Hypothyroidism in Young Children Following Exposure to Iodinated Contrast Media: An Observational Study and a Review of the Literature.

While it is well documented that exposure to iodinated contrast media (ICM) can interfere with thyroid function in adults, much less is known about the incidence and risk factors associated with ICM induced hypothyroidism in young children. Using a computerized database we identified 843 children who were exposed to ICM between 1998 and 2015. The incidence rate of ICM induced hypothyroidism per 1000 person-years was 9.66 (95% CI: 4.17-19.04). When compared to the rest of the cohort, children with hypothyroidism were more likely to be younger, weigh less and to have undergone cardio-angiography. These results are supported by findings described in the literature review. The risk of ICM- induced hypothyroidism needs to be considered especially in young children with low weight, undergoing cardio-angiography examinations. Systematic monitoring of thyroid function should be conducted in this focused patient population to avoid potential adverse consequences on child development.

Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study.

OBJECTIVES: To investigate the safety and tolerability of gadobutrol at the recommended dose in patients requiring contrast-enhanced magnetic resonance imaging/angiography (MRI/MRA) in the routine setting. METHODS: GARDIAN prospectively enrolled 23,708 patients undergoing routine gadobutrol-enhanced MRI/MRA for approved indications at 272 study centres in Europe, Asia, North America, and Africa and monitored for adverse events. RESULTS: Median gadobutrol dose was 0.11 mmol/kg body weight. The overall incidence of adverse drug reactions (ADRs) was 0.7 % (n = 170 patients), with similar incidences in patients with renal impairment or cardiac disease, from different geographic regions and in different gadobutrol dose groups. Patients at risk for contrast media reaction had an ADR incidence of 2.5 %. Five patients (0.02 %) experienced serious adverse events, four were drug-related. One patient experienced a fatal anaphylactoid shock, assessed to be related to injection of gadobutrol. The contrast quality of gadobutrol-enhanced images was rated by treating physicians as good or excellent in 97 % cases, with similar ratings in all patient subgroups and indications. CONCLUSIONS: The GARDIAN study shows that gadobutrol at the recommended dose is well tolerated across a large, diverse patient population. KEY POINTS: • Gadobutrol at recommended dose shows low rates of adverse drug reactions • Gadobutrol demonstrates a uniform safety profile across diverse patient groups • Gadobutrol provides excellent contrast quality in routine practice.

Safety of gadobutrol in more than 1,000 pediatric patients: subanalysis of the GARDIAN study, a global multicenter prospective non-interventional study.

BACKGROUND: Gadobutrol is a gadolinium-based contrast agent, uniquely formulated at 1.0 mmol/ml. Although there is extensive safety evidence on the use of gadobutrol in adults, few studies have addressed the safety and tolerability of gadobutrol in pediatric patients. OBJECTIVE: This subanalysis of data from the GARDIAN study evaluated the safety and use of gadobutrol in pediatric patients (age <18 years). MATERIALS AND METHODS: The GARDIAN study was a large phase IV non-interventional prospective multicenter post-authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial or spinal MRI, liver or kidney MRI, or MR angiography with gadobutrol enhancement. The primary study endpoint was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following gadobutrol administration. RESULTS: The GARDIAN study included 1,142 children (age <18 years) who received gadobutrol at a mean dose of 0.13 (range 0.04-0.50) mmol/kg body weight. Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. Investigators rated the contrast quality of gadobutrol-enhanced images as good or excellent in 97.8% of pediatric patients, similar to the main study population. CONCLUSION: Gadobutrol is very well tolerated and provides excellent contrast quality at the recommended weight-adjusted dose in children (age <18 years), similar to the profile in adults.

Safety and tolerability of iopromide intravascular use: a pooled analysis of three non-interventional studies in 132,012 patients.

BACKGROUND: Determining the safety of contrast agents is challenging. In the absence of large controlled clinical trials, non-interventional (post-marketing surveillance) studies provide an opportunity to clearly investigate the safety profile of contrast agents. PURPOSE: To assess the safety profile of iopromide in contrast-enhanced X-ray in clinical practice, using pooled data from three non-interventional studies. MATERIAL AND METHODS: All studies were international, multicenter, non-interventional studies examining iopromide tolerability in clinical practice. Patients received iopromide (iodine concentrations of 300 mg/mL or 370 mg/mL) via intravenous or intra-arterial administration according to the diagnostic indication and in compliance with the local package insert. RESULTS: In total, 132,012 patients (37 countries, >1600 centers) were included. Overall, 3823 patients (2.49%) reported an adverse drug reaction (ADR) and 1983 patients (1.50%) reported an ADR without tolerance indicators (injection site warmth, feeling hot or injection site pain, of mild intensity only). This is a similar rate to other low osmolar contrast media. In most patients, ADRs were mild (n = 2632; 1.99% of all patients) and did not require any action (n = 2799; 2.12% of all patients). ADRs were more common among women (n = 1680 [2.8%]) than men (n = 1586 [2.2%]) and among younger patients (<18 years: n = 98 [3.2%]) than older patients (18-49 years: n = 1261 [3.5%]; 50-69 years: n = 1224 [2.2%]; ≥70 years: n = 362 [1.5%]). The most common ADRs were injection site warmth/feeling hot, nausea/vomiting, and dysguesia. Forty-five serious ADRs were reported in 19 patients. ADRs were more common in at-risk patients (5.00%) than in the overall population. CONCLUSION: This pooled analysis confirms the well-established good safety profile of iopromide in clinical practice in Asian and European countries and the USA.

Relationship of Dose and Signal Enhancement Properties of Gadoquatrane, a New Tetrameric, Macrocyclic Gadolinium-Based Contrast Agent, Compared With Gadobutrol: A Randomized Crossover Study in Healthy Adults.

OBJECTIVES: To investigate the signal-enhancement properties of the tetrameric gadolinium-based contrast agent (GBCA) gadoquatrane in relation to the administered dose and compare its properties to those of a standard dose of gadobutrol, as a representative of the currently established macrocyclic GBCAs for magnetic resonance imaging. MATERIALS AND METHODS: In this randomized, single-blind, 4 × 4 crossover study, 43 healthy adults (19-50 years of age) received 3 single IV injections of gadoquatrane (0.01, 0.03, and 0.06 mmol gadolinium/kg body weight) and 1 injection of gadobutrol (0.1 mmol gadolinium/kg body weight) in randomized sequence with 1-week washout periods between administrations. The relative signal enhancement (RSE) was determined in predefined areas of interest in magnetic resonance image sets of the head-neck region. RSE-vs-dose curves (dose-response curves) were established by linear regression, and comparator-equivalent doses were determined by Bayesian inverse regression analysis. Further, 3 blood samples were taken after each injection for pharmacokinetic analyses, and safety data were assessed. RESULTS: The RSE increased with gadoquatrane dose. A linear function adequately fitted this relationship. In line with the more than 2-fold higher r1 relaxivity of gadoquatrane per gadolinium ion, gadobutrol-equivalent RSE was achieved with gadoquatrane at less than half the gadolinium dose and less than one eighth of the molecule dose.Administration of gadoquatrane and gadobutrol resulted in very similar dose-normalized gadolinium concentrations in plasma, indicating that the pharmacokinetic profiles are essentially the same. Both contrast agents were well tolerated. Adverse events were rare and not dependent on the dose administered. CONCLUSIONS: Gadoquatrane has the potential to be an effective GBCA that can be used at substantially lower doses in clinical routine than the currently established macrocyclic GBCAs.

Safety and diagnostic image quality of iopromide: results of a large non-interventional observational study of European and Asian patients (IMAGE).

BACKGROUND: Iodine-based contrast agents such as iopromide play a central role in improving the diagnostic quality of imaging modalities using ionizing radiation. PURPOSE: To investigate the safety and diagnostic image quality of iopromide in the routine clinical setting. MATERIAL AND METHODS: This was an international, multicenter, prospective, single-arm, non-interventional study (NIS). The study was performed in out- and inpatients in 738 study centers in 21 countries in Europe and Asia. Iopromide was administered in a routine manner, in compliance with the local package insert. The use of premedication was at the discretion of the attending physician. Case report forms for 44,835 patients were analyzed (57.4% men). The median age of the patients was 55 years. RESULTS: For the vast majority of patients (94.8%), the contrast quality was rated as 'good' (55.8%) or 'excellent' (39.0%). For 1265 (2.8%) patients, there were reports of adverse drug reactions (ADRs) excluding tolerance indicators (TIs) (i.e. injection site warmth, feeling hot, or injection site pain of mild intensity). At least one ADR including TIs was reported in 2415 (5.4%) patients. There were 11 (0.02%) patients with serious ADRs, and no drug-related deaths. Events of injection site warmth and/or feeling hot were reported by 3.5%, nausea and/or vomiting by 0.96%, and urticaria, erythema, and/or rash by 0.54% of patients. Patients at risk for an acute idiosyncratic reaction (i.e. patients with a history of bronchial asthma, allergies, and/or contrast media reaction) had a higher incidence of ADRs compared with the overall study population. At-risk patients who did not receive premedication reported distinctly more ADRs compared with those who received premedication (12.0% versus 5.9%). CONCLUSION: Iopromide was shown to be a well-tolerated contrast agent whose usage resulted in high image quality. No unknown ADRs were observed. Premedication with antiallergy drugs should be considered in at-risk patients.

Developments in X-Ray Contrast Media and the Potential Impact on Computed Tomography.

Over the past 120 years, continuous developments in medical imaging has improved diagnosis and treatment for many diseases and has thereby improved treatment outcome and quality of life of many patients. The number of computed tomography (CT) examinations is today increasing by 4% per year worldwide, for a total of approximately 300 million CT scans per year. About 40% of CT scans are contrast enhanced. Intravenous iodinated contrast media are commonly used for contrast enhancement in CT scans to evaluate diseases and determine treatment response. The current gold standards for intravenous x-ray contrast media in CT or interventional angiography are iodinated low- and iso-osmolar compounds such as iopromide, iohexol, or iodixanol. Both classes have similar and favorable efficacy and safety profiles. Although iodine is biologically inert, iodinated contrast media can cause adverse reactions. In the future, one possibility would be to develop iodine-free contrast media that are better suited to higher x-ray tube voltage ranges, allowing greater flexibility for scanning protocols and thus leading to techniques that can provide equivalent diagnostic value at lower doses of radiation. Iodine-free contrast media would in addition provide an alternative to the market standard that could offer benefits for patients with known reactions to low-osmolality contrast media or thyroid disorders. The development of a new contrast medium, however, needs to be put in context with all upcoming technological advances in x-ray and CT. New detector technologies and artificial intelligence algorithms will in the future also improve the CT image reconstruction enabling the reduction of contrast media and radiation doses.

Iodinated Contrast Agents and Risk of Hypothyroidism in Young Children in the United States.

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.

Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use.

PURPOSE: We evaluated the safety of gadopentetate dimeglumine (Gd-DTPA), the first contrast agent for magnetic resonance imaging, using pharmacovigilance data for spontaneously reported adverse events (AEs) after 120 million cumulative administrations worldwide. METHODS: We analyzed spontaneously reported AEs for Gd-DTPA for pre-specified time periods between 1988 and 2011. RESULTS: Since the market introduction of Gd-DTPA in 1988, its global utilization reached 120 million cumulative administrations in 2011, more than 80% of which was by the USA, countries in the European Union (EU), and Japan. The global AE reporting rate was 21.2 in 100,000 administrations in 1988 and 14.4 in 100,000 administrations by 2011. Regional differences included higher reporting rates in the USA and Japan, and reporting rates lower than global rates in the EU. The reported rate of global serious AEs changed from 1.4 in 100,000 administrations in 1988 to 4.0 in 100,000 administrations in 2011. The highest number of reports of nephrogenic systemic fibrosis (NSF) was received from 2006 to 2008. Since 2009, no report of a current onset of NSF has been received. The reduced report rate of NSF may be due to increased awareness about the use of gadolinium-based contrast agents (GBCAs). CONCLUSION: After more than 120 million cumulative administrations, Gd-DTPA is a widely used GBCA that shows a consistently low and stable incidence of AEs.

Evaluation of the effect of two gadolinium-containing contrast-enhancing agents, gadobutrol and gadoxetate disodium, on colorimetric calcium determinations in serum and plasma.

OBJECTIVE: To determine the extent to which the gadolinium-containing contrast agents, gadobutrol (Gadovist) and gadoxetate disodium (Primovist/Eovist), interfere with the colorimetric measurement of calcium concentrations in serum and plasma. MATERIALS AND METHODS: Gadobutrol and gadoxetate disodium were added in various concentrations to serum and plasma from healthy volunteers; the calcium concentration in these samples was then measured by standard colorimetry methods and atomic absorption. RESULTS: At clinically relevant concentrations, neither gadobutrol nor gadoxetate disodium influenced the results of the calcium measurement in serum or plasma. Only at the highest concentrations tested (50 mM gadobutrol; 25 mM gadoxetate disodium), an effect was seen in some cases. Results were confirmed by atomic absorption spectroscopy as the reference method. CONCLUSIONS: At clinically relevant concentrations, gadobutrol and gadoxetate disodium did not interfere with standard colorimetric methods for calcium determination.

Prevalence of acute adverse reactions to gadobutrol--a highly concentrated macrocyclic gadolinium chelate: review of 14,299 patients from observational trials.

OBJECTIVE: To determine the safety and tolerability of gadobutrol in a large number of non-selected patients from routine clinical radiology practices. MATERIALS AND METHODS: Six prospectively planned, observational surveillance studies were conducted at more than 300 institutions in Europe and Canada from 2000 to 2007. Demographic and medical status data, details of the diagnostic procedure, contrast agent administration and adverse drug reaction (ADR) data were collected using a standardized questionnaire. RESULTS: A total of 14,299 patients were enrolled. The mean age of the patients was 53.7 years; 1.3% of the patients were <18 years old and 40.8% were 60 years or older. The body regions most frequently examined were head/neck/brain (54.3%), followed by spine (7.2%), pelvis/joints/limbs (6.7%) and multiple body regions (6.4%). Gadobutrol-enhanced magnetic resonance angiography (MRA) was performed in 14.7% of patients. Overall, the mean volume of gadobutrol administered for contrast-enhanced magnetic resonance imaging was 12 mL (0.16 mmol gadolinium [Gd]/kg body weight [BW]; mean BW: 75.5 kg), whereas for contrast-enhanced MRA the mean volume was 15.7 mL (0.21 mmol Gd/kg BW). Seventy-eight of the 14,299 patients (0.55%) reported at least one ADR. Two (0.01%) serious ADRs were reported. The most frequently reported ADR was nausea, which occurred in 36 patients (0.25%). CONCLUSION: Gadobutrol 1.0M is very well tolerated and has a good safety profile. The occurrence of ADRs observed following the intravenous injection of gadobutrol is comparable with the published data of other Gd-based contrast agents.