In MRI scanners, sections of the body are exposed to a strong
magnetic field causing primarily the 1H hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intense
radiofrequency pulse is applied that tips the magnetization generated by the hydrogen nuclei in the direction of the receiver coil where the spin polarization can be detected. Random molecular rotational oscillations matching the resonance frequency of the nuclear spins provide the "relaxation" mechanisms that bring the net magnetization back to its equilibrium position in alignment with the applied magnetic field. The magnitude of the spin polarization detected by the receiver is used to form the MR image but decays with a characteristic time constant known as the
T1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons thereby altering the contrast in the image. Most clinically used MRI contrast agents work by shortening the T1 relaxation time of protons inside tissues via interactions with the nearby contrast agent. Thermally driven motion of the strongly paramagnetic metal ions in the contrast agent generate the oscillating magnetic fields that provide the relaxation mechanisms that enhance the rate of decay of the induced polarization. The systematic sampling of this polarization over the spatial region of the tissue being examined forms the basis for construction of the image. MRI contrast agents may be administered by injection into the blood stream or orally, depending on the subject of interest. Oral administration is well suited to
gastrointestinal tract scans, while intravascular administration proves more useful for most other scans. MRI contrast agents can be classified by their: • Chemical composition • Administration route • Magnetic properties • Biodistribution and applications: • Extracellular fluid agents (intravenous contrast agents) •
Blood pool agents (
intravascular contrast agents) • Organ specific agents (gastrointestinal contrast agents and hepatobiliary contrast agents) • Active targeting/cell labeling agents (tumor-specific agents) • Responsive (smart or bioactivated) agents • pH-sensitive agents == Gadolinium(III) ==
Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels in
MR angiography or for brain tumor enhancement associated with the degradation of the
blood–brain barrier (BBB). Over 450 million doses have been administered worldwide from 1988 to 2017. For large vessels such as the
aorta and its branches, the dose can be as low as of body mass. Higher concentrations are often used for finer vasculature. At much higher concentration, there is more T2 shortening effect of gadolinium, causing gadolinium brightness to be less than surrounding body tissues. However at such concentration, it will cause greater toxicity to bodily tissues. Gd3+ chelates are hydrophilic and do not readily cross the intact blood–brain barrier. Thus, they are useful in enhancing lesions and tumors where the blood–brain barrier is compromised and the Gd(III) leaks out. In the rest of the body, the Gd3+ initially remains in the circulation but then distributes into the interstitial space or is eliminated by the
kidneys. The first gadolinium-based contrast agent (GBCA),
gadopentetate dimeglumine (Magnevist), was approved nearly simultaneously by the
EMA and by the
FDA in the late 1980's. (
standard dose)): However, beginning in 2017, the EMA restricted several older linear gadolinium contrast agents that had previously been approved for human use in the EU.
Extracellular fluid agents •
Macrocyclic •
ionic •
gadoterate (
Dotarem,
Clariscan): EMA, FDA () • non-ionic •
gadobutrol (
Gadovist [EU] /
Gadavist [US]): EMA, FDA () •
Linear (suspended by EMA) • ionic •
gadopentetate (
Magnevist, EU:
Magnegita,
Gado-MRT ratiopharm): FDA () a rare but severe systemic disease resembling
scleromyxedema and to some extent
scleroderma. It may occur months after contrast injection. Patients with severely deteriorated
kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with mild
chronic kidney disease. NSF can be caused by linear and macrocyclic gadolinium-containing MRI contrast agents, although macrocyclic ionic compounds have been found the least likely to release the Gd3+. As a free solubilized aqueous ion, gadolinium(III) is highly toxic, but the
chelated compounds are relatively safe for individuals without kidney disease. Free Gd3+ has a
median lethal dose of (IV, mouse) or but the
LD50 is increased by a factor of 31 times when Gd3+ is chelated. The spectrum of adverse drug reactions is greater with gadolinium-based contrast agents than with iodinated contrast agents (
radiocontrast agents). Gadolinium has been found to remain in the brain, heart muscle, kidney, liver, and other organs after one or more injections of a linear or macrocyclic gadolinium-based contrast agents, even after a prolonged period of time. The amount differs with the presence of kidney injury at the moment of injection, the
molecular geometry of the ligand, and the dose administered. In vitro studies have found gadolinium-based contrast agents to be
neurotoxic, and a study found signal intensity in the
dentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency.
Confusion is often reported as a possible clinical symptom.
Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death. The
glymphatic system could be the main access of GBCA to the brain in intravenous injection. Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led the
EMA to restrict or suspend authorization for the intravenous use of most brands of linear gadolinium-based media, in which Gd3+ has a lower binding affinity, in 2017. In the United States, the research has led the
FDA to revise its class warnings for gadolinium-based contrast media. It is advised that the use of gadolinium-based media should be based on careful consideration of the retention characteristics of the contrast, with extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. They also advise minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies, but not avoiding or deferring necessary GBCA MRI scans. In December 2017, the FDA announced that it was requiring these warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents. The
French health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it. The
World Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (
Optimark,
Omniscan,
Magnevist,
Magnegita, and
Gado-MRT ratiopharm) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age." In
magnetic resonance imaging in pregnancy, gadolinium contrast agents in the first trimester is associated with a slightly increased risk of a childhood diagnosis of several forms of
rheumatism,
inflammatory disorders, or infiltrative
skin conditions, according to a retrospective study including 397 infants prenatally exposed to gadolinium contrast. In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study. are that dialysis patients should receive gadolinium agents only where essential and that they should receive dialysis after the exam. If a contrast-enhanced MRI must be performed on a dialysis patient, it is recommended that certain high-risk contrast agents be avoided but not that a lower dose be considered. The FDA recommends that potential for gadolinium retention be considered when choosing the type of GBCA used in patients requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions.
Anaphylactoid reactions are rare, occurring in about 0.03–0.1%. == Iron oxide: superparamagnetic ==