Gadolinium

Note on brand names

The various gadolinium salts are often known by their brand names, because their chemical names are complex. Gadolinium salts that are used as contrast media in magnetic resonance imaging (MRI) are listed in Table 1 .

General adverse effects and adverse reactions

The reported rate of adverse reactions of gadolinium chelates at a dose of 0.1 mmol/kg is 2.4%. Most of these reactions tend to be mild and do not require treatment [ ]. Serious reactions are extremely rare. However, several severe anaphylactoid reactions and angioedema have been reported [ ]. The incidence of adverse reactions is slightly higher in patients with a history of asthma or allergy (3.7%). For patients with a history of a previous reaction to an MRI or iodinated X-ray contrast agent, the reported adverse reaction rates were 21% and 6% respectively [ ]. Adverse reactions at a dose of 0.3 mmol/kg included urticaria, vomiting, diarrhea, flushing, paresthesia, and headache, which have previously been reported with standard doses. The most common adverse reactions were nausea and a metallic taste. In a study of 79 patients given 0.3 mmol/kg no adverse reactions were recorded [ ].

There is no significant difference in the incidence of adverse reactions between ionic and non-ionic gadolinium chelates [ ].

Gadobenate dimeglumine (Gd-BOPTA)

Gadobenate dimeglumine is a novel paramagnetic contrast agent that combines the properties of a conventional extracellular contrast agent with those of a liver-specific contrast agent. It has potential for both hepatic and non-hepatic targeted imaging. Unlike standard gadolinium chelates, which are excreted by the kidneys, 3–5% of gadobenate dimeglumine is taken up by functioning hepatocytes and is excreted unchanged in the bile. It also has an inherently higher T1 relaxivity than conventional gadolinium chelates, and so causes very marked enhancement of the liver parenchyma on T1 images, which persists for up to 2 hours. Liver tumors generally do not contain functioning hepatocytes and therefore do not take up gadobenate dimeglumine; they therefore appear as unenhanced hypointense lesions.

In 74 patients over the age of 18 years with possible metastatic brain disease, a total cumulative dose of 0.2 mmol/kg of gadobenate dimeglumine injected intravenously over 20 minutes was safe and enhanced the assessment of brain secondaries [ ].

The safety and efficacy of gadobenate dimeglumine in phase 1, 2, and 3 studies have been reviewed in 732 patients, of whom 168 received 0.05 mmol/kg and 564 received 0.1 mmol/kg [ ]. The overall incidence of adverse events was 14% with the lower dose and 9.9% with the higher dose. The vast majority of events were mild, transient, and self-limiting. There were no sex-, age-, or dose-related differences and no clinically important effects on vital signs or laboratory parameters. The most common adverse events were hypertension (1.37%), nausea (1.09%), tachycardia (0.96%), and albuminuria (0.75%). The authors concluded that gadobenate dimeglumine is safe and efficacious as a contrast agent for use in hepatic MRI.

The safety of gadobenate dimeglumine has been assessed in phase 2 and phase 3 studies in Japan [ , ]. The overall adverse reaction rate was 3.5–5% and all the reactions were mild or moderate. There were no differences in the rates of adverse reactions with different dosage regimens (0.05–2.0 mmol/kg).

A safety evaluation of gadobenate dimeglumine in patients with renal impairment has also been reported [ ]. In a placebo-controlled, double-blind study there were no changes in laboratory parameters or vital signs and no clinically important adverse events.

The safety of gadobenate dimeglumine has been evaluated in 2367 adults aged 18–88 years and 173 children. The overall incidence of adverse events was 20%. Events related to the contrast agent were reported in 15% of the adults. Most of the adverse events were mild and transient and resolved spontaneously. Headache, injection site reactions, nausea, taste disturbance, and vasodilatation were the most common, with frequencies of 1.0–2.6%. Serious adverse events potentially related to the contrast agent were reported in 0.2%. These events included laryngospasm, which developed 10 minutes after the contrast injection in a 51-year-old woman, severe vomiting in a 5-year-old child, and pulmonary edema in a 65-year-old patient.

Gadobenate dimeglumine (intravenous bolus injection of 0.05 mmol/kg) was well tolerated by 103 patients (mean age 56 years) with acute myocardial infarction [ ]. Minor adverse reactions in 27 patients included injection site reactions (13%), paresthesia (6.8%), dry mouth (6.8%), taste disturbance (2.9%), and headache (1.9%). The authors concluded that the use of a bolus dose of gadobenate dimeglumine 0.05 mmol/kg up to 6 days after acute myocardial infarction is safe.

The safety of intravenous gadobenate dimeglumine 0.025, 0.05, 0.1, and 0.2 mmol/kg in MR angiography has been assessed in 94 patients (mean age 58 years). Diagnostic accuracy was optimal at a dose of 0.1 mmol/kg [ ]. All the doses were well tolerated and there were no significant changes in safety parameters. Six patients reported mild adverse effects and reactions related to the contrast agent, including urticaria (n = 2), nausea (n = 2), and mild increases in liver enzymes (gamma-glutamyl transpeptidase, alanine transaminase, and aspartate transaminase) (n = 2). All the adverse events resolved spontaneously.

Similar observations were made in another study using similar doses of gadobenate dimeglumine for MR angiography [ ]. There were no important adverse reactions, and the authors concluded that gadobenate dimeglumine is safe for MR angiography and that the optimal diagnostic dose is 0.1 mmol/kg.

Gadobutrol

Gadobutrol 1.0 is an extracellular neutral gadolinium chelate belonging to the class of macrocyclic neutral gadolinium complexes. It has the lowest osmolality of gadolinium-based contrast agents (1.60 osmol/kg). In preclinical evaluation there was good tolerance up to a dose of 0.5 mmol/kg, and this has been confirmed in phase I clinical studies. In a phase II study, 89 patients with suspected cerebrovascular insufficiency received Gadovist 1.0 in doses of 0.1 (n = 11), 0.2 (n = 21), 0.3 (n = 21), 0.4 (n = 21), or 0.5 (n = 15) mmol/kg [ ]. There were no significant changes in vital signs or any serious adverse reactions. Two patients had nausea and dry mouth. A dose of 0.3 mmol/kg was diagnostically adequate.

Gadodiamide

Adverse events associated with the non-ionic, gadolinium-based contrast agent gadodiamide have been reported in 1–2% of patients. Most of the commonly reported adverse reactions have been headache, dizziness, or nausea and vomiting.

The safety and effectiveness of gadodiamide-enhanced magnetic resonance angiography (MRA) with single and triple doses in the assessment of abdominal arterial stenosis has been investigated in 105 patients, of whom 53 (aged 45–83 years) received 0.1 mmol/kg and 52 (aged 38–85 years) received 0.3 mmol/kg [ ]. There were no serious adverse events. Six patients in the single-dose group felt a sensation of heat or warmth in the abdomen, lumbar spine, upper legs, hips, or groin; five of these events were mild and one was moderate; one patient felt a mild cold sensation at the injection site. Six patients in the triple-dose group felt a warm discomfort in the abdomen, pelvis, or buttocks (two mild and four moderate); four other patients felt a cold sensation at the injection site or in the arm (three mild and one moderate). The authors concluded that gadodiamide-enhanced MRA performed with single and triple doses is safe and effective in assessing major abdominal arterial stenosis. Triple-dose MRA was better at evaluating image quality and the degree of arterial stenosis.

The safety of gadodiamide-enhanced MRI in staging suspected or recurrent soft tissue tumors of the head and neck has been investigated in 48 patients (aged 37–86) [ ]. There was only one adverse event, moderate thirst. The authors concluded that the use of gadodiamide for MRI contrast-enhanced examination of the head and neck is safe and provides more diagnostic information than unenhanced images.

Gadofosveset

Gadofosveset (MS-325) is a gadolinium-based small molecular weight chelate, which binds strongly and reversibly to human serum albumin after injection [ ]. Because of albumin binding it has a long half-life and increased relaxivity (RI = 48 mM ^{− 1} sec ^{− 1} at 0.47 T and 37 ¯C, which is 10 times higher than gadolinium DTPA). These properties are particularly useful for contrast-enhanced, three-dimensional MRA. Furthermore, MS-325 can be given as a bolus, allowing dynamic arterial imaging. Prolonged blood-pool retention also allows steady-state imaging. There are promising results from early studies of carotid and coronary arteries. No serious adverse reactions have been reported after the injection of gadofosveset, although transient nausea and paresthesia were reported in two of seven volunteers [ ].

The safety and diagnostic efficacy of gadofosveset in MRA of the carotid arteries has been investigated in 26 patients aged 42–81 years with suspected carotid artery stenosis. It was given intravenously to 4, 9, and 13 patients in single doses of 0.01, 0.03, or 0.05 mmol/kg respectively. There were no serious or severe adverse events. Two patients who received 0.05 mmol/kg had five adverse events within 3 hours after the injection (nausea, cramps, metallic taste, and pruritus), which were rated as mild. There were no significant changes in serum chemistry. High-quality MRA scans were obtained in all the patients.

Gadopentetate dimeglumine

Gadopentetate dimeglumine (1 ml mixed with 4 ml of 5% saline) has been used in myelocisternography in four patients (aged 28–62 years) to demonstrate the exact site of cerebrospinal fluid (CSF) leakage in patients with CSF rhinorrhea [ ]. All tolerated the examination without adverse effects or reactions.

Gadoversetamide

The safety of intravenous gadoversetamide, 0.1, 0.3, and 0.5 mmol/kg, has been confirmed in a study of its pharmacokinetics, safety, and tolerability in 163 patients with nervous system or liver pathology and varying degrees of renal function [ ]. All the adverse events that were thought to be related to gadoversetamide were mild or moderate, and there was no difference between doses. There were no changes in laboratory parameters. Gadoversetamide was well tolerated, even in patients with prolonged elimination due to renal impairment.

The safety of gadoversetamide at doses of 0.1–0.7 mmol/kg has been evaluated in 18 clinical studies [ ]. Adverse events related to the contrast agent were reported in 31% of injections. There were no serious adverse events.

Gadoxetic acid

Gadoxetic acid (gadolinium ethoxybenzyl diethylenetriaminepenta-acetic acid) was developed as a tissue-specific contrast agent for the liver and biliary system to be used in MRI and is a derivative of gadolinium DTPA with higher lipophilicity. It is taken up into hepatocytes and undergoes biliary excretion. Intravenous gadoxetic acid disodium has been used to assess liver enhancement and detect lesions in CT scanning of 15 patients with known liver metastases. The contrast agent was administered as an intravenous infusion over 20 or 30 minutes in doses of 0.2, 0.35, and 0.5 mmol/kg. There were three mild adverse reactions and one moderate reaction. Two patients reported a burning sensation at the site of infusion or retrosternally, which resolved when the flow rate of the infusion was reduced. Two other patients reported right upper quadrant pain, which began 4 hours after the infusion; this resolved spontaneously after a few hours. There were also minor reversible alterations in liver enzymes in some patients. Overall patient tolerance was acceptable and the images showed good or excellent liver enhancement, liver to tumor attenuation difference, and tumor visualization in the majority of cases with doses of 0.35 and 0.5 mmol/kg [ ].

Uses of gadolinium other than in MRI scanning

Gadolinium can sufficiently attenuate X-rays to be visualized with digital subtraction angiography, although the quality of image is consistently inferior to that produced by iodinated agents. Of 13 patients who underwent transplant angiography with 16–20 ml of either gadopentetate dimeglumine (0.5 mmol/ml) or gadolinium (0.5 mmol/ml), there was no significant deterioration in renal function in 11 patients [ ]. In the other two there were significant increases that were not considered to be due to either gadolinium or the administration of CO ₂ . These findings are consistent with previous studies [ ] showing that gadolinium compounds are not nephrotoxic.