Gadolinium-Based MRI Contrast Agents

Indications

MRI is a procedure that uses non-ionizing radiation to obtain detailed images of tissues and organs throughout the human body. In contrast to CT, which uses ionizing radiation, MRI employs a high-strength main magnetic field, magnetic field gradients, radio waves, and a computer to generate images that demonstrate disease processes, pathological conditions, and injuries.[8][9][10] During an MRI procedure, the patient is positioned inside a large, cylindrical magnet that is open at both ends, called the MRI scanner. The high-strength main magnetic field aligns mobile hydrogen protons that exist in most tissues of the human body. A specific radio-frequency signal is applied to cause these mobile protons to produce signals that are picked up by receiver coils associated with the MRI scanner. The collected signals are characterized using gradient magnetic fields, and software processes them to create images of tissues as field-of-view slices that can be visualized and evaluated for pathological conditions.

The electromagnetic fields generated during MRI are not known to cause tissue damage or pain during an examination. MRI scanners produce loud knocking, tapping, and other noises that can be characterized as rhythmic musical sounds during the procedure. Earplugs can attenuate these noises. During the procedure, an intercommunication system allows the MRI technologist to monitor and communicate with the patient. The patient can also communicate with the MRI technologist.

To improve visualization of normal and abnormal tissues on MRI, a gadolinium-based contrast agent may be injected into a hand or wrist vein during certain MRI studies. In contrast to iodinated contrast agents used in CT and radiography studies, gadolinium-based MRI contrast agents do not contain iodine. Therefore, these agents rarely cause adverse effects or allergic reactions. However, patients with a history of a kidney transplant, kidney disease, kidney failure, or liver disease should inform the radiologist or MRI technologist before receiving a gadolinium-based MRI contrast agent. Patients who are uncertain about their history of allergic reactions should discuss this concern with the radiologist or MRI technologist before the MRI procedure.

Contraindications

Patients are required to complete a screening form before an MRI procedure to identify any foreign materials that might interfere with image acquisition or create a health risk. Objects that may create a problem or health hazard during an MRI evaluation include:

• A metallic foreign body within or near the eye (these objects may be identified on radiography; metalworkers and machine shop workers may be at increased risk)
• Some implanted or external medication pumps (insulin delivery, analgesic drugs, or chemotherapy pumps)
• Ferromagnetic metallic vascular clips are placed to prevent bleeding from intracranial aneurysms
• Some neurostimulation systems
• Some cochlear (inner ear) implants
• Catheters with metallic components
• Bullets, metal shrapnel, or another type of metallic fragment
• Certain cardiac pacemakers or implantable cardioverter defibrillators

Some devices, including certain neurostimulation systems, medication pumps, and cardiac pacemakers, are acceptable for MRI under specified conditions. However, the radiologist and MRI technologist must know the type of device implanted in the patient to ensure safety.

Patients and other individuals must remove the following items before entering the MRI scanner room:

• Any article of clothing that has metallic fibers or threads, metallic zippers, buttons, snaps, hooks, or underwire
• Hair barrettes and hairpins
• Pagers and cell phones
• Hearing aids
• Paper clips, coins, pens, and keys
• Belt buckles, shoes, and safety pins
• Watches and metallic jewelry
• Purses, money clip, wallet, cards with magnetic strips, including credit and debit cards

The following objects, if near the areas being imaged, may interfere with the image quality generated:

• Dental fillings (which may distort images of the brain or facial areas; the same is true for orthodontic retainers and braces)
• Plates, screws, pins, or metallic mesh used in repairing a joint or bone
• Some tattoos or tattooed eyeliner (these distort MRI images, and there is a chance of skin swelling or irritation, of which black and blue pigments are the most troublesome)
• Metallic jewelry, including jewelry used for body modification or body piercing
• Joint replacements or prosthesis
• Makeup, another cosmetic with metallic components, and nail polish
• Metallic spinal rods

Patients who are pregnant or may be pregnant should inform the MRI technologist or radiologist during the screening process before the MRI procedure. No adverse effects associated with MRI without gadolinium-based contrast agents have been identified in pregnant patients to date. Nonetheless, MRI without gadolinium-based contrast agents is used in pregnant patients only to evaluate suspected abnormalities or clinically important conditions. Results from clinical studies indicated that MRI without gadolinium-based contrast agents is safer for the fetus than CT and radiography.

Patients scheduled for an MRI study should inform the radiologist and MRI technologist if they are breastfeeding, particularly when a gadolinium-based MRI contrast agent may be required for the evaluation. In this situation, patients may pump and store breast milk before the study. Patients may resume breastfeeding about 24 to 48 hours after the injection of a gadolinium-based contrast agent. Patients who are breastfeeding should request additional information from the radiologist regarding this issue.

Adverse Effects

Atomic gadolinium is highly toxic, but gadolinium-based MRI contrast agents contain gadolinium bound within a chelate.Gadolinium is a metal in the lanthanide series of the periodic table and has a general depressant effect on all body systems. Death is usually due to cardiovascular collapse and respiratory paralysis.

• Cardiovascular: Hypotension, hypertension, tachycardia, migraine, syncope, vasodilatation, pallor.
• Gastrointestinal: Abdominal discomfort, toothache, increased salivation, abdominal pain, vomiting, diarrhea.
• Nervous system: Agitation, anxiety, thirst, somnolence, diplopia, loss of consciousness, convulsions (including grand mal seizure), paresthesia.
• Respiratory system: Throat irritation, rhinitis, sneezing.
• Skin: Rash, sweating (hyperhidrosis), pruritus, urticaria (hives), facial edema.
• Special senses: Conjunctivitis, taste abnormality, dry mouth, lacrimation, eye irritation, eye pain, ear pain.
• The effects of gadolinium deposition in the brain remain unknown. Macrocyclic gadolinium-based agents are commonly used because these agents appear less likely to deposit in the basal ganglia (Kanda et al, AJNR Letter to the Editor, February 26, 2016).

Postmarketing Experience

The following additional adverse reactions have been identified during the postmarketing use of gadolinium-based contrast agents. Because these reactions are reported voluntarily from a population of uncertain size, reliable estimation of their frequency or establishment of a direct causal relationship to drug exposure is not possible.

• Anaphylactic shock, respiratory distress, and laryngeal edema [see Warnings and Precautions]
• Cardiac/respiratory arrest and shock
• Nephrogenic systemic fibrosis [see Warnings and Precautions]

The most frequently reported adverse reactions during postmarketing experience were nausea, vomiting, urticaria, and rash.

Equipment

MRI is a technique for generating detailed images of tissues and organs throughout the human body without ionizing radiation. In contrast, MRI employs a powerful main magnetic field, gradient magnetic fields, radiofrequency waves, and a computer to create images that show normal and abnormal processes, infections, or inflammatory conditions.[11][12]

For the MRI procedure, the patient is positioned in a wide, tube-like device called the MRI scanner, which is open at both ends. The strong main magnetic field aligns mobile hydrogen protons, which are present in most tissues of the human body. Radiofrequency waves are then applied by the transmit coil to cause these mobile protons to produce response signals, which are picked up by a receiver or transmit-receiver coil, a component of the MRI scanner. Gradient magnetic fields specifically characterize these response signals. In conjunction with computer software processing, images of tissues and organs are generated as field-of-view slices that can be visualized and evaluated by radiologists in sagittal, coronal, transverse, and oblique planes.

MRI procedures cause no pain, and the main and gradient magnetic fields are not known to produce tissue damage. During the MRI procedure, knocking, tapping, and other noises are produced; these noises have a rhythmic quality. Earplugs can attenuate these noises during the MRI procedure. Patients are continuously monitored and can communicate with the MRI scanner operator or technologist via an intercom system during the procedure.

Personnel

Magnetic Resonance Personnel and Nonmagnetic Resonance Personnel

All individuals working within at least Zone III of the magnetic resonance environment should be documented as having successfully completed at least 1 MR safety live lecture or prerecorded presentation approved by the MR medical director. Attendance should be repeated at least annually, and appropriate documentation should confirm these ongoing educational efforts. These individuals are referred to as MR personnel.

Two levels of MR personnel include:

• Level 1 MR personnel: Those who have completed minimal safety training to ensure their safety while working within Zone III will be referred to henceforth as Level 1 MR personnel.
• Level 2 MR personnel: Individuals who have received more extensive training and education on broader MR safety issues. These safety issues include the potential for thermal loading or burns and direct neuromuscular excitation from rapidly changing gradients. The MR medical director is responsible for identifying the required training and determining which individuals qualify as Level 2 MR personnel. The MR medical director must have sufficient education and experience in MR safety to qualify as level 2 MR personnel.

Individuals who have not completed the required MR safety training are referred to as non-MR personnel. Specifically, non-MR personnel include individuals or groups who have not completed formal MR safety training within the previous 12 months, as defined by the MR safety director at that installation.

MR Technologist

1. MR technologists should be registered with the American Registry of Radiologic Technologists. Furthermore, all MR technologists must be trained as level 2 MR personnel during their orientation before being permitted unrestricted access to Zone III.
2. All MR technologists must maintain current American Heart Association basic life support certification at the healthcare professional level.
3. Except for emergent coverage, a minimum of 2 MR technologists or 1 MR technologist and at least 1 other individual designated as MR personnel should be present in the immediate Zone II through Zone IV environment. For emergent coverage, an MR technologist may perform scanning without another individual present in the Zone II through Zone IV environment if designated radiology MR personnel, such as radiology house staff or attending radiologists, are readily available to provide emergency assistance. (ACR WHITE PAPER ON MAGNETIC RESONANCE (MR) SAFETY Combined Papers of 2002 and 2004)
4. The MRI scanner remains continuously active and can pose a safety hazard if loose ferromagnetic materials are propelled into the magnet bore. The 4 classic MR safety zones are Zone I, the hallway; Zone II, the MRI reception area; Zone III, the MRI technologist control area; and Zone IV, the magnet room.

Preparation

The patient will be provided with a gown to wear during the MRI procedure. Before entering the MRI scanner room, the patient and any accompanying relatives or friends will be asked to complete a screening form to identify any metallic devices or implants. Patients will also be instructed to remove all metallic jewelry and metallic objects from their pockets and hair. Any accompanying individual will be instructed to complete a screening form to confirm that entry into the MRI scanner room is safe. Patients should discuss additional questions or concerns with the radiologist or MRI technologist before the MRI procedure.

When a patient is prescribed MRI with a contrast agent, an intravenous catheter is inserted into a vein in the arm or another accessible extremity during initial preparation and positioning. Following placement of the intravenous catheter, it is flushed with heparin to prevent clogging. In general, a set of noncontrast-enhanced images will be obtained before the contrast-enhanced images. Patients are injected with a specific gadolinium-based contrast agent at a dose of 0.1 mmol/kg for the examination. Following contrast agent injection, the intravenous catheter is flushed with saline. The gadolinium-based MRI contrast agent is administered intravenously at approximately 0.2 mL/kg (0.1 mmol/kg) over 15 seconds per 10 mL.

Gadolinium-based MRI contrast agents are available from the manufacturer in the following packages:

1. Single-dose vials (5, 10, 15, 20 mL)
2. Single-dose, prefilled syringes (10, 15, 20 mL)
3. Pharmacy bulk packages (50, 100 mL)

Technique or Treatment

An MRI study is performed in a dedicated room housing the MRI system, called the scanner room. Patients are led into the scanner room by an MRI technologist and placed on a padded, comfortable table that slowly glides into and out of the scanner. Typically, scanners are tube-like machines that are open at both ends. To prepare for the MRI study, patients are given earplugs or headphones to protect their hearing, as scanners produce loud noise during operation. These rhythmic noises are normal and should not cause concern.

During some MRI procedures, a gadolinium-based contrast agent is injected into a vein to help produce a clearer, more detailed image of the area being evaluated. At some point during the study, an MRI technologist or nurse pulls the table out of the scanner to inject the contrast agent. Injection of the gadolinium-based contrast agent is performed through a small intravenous catheter placed in a vein in the patient's hand or arm. A normal saline solution with heparin is instilled through the intravenous line to prevent clotting until the gadolinium-based contrast agent is injected during the MRI procedure. Most MRI studies last between 15 and 45 minutes, depending on the body areas imaged and how many images are collected, although some may take as long as 60 minutes. The most important thing for the patient to do is to lie still and relax. Patients are told before the start of the clinical study the duration of each scanning protocol. Patients are asked to remain motionless during image acquisition. Minor movements are permitted between imaging protocols. The MRI technologist will advise the patient when movement is permitted.

When the MRI protocol begins, the patient can breathe normally. However, some specific evaluations require the patient to hold their breath briefly. During an MRI procedure, the MRI technologist can communicate with the patient, hear them, and continuously observe them. Patients can also communicate with the MRI technologist at all times. When the MRI evaluation is complete, patients may be required to wait until the images are reviewed to determine whether additional imaging is needed. After the scanning procedure, patients have no restrictions and can resume their normal activities. Patients who receive gadolinium-based MRI contrast agents are advised to drink additional water for a few hours after the procedure to help clear the contrast agent from their bodies. After the MRI is completed, a radiologist reviews the images, evaluates them, and sends a report to the patient's primary clinician.

MRI produces images through a complex interaction among mobile hydrogen protons in biological tissues, a main static magnetic field, and excitation energy in the form of radio waves of a specific frequency introduced by transmitting coils positioned next to the areas of the body being evaluated. Images of the areas being evaluated are produced by computer processing of resonance data received from protons in the body's field of view. The field strength of the main static magnet is directly related to the signal-to-noise ratio (SNR) of the images acquired; the higher the field strength, the higher the SNR. While 1.5 T static main magnets are the standard high-field MRI units, 3.0 T static main magnets are also widely used and offer distinct advantages for imaging the musculoskeletal system and brain due to higher SNR and improved soft-tissue differentiation.

Spatial localization of the body's areas of interest is obtained by gradient magnetic fields within or surrounding the main magnetic field, which produce minor changes in the magnetic field throughout the imaging volume. Radiofrequency pulses momentarily excite the energy state of the mobile hydrogen protons in the body's areas of interest. A radiofrequency pulse is applied at a frequency specific to the main magnetic field strength. For example, the frequency for a 1.5 T magnetic field is 63.85 MHz. The mobile hydrogen protons subsequently return to the equilibrium energy state (a process called relaxation) and release radiofrequency energy (an echo), which is detected by the receiver coils or transmit-receiver coils. Fourier transform analysis is applied to the echo signals to generate the data used to form the acquired MRI images. The acquired MRI images consist of a map of the distribution of mobile hydrogen protons, with signal intensity arising from differences in the relaxation times and densities of hydrogen protons in different molecules. Although clinical MRI uses abundant mobile hydrogen protons, researchers are also investigating carbon and sodium imaging and spectroscopy.

MRI Imaging Relaxation Times (T1 & T2) 

The time required for excited mobile hydrogen protons to return to the equilibrium state is called the relaxation time. Relaxation times differ between normal and abnormal tissues. The relaxation time of a mobile hydrogen proton in tissue is determined by local interactions with neighboring molecules and atoms. Two relaxation times, T1 and T2, affect image signal intensity. The T1 relaxation time, also called the longitudinal relaxation time, is the time required for 63% of excited mobile hydrogen protons to return to their equilibrium state. The T2 relaxation time, also called the transverse relaxation time, is the time required for 63% of excited mobile hydrogen protons to dephase because of interactions with nearby hydrogen protons.

The signal intensity and image contrast of various tissues can be controlled by altering acquisition parameters, such as the time between the radiofrequency pulse and signal reception (echo time) and the interval between radiofrequency pulses (repetition time). T1-weighted images are acquired by setting the repetition time and echo time relatively short, whereas applying longer repetition and echo times produces T2-weighted images. Subacute hemorrhage and fat have relatively shorter T1 relaxation times and thus higher signal intensity than the brain on T1-weighted images. Tissues and organs with higher water content, such as edema and cerebrospinal fluid, have long T1 and T2 relaxation times, resulting in relatively lower signal intensity on T1-weighted images and higher signal intensity on T2-weighted images. Gray matter consists of 10% to 15% more water than white matter; this difference accounts for much of the intrinsic contrast between the 2 tissues on MRI. T2-weighted images are more sensitive than T1-weighted images to demyelination, infarction, edema, and chronic hemorrhage, whereas T1-weighted images are more sensitive to fatty tissues and subacute hemorrhage.

Complications

Some patients undergoing MRI procedures may feel frightened, enclosed, or confined. Approximately 1 in 20 patients may require a prescribed sedative to remain calm. Patients with claustrophobia may also undergo imaging in newer scanners with a wide-bore design or in an open MRI scanner, although open scanners have a lower magnetic field strength. Most MRI centers allow a friend or relative to be present in the MRI scanner room with the patient, which may decrease anxiety, apprehension, and fear. Appropriate instruction regarding what to expect allows most MRI studies to be completed successfully.

Some patients, generally those with renal dysfunction, may develop nephrogenic systemic fibrosis after exposure to a gadolinium-based contrast agent. Nephrogenic systemic fibrosis is a serious adverse effect associated with gadolinium-based MRI contrast agents, in which the protective chelate may break down in patients with renal failure. Nephrogenic systemic fibrosis is a rare systemic disorder of unknown etiology with high morbidity and mortality rates that occurs almost exclusively in patients with impaired renal function. Although nephrogenic systemic fibrosis is often discussed in the setting of gadolinium-based contrast agents, the diagnosis does not require a history of exposure to these agents. Renal impairment, however, is an important predisposing factor, and almost all cases of nephrogenic systemic fibrosis have been reported in patients with stage 4 or 5 chronic kidney disease or acute kidney injury. When associated with gadolinium-based contrast agents, nephrogenic systemic fibrosis usually presents 2 to 10 weeks after administration and is more common with a particular class of gadolinium-based contrast agents. Macrocyclic agents are shaped like cages around the gadolinium ion and have a lower probability of releasing free gadolinium. These agents are considered more stable than other contrast agents and have a lower risk of nephrogenic systemic fibrosis. Linear nonionic agents are the least stable, and linear ionic agents have intermediate stability. For example, most patients with nephrogenic systemic fibrosis have been exposed to the linear nonionic agent gadodiamide, even though this agent accounts for only about 15% of the worldwide market share of gadolinium-based contrast agents. Gadolinium-based MRI contrast agents may pose risks to the fetus. Therefore, these agents are generally avoided during pregnancy, except in rare cases when the potential benefits outweigh the risks.

Clinical Significance

Unlike nuclear magnetic resonance (NMR), which is used in chemistry and biochemistry to characterize molecules, magnetic resonance imaging (MRI) lacks sufficient sensitivity to detect individual molecules. MRI can only detect molecular motions and compositions in relation to the characteristics of the surrounding tissues. Gadolinium-based contrast-enhanced MRI can detect changes in molecular composition and motion, and therefore plays a significant role in the development of MRI-based molecular imaging. Gadolinium-based MRI contrast agents dynamically alter one or more of their physicochemical properties when interacting with the surrounding tissue environment. Developing and applying gadolinium-based MRI contrast agents in biological or biomedical studies often requires an interprofessional research team of scientists and clinicians with a thorough understanding of molecular and cellular biology, chemistry and biochemistry, physiology, biomedical engineering for imaging methods, and radiology.

Gadolinium-based MRI contrast agents have been used for diagnosis and treatment planning in more than 100 million patients worldwide during the last 25 years. These agents enhance MRI image quality by perturbing the magnetic properties of nearby water protons in the body. Gadolinium-based MRI contrast agents aid clinicians in diagnosing and treating a variety of pathological processes by improving the visualization of specific organs, tissues, and blood vessels.

Enhancing Healthcare Team Outcomes

MRI is the preferred imaging study for diagnosing numerous neurological and neurodegenerative diseases, infections, and other abnormalities throughout the body. In general, MRI generates images that show subtle differences between pathological and healthy tissues. Clinician-scientists, nurse practitioners, clinicians, and scientists use MRI to evaluate the abdomen, pelvis, breast, blood vessels, heart, brain, spine, and spinal cord (the central nervous system), as well as joints (including the shoulder, wrist, knee, ankle, and hip), the musculoskeletal system, and other areas of the body. Healthcare professionals need to know when to order an MRI and understand its limitations.