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Background: The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety., Objective: The aim of this study was to perform a thorough review and status update on gadobutrol's safety., Materials and Methods: Safety data from the clinical phase II-IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized., Results: Forty-five clinical phase II-IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age ("elderly") were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol., Conclusions: More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations., Competing Interests: Conflicts of interest and sources of funding: J.E., L.S., C.H., and A.B. are employees of Bayer. The other authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Previous research on the necessity to reduce the viscosity of contrast media (CM) by either prewarming CM before injection during computed tomography (CT) or by using less concentrated CM has yielded conflicting results. In addition, there is limited evidence on patient comfort., Objectives: The aim of the study was to examine if prewarming CM, with varying CM concentrations, is superior to CM at room temperature, with respect to patient comfort and safety in CT., Materials and Methods: All elective patients scheduled for contrast-enhanced CT scans at Maastricht University Medical Center+ between October 27, 2021 and October 31, 2022 were eligible for inclusion when a questionnaire evaluating patient comfort was completed. This 1-year period was divided into 4 intervals (4 groups): group 1 (370 mg I/mL, 37°C), group 2 (370 mg I/mL, room temperature), group 3 (300 mg I/mL, 37°C), and group 4 (300 mg I/mL, room temperature). All CT scans were performed using state of the art equipment (Siemens Healthineers; SOMATOM Force and SOMATOM Definition AS, Forchheim, Germany). Contrast media injections were performed using a dual-head power injector (Stellant; Bayer Healthcare, Berlin, Germany) and individualized to body weight and/or tube voltage, depending on the CM protocols. After the CT scan, patients completed a questionnaire covering the primary outcomes comfort, pain, and adverse events such as feelings of heat, nausea, vomiting, itchiness, urticaria, difficulty breathing, dizziness, goosebumps, or an odd taste. Technicians were asked to report any adverse events, including extravasation and allergic-like reactions. The secondary outcome involved attenuation (in Hounsfield unit, HU), which was evaluated by assessing the HU of the coronary arteries for vascular CT, and liver enhancement in portal venous CT. The Kruskal-Wallis test was used for continuous scale outcomes and χ 2 tests for examining adverse events., Results: Results showed no significant differences examining comfort score ( P = 0.054), pain sensation ( P = 0.469), extravasation ( P = 0.542), or allergic-like reaction ( P = 0.253). Significant differences among the 4 groups were found with respect to heat sensation and dizziness ( P = 0.005 and P = 0.047, respectively), showing small effect sizes. All other adverse effects showed no significant results. No significant differences were observed in coronary attenuation among the 4 groups in coronary CT angiography ( P = 0.113). When analyzing attenuation in portal venous CT scans, significant differences were found among the 4 groups ( P = 0.008)., Conclusions: Administrating prewarmed CM is nonsuperior compared with CM at room temperature in relation to patient comfort and safety, regardless of CM concentration. These findings suggest that prewarming CM before usage is unnecessary, which will improve the efficiency of daily clinical workflow and brings environmentally friendly benefits., Competing Interests: Conflicts of interest and sources of funding: This article has not received any funding, and the authors report no conflicts of interest. The authors declare relationships with the following companies: C.M. and B.M. receive personal fees (speakers bureau) from Bayer. All outside the submitted work. J.E.W. reports institutional research grants from Agfa, Bayer, Bard, GE, Philips, Optimed, and Siemens and personal fees (speakers bureau) from Siemens and Bayer, all outside the submitted work., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: This review describes the pharmacokinetics, efficacy, and safety of gadopiclenol, a new macrocyclic gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration at the dose of 0.05 mmol/kg. Gadopiclenol is a high relaxivity contrast agent that shares similar pharmacokinetic characteristics with other macrocyclic GBCAs, including a predominant renal excretion. In pediatric patients aged 2-17 years, the pharmacokinetic parameters (assessed through a population pharmacokinetics model) were comparable to those observed in adults, indicating no need for age-based dose adjustment. For contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) and body indications, gadopiclenol at 0.05 mmol/kg was shown to be noninferior to gadobutrol at 0.1 mmol/kg in terms of 3 lesion visualization parameters (ie, lesion border delineation, internal morphology, and contrast enhancement). Moreover, for contrast-enhanced MRI of the CNS, compared with gadobenate dimeglumine at 0.1 mmol/kg, gadopiclenol exhibited superior contrast-to-noise ratio at 0.1 mmol/kg and comparable contrast-to-noise ratio at 0.05 mmol/kg. A pooled safety analysis of 1047 participants showed a favorable safety profile for gadopiclenol. Comparative studies showed that the incidence and nature of adverse drug reactions with gadopiclenol were comparable to those observed with other GBCAs. Importantly, no significant safety concerns were identified in pediatric and elderly patients, as well as in patients with renal impairment. Overall, these findings support the clinical utility and safety of gadopiclenol for MRI in adult and pediatric patients aged 2 years and older in CNS and body indications., Competing Interests: Conflicts of interest and sources of funding: All authors are employed by Guerbet. The clinical studies performed for the evaluation of the efficacy and safety of gadopiclenol were funded by Guerbet., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Gadolinium (Gd)-based contrast agents are well established in clinical routine and have been proven safe and effective. However, there is a need for "next-generation" Gd-based contrast agents that would allow lowering the Gd dose used for routine contrast-enhanced magnetic resonance imaging procedures. The objective of this first-in-human study was to investigate the pharmacokinetic profile, safety, and tolerability of gadoquatrane, a novel high-relaxivity Gd-based contrast agent., Materials and Methods: This study was conducted in 2018/2019 as a prospective, randomized, single-blind, single-dose, placebo-controlled, escalating-dose study. Healthy volunteers were randomly assigned (6:2) to intravenous administration of gadoquatrane (0.025 to 0.2 mmol Gd/kg body weight) or placebo. Study procedures included collection of blood samples and excreta for pharmacokinetic analyses and safety assessments., Results: Forty-nine healthy study participants (mean age ± SD, 35 ± 6.3 years; 24 female) were evaluated. The effective half-life of gadoquatrane in plasma was short and similar in all dose groups (1.4-1.7 hours). Plasma concentrations around the lower quantitation limit (0.0318 μmol Gd/L) were reached 15-72 hours after administration. The volume of distribution at steady state was ~0.2 L/kg in all dose groups. The clearance (total and renal) was ~0.1 L/h per kilogram in all groups. Across dose groups, the exposure of gadoquatrane increased dose-proportionally. Metabolite profiling revealed no hint of degradation in vivo or release of free Gd. Seven of 36 participants (19.4%) receiving gadoquatrane and 4 of 13 participants (30.8%) receiving placebo experienced mild or moderate treatment-emergent adverse events. No serious adverse events occurred. The analysis of the Gd concentration-QTc interval relationship indicated no risk of QT/QTc prolongation (>10 milliseconds) with gadoquatrane at clinical dose levels., Conclusions: Gadoquatrane with its high-relaxivity, pharmacokinetic similarity to established Gd-based contrast agents and high tolerability is a promising "next-generation" contrast agent for magnetic resonance imaging., Competing Interests: Conflicts of interest and sources of funding: The study was sponsored by Bayer AG. All authors are or were working at Bayer AG or on behalf of Bayer AG., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: This review describes the current knowledge of a form of gadolinium toxicity termed gadolinium deposition disease (GDD), supplemented with the opinions of the authors developed during 6 years of clinical experience treating GDD. Gadolinium deposition disease can also be considered a subset under the symptoms associated with gadolinium exposure rubric. Young and middle-aged White women of central European genetic origin are the most affected. The most common symptoms are fatigue, brain fog, skin pain, skin discoloration, bone pain, muscle fasciculations, and pins and needles, but a long list of additional symptoms is reported herein. The time of onset of symptoms ranges from immediate to 1 month after gadolinium-based contrast agent (GBCA) administration. The primary treatment is to avoid further GBCAs and metal removal through chelation. Presently, the most effective chelating agent is DTPA because of its high affinity with gadolinium. Flare development is an expected outcome, amenable to concurrent immune dampening. We emphasize in this review the critical nature of recognizing GDD when it first arises, as the disease becomes progressively more severe with each subsequent GBCA injection. It is generally very treatable after the first symptoms of GDD, often arising after the first GBCA injection. Future directions of disease detection and treatment are discussed., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest and sources of funding: none declared.

Objective: Recent scientific publications have reported cases of patients who complained from a variety of symptoms after they received a gadolinium-based contrast agent (GBCA). The aim of this study was to appreciate the importance of these clinical manifestations in the overall population by assessing the weight of "symptoms associated with gadolinium exposure" (SAGE) among the bulk of safety experiences reported to major health authorities., Materials and Methods: Symptoms associated with gadolinium exposure were identified from a review of the scientific literature, and the corresponding preferred terms were searched in each system organ class (SOC) category recorded in the European and North American pharmacovigilance databases EudraVigilance (EV) and FDA Adverse Event Reporting System (FAERS), respectively. The numbers of SAGE per preferred term, and cumulatively per SOC, were recorded and their weights in the overall spectrum of adverse events (AEs) were determined for each GBCA., Results: The analysis of the selected AEs revealed a significantly higher SAGE weight for gadobenate dimeglumine (EV: 25.83%, FAERS: 32.24%) than for gadoteridol (EV: 15.51%; FAERS: 21.13%) and significantly lower SAGE weights for gadobutrol (EV: 7.75%; FAERS: 13.31%) and gadoterate meglumine (EV: 8.66%; FAERS: 12.99%). A similar ranking was found for most of the SOCs except for "nervous system disorders," probably owing to a limitation in the methods of data selection. Furthermore, this analysis showed a greater percentage of reports mentioning a decrease in the quality of life of the patients when they were exposed to gadobenate dimeglumine or gadoteridol than to gadobutrol or gadoterate meglumine., Conclusion: This study showed that SAGE represent a significant percentage of the bulk of AEs reported to the health authorities for each GBCA. It provided real-life arguments suggesting that SAGE may be more prevalent with linear than macrocyclic GBCAs and that gadoteridol may present a higher SAGE risk than the other macrocyclic contrast agents., Competing Interests: Conflicts of interest and sources of funding: I. Shahid, A. Joseph, and E. Lancelot are employees of Guerbet., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The aims of this study were to evaluate the pharmacokinetics (PK) of gadopiclenol, a new macrocyclic gadolinium based-contrast agent, in subjects with impaired renal function, and to assess its dialysability in subjects with end-stage renal disease (ESRD)., Methods and Materials: This 2-center, open-label, phase 1 study included 5 successive cohorts of 8 adult subjects: healthy subjects (cohort 1), subjects with mild (cohort 2), moderate (cohort 3), severe (cohort 4) renal impairment, or ESRD (cohort 5), who received a single intravenous injection of gadopiclenol (0.1 mmol/kg). Blood and urine samples were collected at different time points in cohorts 1 to 4, and blood and dialysate samples were collected at each hemodialysis session (4-hour session on day 1, day 3, and day 5) in cohort 5. Gadopiclenol elimination and safety were assessed for up to 6 months. Pharmacokinetics parameters were calculated using noncompartmental analysis., Results: A total of 40 subjects were included, with a mean age of 51.5 years (range, 18-71 years). No significant difference in the mean maximum concentration values and the distribution volume was observed among cohorts 1 to 4. Urinary excretion of unchanged gadopiclenol was delayed with the degree of renal impairment and ranged between 96% and 84% in subjects with mild to severe renal impairment. Compared with that of healthy subjects, the mean area under the plasma concentration curve was 54%, 148%, and 769% higher in subjects with mild, moderate, or severe renal impairment, respectively. The mean terminal half-life was prolonged with the degree of renal impairment (1.9, 3.3, 3.8, and 11.7 hours for cohorts 1-4). In ESRD subjects, gadopiclenol was effectively removed from the plasma (95% to 98%) after the first hemodialysis session. Gadopiclenol concentration in plasma was below the limit of quantification for all subjects after the second hemodialysis session. Gadopiclenol concentration was below limit of quantification in all plasma and urine samples collected at 1, 3, and 6 months. Five subjects (12.5%) experienced adverse events related to gadopiclenol, none serious and all resolved. Laboratory measurements, vital signs, and electrocardiography did not raise any safety concern., Conclusions: Gadopiclenol elimination half-life was prolonged in subjects with mild to severe renal impairment, yet its renal clearance remains complete or nearly complete. In ESRD subjects, gadopiclenol was effectively removed from the plasma after 1 hemodialysis session, and up to 3 hemodialysis sessions were sufficient to completely clear it. No safety concern was raised. Therefore, no dose adjustment seems necessary in this patient population., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Avoiding culprit agents is recommended for subjects who have had previous hypersensitivity reaction (HSR) to low-osmolar contrast media (LOCM). However, the guidelines for choosing optimal alternatives have not been determined. We investigated the outcomes of reexposure in patients with previous immediate HSRs to provide a safe option., Materials and Methods: The outcomes of reexposure were assessed in a cohort with previous LOCM-associated HSR based on skin testing results and the presence of a common N-(2,3-dihydroxypropyl) carbamoyl side chain., Results: Among 482 skin tests, 38.7% (31/80), 45.8% (99/216), and 64.0% (119/186) of mild, moderate, and severe index HSRs showed positivity to at least 1 LOCM, of which 62.8% showed positivity to at least 2 different LOCM. The overall recurrent HSRs were reduced from 43.8% upon reexposure to the culprit LOCM to 12.3% upon using nonculprit skin test negative LOCM (P = 0.004); those with severe index HSRs exhibited a significant reduction (11.3% vs 100%), but those with non-severe HSRs to LOCM did not. In subjects with severe index HSRs, the skin test cross-reactivity between LOCM was associated with sharing the common side chain (20.7% vs 11.5%, P = 0.003), and the recurrence rate of HSRs was effectively reduced by avoiding the common side chain (24.0% vs 7.8%, P = 0.039). However, these differences were not observed in those with non-severe index HSRs., Conclusions: In patients who experienced a severe index HSR to LOCM, skin test negative LOCM without a common side chain could be suggested as an option for safe reexposure., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: There is increasing evidence that Gd may be retained within the skin, bones, and solid organs in patients with normal renal function after exposure to Gd-based contrast agents (GBCAs). Here we present clinical data from 19 patients who requested referral to our clinical toxicology service for assessment of potential "Gd toxicity.", Materials and Methods: Patients had undergone a median of 2 (interquartile range [IQR], 1-5) exposures to GBCAs and were reviewed at a median of 5 months (IQR, 2-8 months) after the last GBCA exposure. Patients had a clinical assessment by a clinical toxicologist, and biological samples were taken in 17 patients (89.5%). Gd concentrations were measured in these samples using inductively coupled plasma mass spectrometry., Results: All patients had significant comorbidities, and after an extensive clinical review, none of the reported symptoms were considered likely to be related to "Gd toxicity." Whole blood, plasma, and urine samples had detectable Gd concentrations in 69.2%, 78.6%, and 95.2% of samples, respectively. Median (IQR) concentrations of Gd were as follows: whole blood, 0.013 ng/mL (IQR, limit of detection [LOD]-0.884 ng/mL); plasma, 0.012 ng/mL (IQR, LOD-0.046 ng/mL); and spot urine, 0.304 μg/g creatinine (IQR, 0.070-3.702 μg/g creatinine). There were positive correlations between whole blood and plasma (P = 0.0024, r = 0.84), whole blood and urine (P = 0.0018, r = 0.82), and plasma and urine (P = 0.0001, r = 0.89) Gd concentrations. There was a negative correlation between Gd concentrations and the period after exposure for whole blood (P = 0.0028, r = -0.80), plasma (P = 0.0004, r = -0.86), and urine (P < 0.0001, r = -0.91)., Conclusions: We identified detectable Gd concentrations in biological matrices from all patients reporting exposure to GBCAs who were reviewed in our clinical toxicology outpatient clinic with concerns regarding potential "Gd toxicity"; however, there were no clinical features of toxicity present in this cohort. Further research is required to explore the pharmacokinetics and pharmacodynamics of GBCAs in patients with normal renal function and to determine the clinical significance of these detectable Gd concentrations., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Breakthrough hypersensitivity reactions (HRs) to gadolinium-based contrast agent (GBCA) occur in 40% of patients despite corticosteroid premedication. Other strategies to reduce HRs are not well studied., Objective: The aim of this study was to prospectively evaluate HR rate to GBCA among patients with history of HR to GBCA, empirically given an alternative GBCA prior to repeat administration., Materials and Methods: From September 2019 to September 2020, patients with prior HR to GBCA received 13-hour oral corticosteroid and diphenhydramine premedication prescription with switching of GBCA to gadoterate (previously unavailable at our institution before September 2019). Power analysis (α error, 0.05; β error, 0.80) determined 21 patients were required. Patients were evaluated under a quality assurance waiver from the institutional review board. A radiologist documented the nature of initial HR and inciting GBCA, premedication received, incidence, and severity of breakthrough HR., Results: After exclusions, we evaluated 26 patients with mild (92.3% [24/26]) or moderate (7.7% [2/26]) HR to gadobutrol (53.8% [14/26]), gadoxetate (3.8% [1/26]), and gadopentetate (3.8% [1/26]). In 38.5% (10/26), inciting GBCA was unknown but was likely gadobutrol or gadopentetate based on availability. There were 22 females. The mean patient age was 52.1 ± 15.8 years.From 27 gadoterate administrations, 59.3% (16/27) patients received corticosteroid and diphenhydramine premedication, 11.1% (3/27) received only diphenhydramine, and 29.6% (8/27) with no premedication.Hypersensitivity reaction rate after empiric switching to gadoterate was 3.7% (1 mild reaction; 95% confidence interval [CI], 0.09%-18.9%) overall with no difference in patients with (6.3% [1/16]; 95% CI, 0.15%-28.7%) or without (0%; [0/11] upper bound 95% CI, 25.0%) corticosteroid premedication., Conclusions: In this prospective single-arm study, empirically switching GBCA to gadoterate in patients with prior HR to GBCA substantially reduced the expected rate of subsequent HRs in patients with and without the use of corticosteroid premedication., Implications for Patient Care: Empirically switching GBCAs, with or without the use of corticosteroid premedication, can substantially reduce the rate of hypersensitivity breakthrough reactions., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Gadolinium-based contrast agents have been used in hundreds of millions of patients in the past 30 years, with an exemplary safety record. However, assumptions made at their inception have been recently challenged, rekindling innovation efforts. This critical review outlines the motivations, technical obstacles, problems, and the most recent published progress toward the creation of alternatives to the existing gadolinium-based contrast agent.

Background: The overall risk of postcontrast acute kidney injury (PC-AKI) after computerized tomography (CT) is negligible, likely because of the small volume of injected iodinated contrast media required. However, the safety of contrast media-enhanced CT in patients with advanced renal functional impairment, an established major risk factor for PC-AKI, is unknown., Materials and Methods: This is a retrospective study using large data analysis of hospitalized patients at a single center. Adults undergoing CT or magnetic resonance imaging were included in the study and were stratified by estimated glomerular filtration rate (eGFR) (≤30 or >30 mL/min/1.73 m) and by either contrast-enhanced or nonenhanced imaging. Only patients with serial determination of creatinine before and after imaging were included. Demographic, clinical, and laboratory data between groups were analyzed and compared using univariate analysis, propensity score matching, and multivariate logistic regression analysis., Results: A total of 22,319 imaging studies were included. Patients with an eGFR of 30 mL/min/1.73 m or lower undergoing contrast-enhanced CT (n = 403) had an increased risk to develop PC-AKI than did similar patients undergoing enhanced or nonenhanced magnetic resonance imaging (n = 96) or nonenhanced CT (n = 1576) or patients undergoing contrast-enhanced CT with a preprocedural eGFR higher than 30 mL/min/1.73 m (n = 9173). These findings remained robust after propensity matching for demographic, procedural, and clinical parameters. Multivariate regression analysis of all patients undergoing CT with preimaging eGFR of 30 mL/min or lower (n = 1979) revealed that iodine-based contrast enhancement increased the likelihood of post-CT AKI by 51% (confidence interval, 1.23-2.05)., Conclusion: Although radiocontrast-enhanced CT is considered safe in most hospitalized patients and in ambulatory settings, the risk of PC-AKI remains significant among inpatients with substantial preimaging renal functional impairment. Caution is warranted using iodine-based enhanced CT in hospitalized patients with an eGFR of 30 mL/min/1.73 m or lower.

This review summarizes 30 years of experience in the development and clinical use of magnetic resonance (MR) contrast agents. Despite their undisputable usefulness for disease diagnosis, gadolinium (Gd)-based contrast agents (GBCAs) have gone through 2 major safety crises. Approximately 10 years ago, the regulatory agencies decided to restrict the use of GBCAs to minimize the risk of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Yet, following the recent discovery of Gd retention in brain, the same agencies adopted different positions ranging from suspension of marketing authorizations, changes in GBCA safety labeling, and performing preclinical and clinical studies to assess the potential long-term consequences of Gd accumulation on motor and cognitive functions. Besides, magnetic resonance imaging (MRI) has benefited from MR technological advances, which provide alternative solutions to increase the MR signal, generate new contrasts on MRI scans, and accelerate their acquisition and analysis. Altogether, GBCAs in combination with new MR techniques have found their place in the diagnostic pathway of various diseases. Despite the large research efforts to identify and develop alternative Gd-free MR agents, manganese- and iron-based contrast agents have failed to reach market approval. In this context, the development of next-generation MR contrast agents should focus on high-stability and high-relaxivity GBCAs, such as gadopiclenol, which offer the possibility to adapt the administered Gd dose to each indication while ensuring an optimal patient safety.

Objectives: In recent years, complaints of patients about burning pain in arms and legs after the injection of gadolinium-based contrast agents (GBCAs) have been reported. In the current study, we investigated changes of small fibers in the epidermis as a potential cause of the patient complaints in a mouse model., Methods: Six groups of 8 mice were intravenously injected with either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine) (1 mmol/kg body weight), or saline (NaCl 0.9%). Four weeks after injection, animals were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IENFD) was calculated, and the median number of terminal axonal swellings (TASs) per IENFD was determined., Results: Nonparametric Wilcoxon signed-rank test revealed significantly lower IENFDs for all GBCAs compared with the control group (P < 0.0001) with the linear GBCAs showing significantly lower IENFDs than the macrocyclic GBCAs (P < 0.0001). The linear GBCAs presented significantly more TAS per IENFD than the control group (P < 0.0001), whereas no significant increase of TAS per IENFD compared with the control group was found for macrocyclic GBCAs (P < 0.237)., Interpretation: It is unclear whether or at what dosage the decrease of IENFDs and the increase of TAS per IENFD found in the current animal model will appear in humans and if it translates into clinical symptoms. However, given the highly significant findings of the current study, more research in this field is required.

Background: The incidence of severe reaction induced by iodinated contrast media (ICM) has increased over the years with an increasing use of imaging modalities. Although ICM anaphylaxis is rare, it can be life-threatening, but currently, there is no biomarker that can identify individuals at risk of ICM anaphylaxis., Objective: The aim of this study is to investigate the genetic susceptibility of ICM anaphylaxis., Methods: Patients who had ICM anaphylaxis were enrolled in the study, and their blood samples were collected for genotyping of human leukocyte antigen (HLA)-A, -B, -C, and -DR. The results were compared with those of healthy Korean general population. MRGPRX2 gene in ICM anaphylaxis group was also sequenced and compared with the Korean standard database of genetic polymorphism., Results: The frequencies of 3 HLA alleles (B*52:01, C*12:02, and DRB1*15:02) were significantly higher in 47 patients with ICM anaphylaxis. In particular, HLA-DRB1*15:02 was 5 times more frequent in the ICM anaphylaxis group than the Korean general population (34.0% vs 6.6%; odds ratio, 7.306; 95% confidence interval, 3.622-14.740), and this difference was most pronounced in subjects with iohexol-induced anaphylaxis (odds ratio, 16.516; 95% CI, 5.241-52.047; P < 0.0001). Eight single nucleotide polymorphisms were identified in MRGPRX2 gene, but their frequencies were not different in those with ICM anaphylaxis compared with the general Korean population., Conclusions: HLA-DRB1*15:02 is associated with ICM anaphylaxis in the Korean population.

Objectives: Our study sought to reevaluate the safety and diagnostic efficacy of iobitridol as a nonionic contrast medium after almost 20 years of use., Materials and Methods: This noninterventional postmarketing surveillance noncontrolled, multicenter (168 centers in Germany) study enrolled 94,960 patients receiving intravenous or intra-arterial iobitridol. The majority of the adjusted population (n = 92,550, 98.2%) underwent either computed tomography examination (n = 46,502, 49.3%) or intravenous urography (n = 46,048, 48.8%). A standardized questionnaire was used to ascertain patient's information, known risk factors, renal function status, premedication, type of examination, injection of contrast agent, imaging quality, diagnostic value, and safety., Results: A total of 469 patients (0.49%) experienced an adverse event (AE), and 24 patients (0.025%) reported a serious AE (SAE). All patients recovered and no fatal event occurred. The prevalence of AE was significantly higher in patients with at least one risk factor, with premedication, with a history of AE, in female and patients younger than 60 years old (P < 0.05). Presence of at least one risk factor is the only predictive factor for the prevalence of SAE (P = 0.042). In patients with a history of AE, premedication did not significantly lower the AE rate (P = 0.737). No statistically significant difference in the prevalence of AE between the different combination of cortisone and/or antihistamines as pretreatment was found., Conclusions: Iobitridol is a safe contrast medium with a high tolerability and efficacy. Presence of risk factors such as cardiovascular diseases, allergies, or asthma was the only significant predictive factor for an AE and an SAE. Premedication did not significantly lower the occurrence of an AE and an SAE.

Objective: The aim of this study was to compare the risk of hypersensitivity reactions to iopromide after intra-arterial (IA) administration and intravenous (IV) administration., Materials and Methods: Four observational studies were pooled. Almost half of the study population (48.1%) was from Europe, and one quarter each from China (27.6%) and other Asia countries (24.1%). All patients received iopromide either intra-arterially or intravenously for angiographic procedures (mostly cardio-angiography) or contrast-enhanced computed tomography. A nested case-control analysis, including a multivariable logistic regression model, was performed. Cases were defined by patients with a typical and unequivocal hypersensitivity (assumed non-IgE-mediated) reaction; controls were patients without any recorded reaction. The primary target variable is the odds ratio of having a hypersensitivity reaction after IA versus IV administration., Results: A total of 133,331 patients met the inclusion criteria, 105,460 and 27,871 patients received iopromide IV or IA, respectively. Hypersensitivity reactions were recorded for 822 patients, and 132,509 patients served as controls.Major risk factors for hypersensitivity reactions were method of injection (IV vs IA), age (18 to <50 years vs ≥65 years), history of allergy or previous contrast media reaction (all P < 0.001), and asthma (P = 0.005).A total of 766 patients (0.7%) and 56 patients (0.2%) were recorded with hypersensitivity reactions after IV or IA administration, respectively (P < 0.0001).Adjusted odds ratio (IA vs IV) was 0.23 (95% confidence interval, 0.16-0.32) for all countries together: for China only, 0.22 (0.11-0.44); for all countries without China, 0.36 (0.25-0.53).Most frequent reactions were erythema/urticaria/rash, pruritus, and cough/sneezing., Conclusions: Hypersensitivity reactions to iopromide were significantly less frequently recorded after IA administrations. This could be related to the delayed and diluted arrival of iopromide to the lungs.

Objectives: Currently, the prevention of recurrent immediate hypersensitivity reactions (HSRs) to contrast media (CM) requests premedication and changing the culprit contrast agent. However, strategies for the prevention of immediate HSRs to gadolinium-based magnetic resonance contrast agents (GBCAs) have not yet been established. This study aimed to evaluate the effectiveness of changing the contrast agent and single-dose premedication for HSR recurrence prevention in patients with a history of mild immediate HSR to GBCA., Materials and Methods: The outcomes of patients with mild immediate HSR to GBCA who subsequently underwent enhanced magnetic resonance imaging between October 2012 and July 2017 were analyzed. The institutional CM monitoring system was retrospectively reviewed, and data on the application of premedication and choice of CM were obtained. Gadolinium-based magnetic resonance contrast agents were classified into 3 classes according to their molecular structure (macrocyclic ionic, macrocyclic nonionic, and linear ionic). Intravenous chlorpheniramine 4 mg, 30 minutes before the GBCA administration, or intravenous methylprednisolone sodium succinate 40 mg plus chlorpheniramine 4 mg, 1 hour before the GBCA administration, was administrated as premedication regimen. Recurrence rates of immediate HSR were compared according to prevention strategies., Results: A total of 185 patients with a history of mild immediate HSR to GBCA were re-exposed to GBCA 397 times during the study period. The overall recurrence rate was 19.6% (78/397). Changing the culprit GBCA significantly reduced the recurrence rate, compared with reusing the culprit GBCA (6.9%, 9/130 and 25.8%, 69/267; P < 0.001). The recurrence rate was lowest when the GBCA was changed to a different molecular structure class from the culprit agent, followed by changing to CM with the same molecular structure and reusing the culprit GBCA (6.2%, 7/113 vs 11.8%, 2/17 vs 25.8%, 69/267; P < 0.001 with χ test for trend). Single-dose premedication demonstrated no significant prophylactic effect on recurrence (20.4%, 17/98 vs 17.3%, 61/299 with and without premedication, respectively; P = 0.509). Premedication in addition to changing CM also showed no additional prophylactic effect (7.2%, 7/97 and 6.1%, 2/33, respectively; P = 0.821)., Conclusions: Changing the CM from the culprit agent could reduce the chance of HSR recurrence in patients with prior mild immediate HSR to GBCA, especially when the CM was changed to one of a different molecular structure class. However, single-dose premedication administration did not show significant HSR recurrence rate difference.

Objectives: We aimed to meta-analytically compare the incidence of acute adverse reactions (AARs) to nonionic iodinated contrast media (ICM) according to the type of ICM in patients who underwent radiologic examinations with administration of ICM via intravascular route., Materials and Methods: A systematic literature search identified studies evaluating the incidence of AARs to 7 nonionic ICM (iobitridol, iohexol, iomeprol, iopamidol, iopromide, ioversol, and iodixanol) with extractable outcomes. These outcomes were pooled using a random-effects model, and the effect of ICM type on the incidence of overall and severe AARs was evaluated using meta-regression analysis., Results: Thirty studies with 1,360,488 exposures to ICM were included. The pooled incidences of overall and severe AARs to nonionic ICM were 1.03% (95% confidence interval [CI], 0.81%-1.30%; I = 0.99) and 0.0141% (95% CI, 0.0108%-0.0183%; I = 0.56), respectively. Iomeprol had the highest overall AAR incidence (1.74%; 95% CI, 0.79%-3.76%; I = 0.99), followed by iohexol (1.21%; 95% CI, 0.67%-2.17%; I = 0.99), iopamidol (1.10%; 95% CI, 0.60%-2.03%; I = 0.99), ioversol (0.88%; 95% CI, 0.43%-1.83%; I = 0.96), iodixanol (0.85%; 95% CI, 0.36%-1.95%; I = 0.99), iopromide (0.82%; 95% CI, 0.43%-1.55%; I = 0.99), and iobitridol (0.77%; 95% CI, 0.36%-1.62%; I = 0.99). Multivariable meta-regression analysis revealed that study design (P = 0.0014) and premedication (P = 0.0230) were statistically significant determinants affecting the incidence of overall AARs. Iodinated contrast media type did not affect the incidence of overall and severe AARs (P = 0.1453 and 0.4265, each)., Conclusions: The varying pooled incidences of overall and severe AARs to specific types of nonionic ICM do not remain as significant after adjusting confounders. Our results may support nonrestriction of certain types of nonionic ICM in the context of AAR avoidance.

Objectives: Clinical guidelines recommend prophylactic intravenous fluids for patients with estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m to prevent adverse postcontrast outcomes. These patients represent a small minority of the population receiving intravascular iodinated contrast material, and data are not readily available. The current study aim is to gain insight into positive and negative effects of prophylaxis by comparing postcontrast outcomes in high-risk patients who did and did not receive prophylaxis., Materials and Methods: Observational data were gathered over 4 years. Inclusion criteria were age 18 years or older, eGFR less than 30 mL/min/1.73 m, and elective intravascular iodinated contrast administration. Exclusion criteria were dialysis and nonstandard periprocedural prophylaxis. Primary outcome was postcontrast acute kidney injury (>25% or >44 μmol/L serum creatinine increase within 2-5 days). Secondary outcomes were change in eGFR, 5 mL/min/1.73 m or greater eGFR decline, dialysis, and mortality at 1 month postcontrast including primary cause, as well as complications of prophylaxis. Results were stratified by contrast procedure type and corrected for potential confounders., Results: Of all 55,474 elective procedures with intravascular contrast administration, 362 patients met the inclusion criteria: 281 (78%) received standard 0.9% NaCl prophylaxis and 81 (22%) received no prophylaxis. Prophylaxis versus no prophylaxis adjusted odds ratios were nonsignificant and less than 1 for postcontrast renal outcomes (postcontrast acute kidney injury, eGFR decline, dialysis), indicating a trend toward a protective effect of prophylaxis. For mortality, adjusted odds ratios were nonsignificant and greater than 1, indicating a trend toward higher mortality risk after prophylaxis. Of the primary causes of death analyzed in prophylaxis patients, 24% (5/21) were related to prophylaxis. Among 281 prophylaxis patients, 18 (6.4%) complications of prophylaxis occurred: 15 heart failures and 3 arrhythmias., Conclusions: Based on this study, no standard recommendation with regard to giving or withholding prophylaxis can be given. Prophylactic fluids may confer some protection against postcontrast renal adverse events but may also contribute toward increased risk of short-term death. In this setting, benefits and risks of prophylaxis must be carefully weighed and cardiac parameters assessed for each individual patient.

Objective: The purpose of this study was to assess the rate and severity of breakthrough allergic-like reactions to gadobutrol., Materials and Methods: Under a waiver from our institutional review board, we performed a key word search of our institutional PACS (Picture Archiving and Communication System) database to identify all allergic-like reactions, which occurred in the setting of gadobutrol administration between December 2009 and August 2018, encompassing approximately 25,000 gadobutrol injections. Patients with an index allergic-like reaction who underwent a subsequent gadobutrol-enhanced magnetic resonance imaging after a standard 13-hour corticosteroid and antihistamine premedication protocol before repeat injection were identified. Patient characteristics, volume of gadobutrol injected, and severity of index and breakthrough reactions were recorded and compared by χ test, t test, and Spearman correlation., Results: The index allergic-like reaction rate to gadobutrol was 0.28% (69/25000). Of the patients who had an index allergic-like reaction, 45% (31/69) had a subsequent magnetic resonance imaging with gadobutrol injection and premedication with a breakthrough reaction rate of 35% (11/31). Most index reactions were mild in severity (91% [63/69]), and most breakthrough reactions were also typically mild (91% [10/11]). One patient escalated from a mild index reaction to a moderate breakthrough reaction despite premedication. There was no correlation between volume of gadobutrol injected (ρ = -0.004, P = 0.98) or association with age (P = 0.74), although female patients had higher breakthrough reaction rates (P = 0.007)., Conclusions: Allergic-like reactions to gadobutrol are rare; however, breakthrough reactions occur with moderate frequency despite premedication, and although generally of mild severity, in our series, one breakthrough reaction escalated in severity.

Introduction: The potential adverse renal outcome among patients undergoing iodine-based contrast-enhanced computerized tomography (CT) has been questioned recently, given the caution undertaken in patients' selection, hydration protocols, and the low radiocontrast volume, used with advanced imaging equipment., Materials and Methods: This study is a retrospective assessment of renal outcome in 12,580 hospitalized patients undergoing contrast-enhanced CT, compared with 754 patients subjected to gadolinium-based magnetic resonance imaging, with subsequent propensity matching for clinical characteristics and potential risk factors., Results: The risk of postcontrast acute kidney injury (PC-AKI) was found to be negligible as compared with patients undergoing enhanced magnetic resonance imaging studies, before and after propensity matching (8% vs 7.3% rate of AKI in the nonmatched iodine-based contrast agents [IBCAs] and gadolinium-based contrast agents [GBCAs], respectively, P = 0.3, and 7% in the matched IBCA group, P = 0.9), including comparisons among subgroups with well-defined risk factors such as chronic renal failure, diabetes, older age, and hypertension. However, lower systolic blood pressure before imaging was associated with higher risk to develop PC-AKI after IBCA administration but not with GBCA (for systolic blood pressure lower than 110 mm Hg, odds ratio for AKI after IBCA was 1.49; 95% confidence interval, 1.16-1.88, and after GBCA; odds ratio, 0.12; 95% confidence interval, 0.003-0.73)., Conclusions: With the current precautions undertaken, the real-life risk of PC-AKI among inpatients undergoing CT is insignificant. Possible reasons for the diverse impact of blood pressure on the propensity to develop acute kidney failure after iodine-based but not gadolinium-based enhancement imaging are discussed.

Background: Although it is generally acknowledged that exposure to iodine contrast agents can interfere with thyroid function, little is known about the incidence of iodine-induced hypothyroidism in young children (younger than the age of 4 years)., Study Objectives: This was a retrospective cohort study to estimate the incidence rate of detected hypothyroidism in a US-based general population of pediatric patients exposed to an iodinated contrast agent., Setting: The study was conducted in Kaiser Permanente Northern California, an integrated health care delivery system., Study Population: This study included 2320 pediatric patients younger than 4 years of age who had a diagnostic procedure with an iodinated contrast agent during years 2008 to 2016., Results: Among 2320 young children who met our study criteria, we identified 34 who met the initial criteria to be a case of hypothyroidism. The incidence density ratio for all hypothyroidism in iodine contrast agent-exposed patients was 1.33 per 1000 person months (95% confidence interval, 0.9-1.8). Most cases appeared to have subclinical hypothyroidism. The rate was higher for the probably iodine-induced cases (0.90 per 1000 person months) compared with cases with a possible alternate etiology (0.43 per 1000 person months), for males compared with females, and among children who had a heart catheterization compared with those with a computed tomography scan. It was also highest among the youngest children (younger than 3 months old), and decreased with increasing age., Discussion: Our finding of hypothyroidism in young children exposed to iodine contrast agents (1.33 per 1000 person months [95% confidence interval, 0.9-1.8]) is broadly consistent with the sparse literature on this outcome.

Objective: This study compares the incidence of new-onset symptoms within 24 hours after enhanced magnetic resonance imaging (eMRI) with intravenous administration of gadodiamide or gadoterate meglumine compared with a control group undergoing unenhanced MRI (uMRI)., Materials and Methods: A prospective cohort study (n = 1088 patients) was designed to assess the incidence of symptoms within 24 hours after administration of gadodiamide or gadoterate meglumine. The participants underwent a structured questionnaire by phone call before and 24 hours after the MRI scan to check for symptoms that were not present before the scan. The questionnaire included a list of active questions aimed to test the prevalence of symptoms that have been proposed in the debated definition of gadolinium deposition disease (GDD) and that we recorded in this study as GDD-like. In particular, the following symptoms and signs were tested: central torso pain, arm or leg pain, bone pain, headache, skin redness (any site of the body), fatigue, and mental confusion.Fisher exact test was used to test differences between groups with significance threshold set at P < 0.05., Results: Within the 24 hours after the MRI scan, 8.3% of patients reported at least one new-onset symptom in the uMRI group versus 17.4% in the gadodiamide eMRI versus 17.8% in the gadoterate meglumine eMRI group. The difference between the eMRI and the uMRI group was statistically significant (P < 0.001 for gadodiamide and P < 0.001 for gadoterate meglumine). There was not a different incidence of symptoms between the gadodiamide and the gadoterate meglumine eMRI groups. For gadodiamide, fatigue (P < 0.05) and dizziness (P < 0.05) were symptoms significantly more frequent than uMRI group; for gadoterate meglumine, fatigue (P < 0.01), mental confusion (P < 0.01), and diarrhea (P < 0.01) were significantly more frequent than uMRI group., Conclusions: We found that the onset of new symptoms within 24 hours after exposure to gadolinium-based contrast agent was more frequent than after uMRI. Among GDD-like symptoms, fatigue and mental confusion were the most frequent symptoms reported after eMRI. The other GDD-like symptoms were not overreported after eMRI versus uMRI. Thus, these results are questioning the term GDD.

Objectives: Recently, safety guidelines for the use of intravascular iodinated contrast material have been updated, and the recommended threshold for giving prophylaxis to prevent contrast-induced nephropathy (CIN) has been reduced to estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m. Data on this population in the context of CIN, especially evidence for efficacy of the recommendation of prophylactic intravenous hydration, are lacking. The aim of the current study was to test implicit assumptions underlying the guideline update: (1) patients with eGFR <30 mL/min/1.73 m, as opposed to former high-risk patients with eGFR ≥30 mL/min/1.73 m, are at high risk of CIN and other unfavorable outcomes after intravascular iodinated contrast material administration; (2) prophylactic intravenous hydration mitigates this risk; and (3) the risk of administering prophylactic intravenous hydration does not outweigh the positive preventive effect., Materials and Methods: Retrospectively, data were collected from all patients with eGFR <30 mL/min/1.73 m referred for an elective procedure with intravascular iodinated contrast material administration and excluded from the AMACING trial (A MAastricht Contrast-Induced Nephropathy Guideline trial). We compared these patients with those prospectively included in the AMACING trial (with eGFR 30-59 mL/min/1.73 m and risk factors). Main outcomes were CIN (defined as an increase in serum creatinine by more than 25% or 44 μmol/L within 2-6 days postcontrast exposure), dialysis and mortality within 35 days postcontrast exposure, and complications of prophylactic intravenous hydration., Results: A total of 28,803 patients referred for an elective procedure with intravascular iodinated contrast administration were prospectively screened for inclusion in the AMACING trial. One hundred fifty-seven (0.5%) patients had eGFR <30 mL/min/1.73 m, and 155 received intravascular iodinated contrast material. Standard prophylaxis was given to 119/155 of these patients. Data on 2- to 6-day serum creatinine, 35-day dialysis 35-day mortality, and complications of prophylactic intravenous hydration were available for 59/119 (50%), 118/119 (99%), 119/119 (100%), and 119/119 (100%) standard prophylaxis patients, respectively. Incidences in eGFR <30 mL/min/1.73 m versus AMACING patients are as follows: CIN 13.6% versus 2.7% (P = 0.0019); 35-day dialysis 0.9% versus 0.0% (P = 0.2646); 35-day mortality 9.2% versus 0.0% (P < 0.0001); complications of prophylactic intravenous hydration 5.9% versus 5.5% (P = 0.8529)., Conclusions: Postcontrast incidences of CIN and mortality at 35 days are significantly higher in the population with eGFR <30 mL/min/1.73 m than in the former high-risk population with eGFR 30 to 59 mL/min/1.73 m, even after prophylactic intravenous hydration. The risk of complications of prophylactic intravenous hydration is similar and substantial in both populations. Obtaining evidence from a randomized trial that efficacy of prophylactic intravenous hydration outweighs the risk of complications is important but may not be feasible.

The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis-like symptoms-including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).

Purpose: The aim of this study was to determine the severity of breakthrough reactions to gadobenate dimeglumine in patients premedicated with a 13-hour premedication regimen., Methods: Institutional review board approval was obtained and informed consent waived for this Health Insurance Portability and Accountability Act-compliant retrospective cohort study. All acute allergic-like reactions to gadobenate dimeglumine from 11/1/2008 to 1/31/2016 were identified. Of these, 19 allergic-like reactions followed 13-hour premedication: 150 mg prednisone and 50 mg diphenhydramine (ie, "breakthrough reactions"). Reasons for premedication, risk factors, index reaction characteristics, and breakthrough reaction characteristics were catalogued. Reaction severities were assigned using American College of Radiology guidelines. Severities of breakthrough (n = 19) and nonbreakthrough reactions (n = 97) were compared with the Cochran-Armitage test for trend., Results: Premedication was most commonly given (63% [12/19]) for a previous allergic-like reaction to gadolinium-based contrast material (GBCM); in 37% (7/19), it was given for a different risk factor. In those premedicated for a previous allergic-like reaction to GBCM of known severity (n = 9), the breakthrough reaction severity was the same as index reaction severity in 56% (5/9), less severe in 11% (1/9), and of greater severity in 33% (3/9). Two severe breakthrough reactions occurred; both were in subjects premedicated for risk factors other than a previous GBCM reaction. No subjects died. Five subjects were reexposed to GBCM a total of 9 times; no repeat breakthrough reactions occurred. Breakthrough reactions were more severe than nonbreakthrough reactions (P = 0.046), but the level of significance was borderline., Conclusion: Premedication does not eliminate severe reactions to gadobenate dimeglumine. Breakthrough reactions to gadobenate dimeglumine can be of greater severity than index reactions.

Objectives: The aim of this study was to critically assess the evaluation and categorization process for nephrogenic systemic fibrosis (NSF) based on reports received by Bayer from 2006 to 2016., Materials and Methods: A total of 779 NSF reports received by Bayer globally from 2006 to 2016 were included in the analysis. Arlington Medical Resources provided gadolinium-based contrast agent (GBCA) market share. Reports were conservatively categorized based on the Cowper/Girardi criteria. A statistical model simulated the impact of market share and market introduction on the number of unconfounded reports., Results: For all reports, reported onset of disease ranged from 1996 and 2012. Of 779 reports, 325 involved a Bayer product only, 208 involved only products from other companies (or unknown GBCA), and 246 involved both Bayer and non-Bayer products. Most of all reports (86%) originated from the United States.Through 2006, Magnevist and Omniscan dominated the US market (>80% combined market share). All other GBCAs with fewer NSF reports comprised the remaining combined market share of less than 20% or were introduced after May 2007, after safety recommendations came into effect.A total of 563 reports (220 single-agent and 343 multiagent reports) involved Magnevist. In at least 150 of the 343 reports, a different GBCA (Omniscan, 118; OptiMARK, 15; MultiHance, 6; and macrocyclic agent, 11) showed the closest temporal relationship to onset of NSF-like symptoms.The simulation model demonstrated that patients receiving a GBCA with lower market share and late market introduction are less likely to be observed in an unconfounded setting., Conclusions: Year of market introduction, as well as US market share in 2000 to 2007, greatly influenced the absolute number of NSF reports for each GBCA, their a priori probability to cause NSF, as well as their a priori probability to be associated with unconfounded cases of NSF. Variability in case interpretation and pharmacovigilance approaches also influence the absolute number of unconfounded cases and should therefore not be used for comparative risk assessments. This should be primarily based on objective product parameters such as structure, stability, pharmacokinetics, and dose.

Objectives: The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD)., Materials and Methods: Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified., Results: Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes., Conclusions: Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.

Objectives: The purpose of this study is to determine the frequency and severity of acute allergic-like reactions to gadolinium-based contrast media (GBCM) in children before, during, and after the transition from gadopentetate dimeglumine to gadoterate meglumine as our primary clinical GBCM., Materials and Methods: Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective investigation. Allergic-like reactions to GBCM in pediatric patients were retrospectively assessed from January 2009 to January 2017, which included a departmental change of GBCM from gadopentetate dimeglumine to gadoterate meglumine. Allergic-like reactions were identified from departmental and hospital databases. The number of doses of GBCM was obtained from billing data. Allergic-like reaction frequencies for each GBCM were calculated and compared using the chi-squared test., Results: A total of 32,365 administrations of GBCM occurred during the study period (327 for gadofosveset trisodium; 672 for gadoxetate disodium; 12,012 for gadoterate meglumine; and 19,354 for gadopentetate dimeglumine). Allergic-like reactions occurred after 21 (0.06%) administrations. Reaction frequencies were not significantly different among the GBCM (0.3% gadofosveset trisodium; 0% gadoxetate disodium, 0.06% gadoterate meglumine, 0.08% gadopentetate dimeglumine; P > 0.05). Ten (47.6%) reactions were mild, 10 (47.6%) were moderate, and 1 (4.8%) was severe. The overall reaction frequency peaked during the 6-month transition period from gadopentetate dimeglumine to gadoterate meglumine (0.20%), compared with 0.07% pretransition (P = 0.048) and 0.04% posttransition (P = 0.0095)., Conclusion: Allergic-like reactions to GBCM in children are rare. Gadoterate meglumine has a reaction frequency that does not significantly differ from other GBCMs. During the transition from gadopentetate dimeglumine to gadoterate meglumine, an increase in the frequency of reported allergic-like reactions was observed, likely reflective of the Weber effect.

Objectives: The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety., Material and Methods: This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization., Results: Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2β) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 μmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2.2%) experienced 1 rash of moderate intensity considered as related to gadoterate meglumine., Conclusions: The pharmacokinetic profile of gadoterate meglumine after a single intravenous injection of 0.1 mmol/kg was appropriately described in newborns and infants younger than 2 years, for whom no dose adjustment is required. The improved efficacy of gadoterate meglumine for contrast-enhanced MRI examination of brain, spine, and associated tissues, as well as its good safety profile, was also demonstrated in this population.

Objectives: The aim of this study was to examine the effects of perinatal exposure to gadolinium (Gd)-based contrast agents (GBCAs) on the behavior of adulthood offspring., Materials and Methods: Pregnant Balb/C mice (n = 5 per group) were intravenously injected with gadoterate meglumine (Magnescope, macrocyclic GBCA), gadodiamide (Omniscan, linear GBCA), or vehicle from pregnancy day 15 to 19, corresponding to embryonic day 15 to 19 of the fetus, at 2 mmol/kg body weight per day. Brain samples from dams and pups were collected on postpartum day 28. The total Gd concentration was quantified by inductively coupled plasma-mass spectrometry (dams, n = 3; gadoterate meglumine-treated pups group, n = 9; and gadodiamide-treated pups group, n = 10). Behavioral testing of offspring was started on postpartum day 70 (control group, n = 22; gadoterate meglumine-treated group, n = 23; and gadodiamide-treated group, n = 20)., Results: Higher levels of Gd retention were observed in dams and pups in the gadodiamide-treated group. Perinatal exposure to GBCAs caused anxiety-like behavior, disrupted motor coordination, impaired memory function, stimulated tactile sensitivity, and decreased muscle strength, particularly in the gadodiamide-treated group., Conclusions: In the present study, we showed that Gd was transferred to pups and was retained in their brain during postnatal development. Gadolinium retention may lead to impaired brain development. These findings indicate that the use of GBCAs in pregnant women should be avoided because it may have adverse effects on the fetus, particularly on brain development.

Objective: Bowel angioedema is an acute adverse reaction to iodinated contrast media (CM) that involves the gastrointestinal tract. We aimed to investigate the incidence and predisposing factors of iodinated CM-associated bowel angioedema during computed tomography (CT) examinations., Materials and Methods: This study was approved by our institutional review board, and informed consent was waived due to its retrospective design. From July 2013 to July 2015, adult patients with a history of adverse reactions to iodinated CM during CT (group A, n = 427) and patients without adverse reactions matched for age and sex with the propensity-score matching method (group B, n = 427) were studied. Contrast media-associated bowel angioedema was determined when bowel wall thickness increased after contrast enhancement compared with the precontrast scan. Potential predisposing factors including patient demographics, symptoms and time of adverse reactions, and CM-related factors were compared between patients with and without angioedema in group A. In addition, the incidence of bowel angioedema was compared between groups A and B., Results: The incidence of CM-associated bowel angioedema in group A was 3.3% (14/427) in the per-patient analysis and 2.6% (15/578) in the per-examination analysis. The CM-associated bowel angioedema involved the distal duodenum and/or proximal jejunum and showed long-segmental circumferential bowel wall thickening on CT. None of the studied predisposing factors was different between patients with and without bowel angioedema (P > 0.05). The incidence of CM-associated bowel angioedema in group B was 1.9% (8/427) and 1.7% (8/458) for per-patient and per-examination analyses, respectively, and these rates were not significantly different between groups A and B (P = 0.346 and P = 0.370, respectively)., Conclusions: The incidence of CM-associated bowel angioedema during CT was 1.7% to 3.3%, and none of the studied predisposing factors was associated with bowel angioedema.

For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents-specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)-for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.

Objectives: Retrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution., Materials and Methods: Fifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet [Nissl]) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively., Results: No histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological nephrogenic systemic fibrosis-like skin lesions. The Gd concentrations observed in the skin/brain samples (in nanomole Gd per gram of tissue) for each agent were as follows: gadodiamide: 1472 ± 115/11.1 ± 5.1, gadopentetate dimeglumine: 80.8 ± 6.2/13.1 ± 7.3, gadobutrol: 1.1 ± 0.5/0.7 ± 0.4, and gadoteridol: 1.7 ± 0.8/0.5 ± 0.2. The average detected residual Gd concentration in the brain was approximately 15-fold higher for linear than for macrocyclic GBCAs. The highest amounts of Gd found in brain corresponded to less than 0.0002% of the injected dose per gram of tissue. Using LA-ICP-MS, high Gd concentrations in the deep cerebellar nuclei and in the granular layer of the cerebellar cortex were detected only for linear gadodiamide and gadopentetate dimeglumine but not for gadoteridol or gadobutrol. The energy dispersive x-ray spectroscopy analysis revealed Gd-containing spots in the skin of animals administered gadodiamide and gadopentetate dimeglumine. Transmission electron microscopy revealed several Gd-containing spots in the region of the dentate nuclei in the brain of 1 animal injected with gadodiamide., Conclusions: After repeated high dosing, nephrogenic systemic fibrosis-like macroscopic and histopathological lesions of the skin were observed only in some of the gadodiamide-treated animals. No histopathological findings were detected in the rodent brain. The administration of linear GBCAs was associated with significantly higher Gd concentrations in the brain and skin compared with macrocyclic GBCA administration. The results of LA-ICP-MS demonstrated local accumulation of Gd within the deep cerebellar nuclei and the granular layer only after the administration of linear agents. In summary, the detected low Gd concentrations in the skin and brain were well correlated with the higher kinetic stability of macrocyclic GBCA.

Objective: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF)., Materials and Methods: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period., Results: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF., Conclusions: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases., Competing Interests: and source of funding: M.A., H.D., G.B., M.G., R.W., W.K., and F.D.C. have no conflicts of interest to disclose. H.M., B.E.-W., and R.H. received honoraria and/or research grants from Bayer. M.R., T.B., and J.E. are Bayer employees. The study was funded by Bayer Pharma AG.

Objectives: The aim of this study was to produce and evaluate a proposed computed tomography (CT) contrast agent based on carboxybetaine zwitterionic (CZ)-coated soluble tantalum oxide (TaO) nanoparticles (NPs). We chose tantalum to provide superior imaging performance compared with current iodine-based clinical CT contrast agents. We developed the CZ coating to provide biological and physical performance similar to that of current iodinated contrast agents. In addition, the aim of this study was to evaluate the imaging, biological, and physicochemical performance of this proposed contrast agent compared with clinically used iodinated agents., Materials and Methods: We evaluated CT imaging performance of our CZ-TaO NPs compared with that of an iodinated agent in live rats, imaged centrally located within a tissue-equivalent plastic phantom that simulated a large patient. To evaluate vascular contrast enhancement, we scanned the rats' great vessels at high temporal resolution during and after contrast agent injection. We performed several in vivo CZ-TaO NP studies in healthy rats to evaluate tolerability. These studies included injecting the agent at the anticipated clinical dose (ACD) and at 3 times and 6 times the ACD, followed by longitudinal hematology to assess impact to blood cells and organ function (from 4 hours to 1 week). Kidney histological analysis was performed 48 hours after injection at 3 times the ACD. We measured the elimination half-life of CZ-TaO NPs from blood, and we monitored acute kidney injury biomarkers with a kidney injury assay using urine collected from 4 hours to 1 week. We measured tantalum retention in individual organs and in the whole carcass 48 hours after injection at ACD. Carboxybetaine zwitterionic TaO NPs were synthesized and analyzed in detail. We used multidimensional nuclear magnetic resonance to determine surface functionality of the NPs. We measured NP size and solution properties (osmolality and viscosity) of the agent over a range of tantalum concentrations, including the high concentrations required for standard clinical CT imaging., Results: Computed tomography imaging studies demonstrated image contrast improvement of approximately 40% to 50% using CZ-TaO NPs compared with an iodinated agent injected at the same mass concentration. Blood and organ analyses showed no adverse effects after injection in healthy naive rats at 3 times the ACD. Retention of tantalum at 48 hours after injection was less than 2% of the injected dose in the whole carcass, which very closely matched the reported retention of existing commercial iodine-based contrast agents. Urine analysis of sensitive markers for acute kidney injury showed no responses at 1 week after injection at 3 times the ACD; however, a moderate response in the neutrophil gelatinase-associated lipocalin biomarker was measured at 24 and 48 hours. Compared with other TaO NPs reported in the literature, CZ-TaO NPs had relatively low osmolality and viscosity at concentrations greater than 200 mg Ta/mL and were similar in these physical properties to dimeric iodine-based contrast agents., Conclusions: We found that a CZ-TaO NP-based contrast agent is potentially viable for general-purpose clinical CT imaging. Our results suggest that such an agent can be formulated with clinically viable physicochemical properties, can be biologically safe and cleared rapidly in urine, and can provide substantially improved image contrast at CT compared with current iodinated agents., Competing Interests: The authors declare no conflicts of interest.

Objectives: The aim of this study was to determine whether intra-arterial administration of contrast material is associated with a higher risk of acute kidney injury (AKI) compared with that of intravenous (IV) administration in a cohort of patients that received both routes of administration., Materials and Methods: All patients who received both a contrast-enhanced computed tomography (CT) and a diagnostic or interventional cardiac catheterization between 2000 and 2014 were identified. Patients who lacked sufficient preprocedure and postprocedure serum creatinine results, who were on preexisting renal dialysis, or who underwent additional contrast-enhanced procedures within 7 days of either procedure were excluded. The rate of AKI (serum creatinine ≥0.3 mg/dL or 50% above baseline) was compared after CT scan and cardiac catheterization using McNemar test., Results: A total of 1969 patients met all study inclusion criteria. The rate of AKI after CT scan was similar to the rate after catheterization when examining all patients (9.9% CT vs 11% catheterization, P = 0.12). A similar rate of AKI after both procedures was observed regardless of procedure order, catheterization type, and patient baseline estimated glomerular filtration rate., Conclusions: Intra-arterial administration of contrast material during cardiac catheterization had a similar risk of AKI as compared with that of CT scanning involving IV administration in a cohort of patients who underwent both procedures. These findings suggest that previously reported much higher rates of AKI after cardiac catheterization compared with that of IV contrast administration reflect higher baseline clinical risk factors for AKI in the former cohort compared with that in the latter.

Objective: The purpose of this study was to assess the incidence of nephrogenic systemic fibrosis (NSF) before and after educational interventions, implementation of a clinical screening process, and change to gadobenate dimeglumine in patients who had an estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.72 m or less., Methods: This is a Health Insurance Portability and Accountability Act compliant, institutional review board exempt study. Two periods were studied-July 2005 to June 2006, during which gadodiamide was utilized as our magnetic resonance (MR) contrast agent, and November 2006 to August 2014, during which gadobenate dimeglumine was used as our MR contrast agent in patients who had an eGFR 30 mL/min per 1.72 m or less. In addition to a change in the MR contrast agent, education of our staff physician to the risks of NSF with MR contrast agents and the implementation of a clinical screening process occurred. The rate of NSF before and after the interventions was compared using the χ test., Results: There was a statistically significant difference in the incidence of NSF in patients with an eGFR 30 mL/min per 1.72 m or less between the 2 periods: July 2005 to June 2006, 6 of 246 patients were diagnosed with NSF (P < 0.001), versus November 2006 to August 2014, 0 of 1423 patients were diagnosed with NSF., Conclusions: Our data demonstrates a marked decrease in the incidence of NSF after education of our referring physicians, implementation of clinical screening process, and change to gadobenate dimeglumine from gadodiamide in patients with renal insufficiency. This approach potentially provides an acceptable risk-benefit profile for patients with renal insufficiency that required MR imaging for clinical care.

Objective: The aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine., Materials and Methods: Forty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998-2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups., Results: In the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups.The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea.For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded., Conclusions: Gadobutrol is well tolerated and has a favorable safety profile for patients of all age groups.

Objective: The aim of this study was to evaluate the safety profile of gadoterate meglumine from clinical trials, postmarketing observational studies, and pharmacovigilance reports of adverse drug reactions (ADRs) encompassing 25 years of clinical use and over 50 million administered doses., Materials and Methods: Assessment of the safety of gadoterate meglumine through processing and review of all safety data was collected after magnetic resonance imaging procedures. All ADRs originated from 3 major sources: (1) a clinical study database including 50 phase I to IV studies involving 2822 patients, (2) a safety database including 8 postmarketing safety studies (PMSs) involving 151,050 patients, and (3) a pharmacovigilance database compiling safety experience following over 50 million doses administered between March 1989 and September 2015., Results: Among the 2822 patients receiving gadoterate meglumine in the clinical trials, 241 (8.5%) experienced 405 postinjection adverse events (AEs), considered related to the contrast agent for 113 patients (4.0%). Serious AEs were reported for 27 patients (1.0%) and assessed as related to gadoterate meglumine for 2 patients (0.07%). None of the PMS studies showed evidence of unexpected safety issues, with a very low rate of AEs (<1%). Postmarketing safety experience with over 50 million doses of gadoterate meglumine prescribed for 25 years of approved use worldwide compiled spontaneous reports for 3797 patients who experienced 8397 ADRs, yielding a very low reported incidence of ADRs of 0.007% of patients. There was no single-agent case of confirmed nephrogenic systemic fibrosis with gadoterate meglumine either from clinical development programs or from postmarketing experience., Conclusions: Based on clinical trials, postmarketing observational studies and pharmacovigilance data, a very low incidence of ADRs was reported with gadoterate meglumine, which has no impact on its favourable benefit-risk ratio.

Objective: The aims of this study were to objectively evaluate patient respiration and breathing change after contrast injection and to assess its potential impact on image quality for the hepatic arterial phase in gadoxetic acid-enhanced magnetic resonance imaging., Materials and Methods: This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. One hundred fifty-four patients underwent gadoxetic acid-enhanced liver magnetic resonance imaging with a 13-second breath-hold hepatic arterial phase. During the acquisition of precontrast and hepatic arterial phases, the respiratory motion signal was acquired and graded on a 4-point scale based on the SD of the respiratory waveform, with the highest grade indicating the worst breath-hold. Breath-holding grades 3 and 4 for the hepatic arterial phases were considered as breath-holding difficulty during the hepatic arterial phase. Gadoxetic acid-related dyspnea was defined as when the SD value of respiratory waveform during the hepatic arterial phase was 200 greater than that of the precontrast image. Then, the precontrast and hepatic arterial phase images were evaluated with respect to overall image quality and motion artifact using a 5-point scale, with the highest score indicating the worst image quality. In the hepatic arterial phase, the correlation between breath-holding degree and image quality parameters was evaluated using Pearson correlation. The differences in mean image quality scores between patients with and without gadoxetic acid-related dyspnea were evaluated using Student t test., Results: Based on the analysis of the respiratory waveforms, the incidence of breath-holding difficulty during the hepatic arterial phase was 23.4% (33/154), and the incidence of gadoxetic acid-related dyspnea was 6.5% (10/154). By image analysis, the incidence of a degraded hepatic arterial phase (overall image quality score ≥4) was 5.2% (8/154). During the hepatic arterial phase, the breath-holding degree correlated with overall image quality and motion artifacts (r = 0.564 and 0.578, respectively). Patients with gadoxetic acid-related dyspnea showed significantly worse image qualities of the hepatic arterial phase than patients without gadoxetic acid-related dyspnea (all, P < 0.001), although image qualities for the precontrast image were not statistically significant between the 2 groups (all, P > 0.05)., Conclusions: The objective analysis of respiratory patterns during a breath-hold is feasible and useful for evaluating gadoxetic acid-related dyspnea and its effect on image quality analysis.

Objectives: This clinical study evaluated the pharmacokinetics (PK) and safety data of macrocyclic extracellular contrast agent gadobutrol in pediatric subjects aged younger than 2 years., Materials and Methods: Pediatric subjects (term newborns to those aged younger than 2 years) with normal renal function undergoing magnetic resonance imaging with gadobutrol (0.1 mmol/kg body weight [BW]) were prospectively enrolled in this open-label, multicenter clinical trial to evaluate PK as a primary end point. Plasma PK was analyzed using a population-based PK approach. Safety and qualitative efficacy (evaluation of images) were secondary end points. Safety and tolerability were assessed throughout study participation (approximately 7 days). Imaging efficacy variables were assessed by investigators., Results: Forty-four subjects were evaluated for safety and efficacy; 43 subjects were eligible for PK evaluation including 9 term newborns and infants aged younger than 2 months. Gadobutrol PK in pediatric subjects aged younger than 2 years were adequately described by a linear 2-compartmental model with elimination from the central compartment. Total median systemic exposure (area under the curve) of gadobutrol was estimated at 776 μmol · h/L (range, 544-1470 μmol · h/L). Simulated median concentration at 20 minutes after injection of gadobutrol (C20) was 339 μmol/L (range, 230-456 μmol/L). Safety and tolerability profile were similar to older populations. In 1 subject (2.3%), vomiting was reported as a mild adverse event related to gadobutrol, and there were no reported serious adverse events. The evaluation of gadobutrol-enhanced images provided improved diagnosis, increased confidence in diagnosis, and contributed to subject clinical management., Conclusions: The PK profile of gadobutrol in children aged younger than 2 years including newborns is similar to that in older children and adults. At the dose of 0.1 mmol/kg BW, gadobutrol had a favorable safety profile and was well tolerated with similar profile across the age range 0 to younger than 2 years and compared with older children and adults. Extrapolation of efficacy data from adults to the younger pediatric population, including term newborns, is justified. The recommended standard dose of gadobutrol (0.1 mmol/kg BW), as used in the population aged 2 years and older, is also appropriate in children aged younger than 2 years.

The dentate nucleus of the cerebellum may appear as hyperintense on unenhanced T1 magnetic resonance images (MRIs) of the brain. Recently, T1 signal hyperintensity has received attention owing to data on the association of this finding with the history of multiple injections of gadolinium-based contrast agents, specifically gadodiamide, in patients with multiple sclerosis and brain metastases. We conducted a retrospective study on patients with a meningioma who had routinely undergone follow-up enhanced MRI scans with gadodiamide. Across a time interval of 18 months (from January 2013 to July 2014), we identified 102 consecutive patients eligible for this study. A significant increase in T1 hyperintensity of the dentate nuclei of the cerebellum on nonenhanced scans was observed between the first and the last MRI in the group of patients with a history of at least 6 enhanced MRI scans (P < 0.01), whereas no differences were observed in the group with 1 to 5 enhanced MRI scans (P = 0.74). Further research is necessary to shed light on the mechanism of the T1 hyperintensity as well as on the histological and microstructural appearance of the dentate nucleus after multiple intravenous injections of gadodiamide. The finding raises the question of substantial dechelation of this agent in patients with normal renal function.

Objective: The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment., Materials and Methods: We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period., Results: A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up., Conclusions: Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed.

Objectives: The objective of this study was to assess whether streptozotocin (STZ)-induced diabetic rats develop iodinated contrast-induced acute kidney injury. The intrarenal R2* (=1/T2*) was evaluated continuously before, during, and after contrast administration. Renal injury was confirmed using urinary neutrophil gelatinase-associated lipocalin measurements., Materials and Methods: Six Sprague-Dawley rats were administered with STZ to induce diabetes (group 1). R2* was measured before, during, and after administration of iodixanol. R2* readings were sampled from 4 renal regions: inner medulla, inner stripe of outer medulla (ISOM), outer stripe of outer medulla, and cortex. Peak R2* and initial upslope of R2* increase after iodinated contrast were calculated. Data from 12 nondiabetic rats pretreated with nitric oxide synthase and prostaglandin inhibitors to induce susceptibility to contrast-induced acute kidney injury (pretreatment model) from a previous study were reanalyzed for peak R2* and initial upslope of R2* increase after contrast. Six of these animals received saline (group 2), and the other 6 received furosemide (group 3) before iodixanol., Results: Peak R2* and initial upslope of R2* increase were used as blood-oxygenation-level-dependent response parameters. R2* in ISOM was comparable in all 3 groups before administration of furosemide/saline. Except for the furosemide group, ISOM showed a rapid increase in R2* immediately after contrast administration. Unlike the L-NAME- and indomethacin-treated groups, the diabetic group showed a quick reversal of R2* toward baseline measurements after contrast administration. Urinary neutrophil gelatinase-associated lipocalin indicated significant increase in diabetic rats 4 hours after contrast administration. The observed trends with peak R2* and initial upslope of R2* increase in renal ISOM were in agreement with those of urinary neutrophil gelatinase-associated lipocalin., Conclusions: The STZ-induced diabetic rat may be suitable for studying the effects of iodinated contrast on renal oxygenation status and may mimic human condition closer than the pretreatment model described before. The peak R2* value and initial upslope of R2* in ISOM appear to be effective magnetic resonance imaging markers to predict renal injury after administration of an iodinated contrast agent.

Purpose: The aim of this preclinical study on healthy Sprague-Dawley rats was to determine whether differences exist in the induction of adverse skin reactions after the intravenous administration of a monomeric and 2 dimeric iodinated nonionic contrast agents., Materials and Methods: After intravenous injection of iopromide (monomeric), iodixanol (dimeric), and iotrolan (dimeric) at a dose of 4 g iodine/kg of body weight, mechanical ear volume measurements (10 minute after injection) and intravital microscopy (baseline, 5 minutes after injection) of the ear with the near-infrared dye indocyanine green were performed to determine the volume change and plasma extravasation. Histopathological analysis (20 minutes, 1 hour, and 3 hours after injection) was performed to diagnose alterations in the skin. Blood plasma was analyzed to identify elevated levels of histamine (5 minutes after injection) and inflammatory markers (a multianalyte profile of 58 markers; 1 hour and 3 hours after injection)., Results: Only iodixanol induced immediate angioedema formation, with a 100% incidence rate and with slight mast cell infiltration in the ear, muzzle, and paws. The ear showed a 53% volume increase and strong extravasation of plasma proteins into the interstitium, which correlated with highly (11-fold) increased plasma histamine levels 5 minutes after injection. Elevated levels of tumor necrosis factor-α (7.1-fold), macrophage inflammatory protein (MIP)-1α (3.2-fold), and MIP-2 (7.7-fold) were identified 1 hour after the iodixanol injection. Increased levels (fold-change) of MIP-1β (14; 6.3), monocyte chemotactic protein-1 (3.3; 3.7), monocyte chemotactic protein-3 (2.4; 3.0), stem cell factor (1.7; 2), vascular endothelial growth factor (2; 2.1), and interferon gamma-induced protein-10 (4.1; 39.1) were identified 1 hour and 3 hours after the iodixanol administration, respectively. The level of these molecules remained unchanged after the iopromide and iotrolan injections (except for stem cell factor)., Conclusions: A reversible anaphylactoid-like reaction in healthy Sprague-Dawley rats was observed after the iodixanol administration but not after the monomeric iopromide or dimeric iotrolan injections. Therefore, we conclude that the induction of adverse skin reactions is not per se because of a class effect of dimeric contrast agent.