more gadolinium-enhanced MR imaging than their nonaffected gadolinium-exposed counterparts. The data support a positive association between gadolinium-based contrast agent administration and development of nephrogenic systemic fibrosis in the established renal failure population; in addition, there is a positive association between cumulative dose of gadodiamide used and dosing events.

Efficacy and safety of gadodiamide (Gd-DTPA-BMA) in renal 3D-magnetic resonance angiography (MRA): A phase II study

Purpose To determine the most efficacious dose of gadodiamide for three-dimensional (3D) contrast-enhanced (CE) magnetic resonance angiography (MRA) of the renal arteries on a patient level based on the sensitivity in detecting the main hemodynamically relevant (≥50% or occlusion) renal artery stenosis (RAS) using intra-arterial digital subtraction angiography (IA DSA) as the gold standard. Materials and Methods This prospective, randomized, double-blind, parallel-group, multicenter study included 273 patients referred to IA DSA for suspected RAS. Patients underwent 3D CE MRA after injection of 0.01, 0.05, 0.1, or 0.2 mmol/kg of body weight gadodiamide (0.5 mmol/ml). The images were assessed for location and degree of RAS by independent blinded readers (MRA: three readers, IA DSA: one reader). Hypothesis testing for a significant trend in sensitivity across dose groups was based on the one-sided Cochran-Armitage style trend test for each independent MRA reader. Results The lowest dose group (0.01 mmol/kg) proved non-efficacious in detecting hemodynamically relevant (i.e., ≥50% or occlusion) RAS. A statistically significant dose trend ( p < 0.001) was shown for each of the three independent readers. Depending on reader, the sensitivity obtained with 0.05, 0.1, and 0.2 mmol/kg was 63.9–86.1%, 75.8–91.4% and 80.6–90.6%, the specificity was 66.7–73.9%, 59.3–75.0%, and 59.3–75.0% and accuracy was 67.8–78.9%, 75.4–77.4%, and 76.3–81.0%, for the three dose groups, respectively. There were eight non-severe adverse events (AEs). Three serious AEs occurring in one patient were judged not related to gadodiamide by the on-site investigator. Conclusion A significant dose trend between the four doses examined was observed. The lowest dose (0.01 mmol/kg) differed significantly from those of the other three doses. Based on the analysis of the primary and secondary endpoints, 0.1 mmol/kg gadodiamide appears to be the most suitable dose in diagnosing hemodynamically relevant RAS. The present study also demonstrated gadodiamide to be safe and well tolerated.

Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a rare acquired disorder that was first recognized in 1997. Presented is a retrospective review of 6 cases of NSF diagnosed by skin biopsy in our institution during the past 4 years and their relationship to gadodiamide exposure. Patient age ranged from 23 to 71 years. The onset of symptoms consistent with NSF was between 19 days and 2 months after gadodiamide exposure. Five patients had severe renal impairment and started dialysis around the period of gadodiamide exposure (1 day before the 37 days after contrast administration). The sixth patient had a clotted access at the time of a contrast-enhanced magnetic resonance venogram and was hence not being adequately dialyzed. The dose of gadodiamide ranged from 16 to 40 mL (0.11 to 0.36 mmol/kg). Despite having normal serum bicarbonate, 5 of the 6 patients had an elevated anion gap metabolic acidosis. In our 6 patients, all had either failing native or transplant kidneys at the time of gadodiamide exposure. The development of NSF was temporally related to gadodiamide injection, suggesting as the etiology dechelation of the agent and thus emphasizing the need for change in clinical practice.

Measurement of serum calcium concentration after administration of gadoversetamide in dogs.

To measure serum calcium concentration with three different analytic methods after administration of gadoversetamide and three other gadolinium chelates in dogs. Six dogs were injected with 0.1-, 0.3-, 1.0-, and 3.0-mmol/kg doses of gadoversetamide; 1.0-mmol/kg doses of gadodiamide, gadopentetate, and gadoteridol; and a 6-mL/kg dose of saline. Baseline blood samples were collected before injection; 5, 15, 30, and 60 minutes after each treatment; and 2, 4, 6, 12, and 24 hours after each treatment. Serum calcium levels were measured with inductively coupled plasma mass spectrometry, an arzenazo III dye assay, and an orthocresolphalthalin (OCP) complexone system. Analysis of variance coupled with the Dunnett procedure was used to compare serum calcium concentrations at different time points after injection with baseline values. Administration of gadoversetamide caused no decrease in serum calcium levels, as measured with inductively coupled plasma mass spectrometry or arzenazo III analytic techniques. In contrast, OCP assays showed a significant (P <.05) decrease in serum calcium values after administration of gadoversetamide. The decrease in serum calcium values peaked immediately after injection, and serum calcium values quickly returned to baseline. Injection of gadodiamide caused a significant (P <.05) decrease in the value of serum calcium when analyzed with the OCP technique but not when analyzed with inductively coupled plasma mass spectrometry or arzenazo III assays. In contrast, administration of gadopentetate or gadoteridol produced no significant change in serum calcium values, regardless of analytic method. Gadoversetamide and gadodiamide caused a transient artifact in measurement of serum calcium levels with an OCP assay but not with an arzenazo III technique or inductively coupled plasma mass spectrometry. The presence of gadopentetate or gadoteridol in the blood did not affect measurement of serum calcium levels.

Myocardial Perfusion Imaging Using OMNISCAN: A Dose Finding Study for Visual Assessment of Stress?Induced Regional Perfusion Abnormalities

Different doses of contrast agent are applied for magnetic resonance perfusion studies and mainly semiquantitative approaches have been reported for analysis. We aimed to determine the optimal dose for a visual detection of perfusion defects. 49 patients (59+/-8 years; 33 male) scheduled for invasive angiography were examined at stress (0.14 mg adenosine/kg body weight/minute) and rest using a TFE-EPI hybrid sequence (Philips ACS NT; 1.5 T). Patients were assigned to three different dose groups of gadodiamide (0.05, 0.1, and 0.15 mmol/kg body weight) injected as a bolus via a peripheral vein. Visual assessment was used to detect a regional reduction of peak signal intensity or speed of contrast agent inflow at stress in comparison to rest. Prevalence for coronary artery disease was 67%. The highest diagnostic accuracy was reached for a dose of 0.1 mmol gadodiamide/kg body weight (86% p=nonsignificant vs. 0.15 and 0.05 mmol gadodiamide/kg). At this dose, no major artifacts related to the contrast agent were found. Visual assessment of myocardial perfusion using a high-flow rate contrast agent bolus injection and a TFE-EPI sequence can be best achieved with a dose of gadodiamide 0.1 mmol/kg bodyweight.

Correlation of Microvascular Permeability Derived from Dynamic Contrast-Enhanced MR Imaging with Histologic Grade and Tumor Labeling Index: A Study in Human Brain Tumors

Rationale and Objectives Dynamic contrast material–enhanced magnetic resonance (MR) imaging may be used to quantify fractional blood volume (fBV) and microvascular permeability in human brain tumors. Hypothesis is that these measurements correlate with tumor histologic grade and immunohistologically assessed mitotic activity. Materials and Methods Thirty-eight patients with newly diagnosed gliomas underwent MR imaging consisting of dynamic three-dimensional spoiled gradient-recalled acquisition in the steady state image sets following bolus injections of a single dose of gadodiamide. Signal intensity changes in blood and tissue were kinetically analyzed, yielding estimates of fBV and microvascular permeability ( k). Tumor specimens were graded with the World Health Organization-II four-point grading score. MIB-1 immunohistochemical labeling (anti–Ki-67 monoclonal antibody) was performed in 22 patients to evaluate mitotic activity. Results Histologic study revealed nine grade 2, 14 grade 3, and 15 grade 4 tumors. fBV ranged from 0.4% to 24%, k from −0.4 to 31.4 mL/100 cm 3 · min, and MIB-1 labeling indexes from 1.7% to 42.8%. Correlation to the tumor grade was highest for permeability ( r = 0.73), followed by the MIB-1 index ( r = 0.63), and fBV ( r = 0.48). Correlation between k and MIB-1 index was strong ( r = 0.84). There was no statistically significant difference between the fBV of any of the groups. Despite some overlap between the permeability values of specific tumors from different grades, differences were statistically significant. The MIB-1 index was significantly different between grades 3 and 4 but not between grades 2 and 3. Conclusion Dynamic contrast-enhanced MR imaging allows noninvasive determination of tumor fBV and microvascular permeability k. k is more reliable than the MIB-1 labeling index for differentiating grade 2 from grade 3 tumors.

MR contrast agents in acute experimental cerebral ischemia: Potential adverse impacts on neurologic outcome and infarction size

The purpose of the study was to investigate the effects of magnetic resonance (MR) contrast agents on neurologic outcome and infarction size in a rat stroke model. Focal cerebral ischemia was induced in 80 rats using an endovascular occlusion technique of the middle cerebral artery. Four hours after occlusion, 64 animals (4 groups of 16 each) received gadodiamide (Gd-DTPA-BMA) in a single (0.1 mmol/kg) or triple (0.3 mmol/kg) clinical dose or the ultrasmall superparamagnetic iron oxide particles contrast agent NC 100150 in a single (0.03 mmol/kg, 1.5 mg Fe(2+)/kg) or double (0.06 mmol/kg, 3.0 mg Fe(2+)/kg) clinical dose, respectively. Sixteen animals received equivolumetric saline (control group). Neurologic score and body weight were recorded every 8 hours. Twenty-four hours after vessel occlusion, infarction size was measured by 2,3, 5-triphenyl-tetrazolium-chloride (TTC) staining. Neither the normal nor the triple clinical dose of gadodiamide or NC 100150 in the single or double dose had any statistically significant effects on infarction volume, mortality, body weight, or neurologic outcome (P > 0.05). Our results suggest that bolus injection of gadodiamide and the ultrasmall superparamagnetic iron oxide particles NC 100150 in clinically relevant doses does not significantly affect infarction volume and clinical outcome of acute cerebral ischemia.

Safety, Tolerance, and Pharmacokinetics of High Doses of Gadodiamide Injection, a Nonionic Magnetic Resonance Imaging Contrast Agent

Rationale and Objectives. Doses of up to 0.3 mmol/kg of gadodiamide injection have been used clinically to provide contrast enhancement in MR imaging of the central nervous system. This double-blind study evaluated the safety, tolerance, and pliarmacokinetics of gadodiamide doses of 0.5–1.5 mmol/kg administered intravenously. Methods. Groups of seven healthy adults were assigned randomly to receive either a placebo (two subjects per group) or one of five ascending doses (0.5, 0.75, 1.0, 1.25, or 1.5 mmol/kg) of gadodiamide (five subjects per group). Results. The frequencies of adverse events and injection-associated discomfort, all of which were nonserious, were statistically similar for gadodiamide and placebo subjects. Flushing occurred more frequently in those subjects having received gadodiamide. No clinically significant effects on vital signs or laboratory values were observed. Gadodiamide was rapidly eliminated from the serum (half-life of approximately 2 hr) and exhibited linear pharmacokinedcs. Nearly the entire dose was recovered in the urine as unmetabolized gadodiamide. Conclusion. Gadodiamide doses of 0.5–1.5 mmol/kg were safe and well tolerated in healthy adults, with no dose-related trends observed in adverse events or other safety parameters. The pharmacokinetics were consistent with those observed for lower doses. Rationale and Objectives. Doses of up to 0.3 mmol/kg of gadodiamide injection have been used clinically to provide contrast enhancement in MR imaging of the central nervous system. This double-blind study evaluated the safety, tolerance, and pliarmacokinetics of gadodiamide doses of 0.5–1.5 mmol/kg administered intravenously. Methods. Groups of seven healthy adults were assigned randomly to receive either a placebo (two subjects per group) or one of five ascending doses (0.5, 0.75, 1.0, 1.25, or 1.5 mmol/kg) of gadodiamide (five subjects per group). Results. The frequencies of adverse events and injection-associated discomfort, all of which were nonserious, were statistically similar for gadodiamide and placebo subjects. Flushing occurred more frequently in those subjects having received gadodiamide. No clinically significant effects on vital signs or laboratory values were observed. Gadodiamide was rapidly eliminated from the serum (half-life of approximately 2 hr) and exhibited linear pharmacokinedcs. Nearly the entire dose was recovered in the urine as unmetabolized gadodiamide. Conclusion. Gadodiamide doses of 0.5–1.5 mmol/kg were safe and well tolerated in healthy adults, with no dose-related trends observed in adverse events or other safety parameters. The pharmacokinetics were consistent with those observed for lower doses.

MR diagnosis of head and neck tumors: comparison of contrast enhancement with triple-dose gadodiamide and standard-dose gadopentetate dimeglumine in the same patients.

The purpose of this study was to compare the relative values of MR images obtained with a triple dose of gadodiamide and MR images obtained with the standard dose of gadopentetate dimeglumine for the detection and determination of the extent of tumors of the head and neck. Forty-two patients with benign and malignant tumors of the head and neck were examined with contrast-enhanced MR imaging in a comparison of a triple dose of gadodiamide (0.3 mmol per kilogram body weight) and a standard dose (0.1 mmol per kilogram body weight) of gadopentetate dimeglumine. All patients underwent MR imaging with both doses of contrast material. Contrast-to-noise ratios and the percentage enhancement of normal and abnormal structures were calculated, and delineation of the lesion and the contrast between tumor and surrounding tissue were evaluated visually. Statistical analysis (Friedman test and Wilcoxon test) of the contrast-to-noise ratios between tumor and white matter, the percentage enhancement, and the visual assessment rating revealed a statistically significant superiority of the triple dose of gadodiamide over the standard dose of gadopentetate dimeglumine. Tumor/muscle contrast-to-noise ratios were not significantly different with the two doses. The detection rate for tumors was no better with the triple dose of gadodiamide than with the standard dose of gadopentetate dimeglumine. Use of the triple dose of gadodiamide results in a statistically significant improvement in the visual assessment rating, but it does not increase the number of tumors detected on MR images over the number detected with the standard dose of gadopentetate dimeglumine and does not appear to alter the differential diagnosis.