MRI contrast agents
The critical role played by Magnetic Resonance Imaging over the past 30 years in the field of diagnostics is unparalleled and incomparable. Its noninvasive technique of usage, coupled with the tissue contrast provided by this imaging modality make it one of the “Go-to” imaging techniques. This natural flexibility allows for the study and assessment of functional systems such as, functional neuroimaging, cardiac imaging, diffusion and perfusion weighted MRI and MR Angiography. There have been efforts made to extend the capabilities of the principles of Magnetic resonance imaging using exogenous contrast agents.
Five intravenous contrast agents have been approved for medical use in the United States by the FDA. The following table illustrates the same.
Mechanism of Action
The biochemical interactions that these contrast agents are responsible for, once administered, are what makes them a unique class of radiologic contrast agents. In lay terms, contrast agents are supposed to, and designed to be biologically inert. Detection of these MR contrast agents, once administered is done indirectly, through the effects they have on the nuclear magnetic relaxation time constants which have been categorized as T1, T2 and T2* of water in tissues. Specifically, Gd shortens all 3 of these time constants; however shortening of T1 is what MR and MRA specifically rely on. The shortened relaxation time of T1 coupled with rapid acquisition, results in increased signal intensity propagated by the enhanced tissues.
To fully understand the concept and underlying phenomenon of T1 and T2 relaxation times, the concept of NMR, i.e. Nuclear magnetic resonance must be grasped and understood. Different tissues in the body have different compositions of H atoms. Water has these H atoms moving more freely when compared to fat and carbohydrates. With the protons in the H atom moving in a particular direction, albeit in the direction of a magnetic field, have a certain frequency and momentum. Diseased tissues in the body are generally more metabolically active, i.e. having a higher state of energy within that tissue. The protons in that tissue would be revolving or preceding (read “precession” aka rotating on a particular axis; X, Y or Z) at a different rate when compared to the protons in the normal tissue. An MRI machine basically exerts a magnetic field using RF pulses to change the axes on which the proton rotates, thereby changing the direction of the magnetic field of the protons from longitudinal to transverse. The energy given off when high energy protons “come back” to their resting state, is read in the form of electrical signals. (For brevity sake the concepts of Tₑ Total echo time, Tr total relaxation time are not being discussed).
T1 relaxation time is the total time taken by the protons preceding (precession) to move from a higher energy state to a lower energy state, thereby increasing the longitudinal magnetic field instead of the transverse magnetic field, and giving off energy of certain frequency and amplitude. This is known as “Spin-Lattice relaxation time). T2 relaxation time is the time taken for the excited protons in precession, to move away from each other due to “like pole” interactions. This is known as “Spin-Spin relaxation time”.
Contrast agents basically reduce the time taken by these protons to come back to their base energy state, due to its paramagnetic nature. Configuration of Gadolinium is 4f₇ 3d₁ 2s₂. The lack of complete filling of the F and D orbitals is what imparts the paramagnetic nature.
Basic Pharmacology
Free Gd ion is a known heavy metal toxin, the United States has approved these agents only after they have been deemed to be safe and stable pharmaceutical agents. Nonetheless, it remains the physician’s responsibility to be aware of and understand the associated side effects and the particular instances wherein the patient would be at increased risk for adverse events if the drug is administered. Free Gd has high toxicity in-vivo, hence it is commonly bound to ligands that make it highly hydrophilic due to the formation of Gd-chelate complexes.
An octadentate chelate of Gd is Gd-BOPTA The relaxivity of this agent is higher when compared to equimolar formulations of other contrast agents, because of it being highly lipophilic in nature and structure. It interacts reversibly and weakly with serum albumin. As a result of which, the T1 relaxivity in human plasma makes it twice as more effective than other Gd agents.
Gd-EOB-DTPA is a paramagnetic contrast agent used for hepatobiliary imaging. This complex has a T1-relaxivity in human plasma, which is higher than Gd-BOPTA, due to its higher binding to protein the plasma for the former.
Following administration, Mn-DPDP (an anionic manganese chelate) dissociates; yielding free Mn (2+) ions.
Pharmacokinetics
The relaxivity of an MR contrast agent reflects how the relaxation rates of a solution change as a function of concentration [C]. Since a contrast agent may affect the two relaxation rates (1/T1 and 1/T2) individually, there are two corresponding relaxivities, denoted r1 and r2.
The paramagnetic effect is imparted by the Gd ion, but the ligand determines the pharmacokinetic behavior. Gd-chelates possess high hydrophilicity and relatively low molecular weight, hence, following IV injection, they diffuse quickly into the interstitial space. The un-metabolized Gd complexes are excreted via the kidneys, with a plasma half-life of 90 min. The compounds are completely eliminated after 24 hrs. Provided the GFR is not diminished, but in patients where renal function is diminished, the half-life is prolonged.
Normal Hepatocytes show selective affinity for Gd-BOPTA and the contrast agent is selectively secreted into bile using the same transporter that is used to eliminate bilirubin. The result of this being that the normal liver parenchyma will display contrast enhanced features (especially T1 relaxation), about an hour following injection of the agent.
A pharmacokinetic profile that is triphasic and similar to that of Gd-BOPTA is provided by Gd-EOB-DTPA. Again, GD-EOB-DTPA is selectively absorbed by the hepatocytes and excreted via the kidneys.
Following injection of Gd-BOPTA, only a small portion of it, about 3-5% is taken up by hepatocytes and eliminated via bile. In the case of Gd-EOB-DTPA half of the injected dose is absorbed and eliminated via the hepatobiliary pathway after approx. 60 min. The signal intensity of the liver parenchyma is at its maximum after approx. 20 min post injection and can last for upto 2h.
Mn-DPDP, dissociates into free Mn(2+) and DPDP, the hepatocytes take up the free ions, whereas a combination (association) with Zn(2+) could be shown by DPDP. The remaining Mn-DPDP is taken up by the remaining hepatocytes, by another specific carrier mechanism and shows intracellular dissociation. The half-life for this agent is difficult to determine due to the fact that the free Mn ions remain in the body for quite a few days, with the ions accumulating to a lesser extent in the gastric mucosa, adrenal glands and some intracerebral structures. The majority of this remnant agent accumulates in the liver.
Pharmacodynamics
Ionicity: An active molecule which dissociates into its component ions in solution, is referred to as ionicity. (Not to be confused with “dechelation,” which refers to dissociation of the Gd ion from its ligand). As iodinated contrast agents have undergone years of transformations and tweaking, the instances of particular concern are the potentially harmful effects on the cardiac rhythm and function. A paper by Lembo et al showed that radiographic contrast agent that is ionic, with high-osmolality; Diatrizoate is frequently associated with more instances of ventricular tachyarrythmia, than the non-ionic, low osmolality agent; iopamidol.
The hemdodynamic effects of MR contrast agents can be divided into two categories; the transient (duration approx. 1 min) and more persistent effects (5-10 min or longer duration).
A study in dogs that were injected with Gd-DTPA rapidly; demonstrated a drop of 20mm Hg in systemic pressure after rapid injection of a 0.5mmol/kg bolus. Lower rates of injection of this contrast agent yielded no significant hemodynamic disturbances.
The ionic medium surrounding electrically active cells affects their performance. The sodium-calcium balance is of utmost importance for effective and balanced myocardial contractility in the case of cardiac myocytes. Muhler et al postulated and investigated the disruption os ionic balance as a possible cause of reversible hemodynamic instability following Gd-DTPA injection. He surmised that the addition of calcium to the injected agent could reduce or completely eliminate the transient cardiovascular effects of Gd-DTPA in a dose-dependent manner.
This paper thus implicated a local effect on serum ionized calcium after a bolus central venous injection of Gd-DTPA as the cause of transient cardiodepression. It is important to note that these effects were elicited under high doses of rapid central venous bolus injections and were also short-lived.
Osmolality: The property of osmolality is intimately related to the property of iconicity. The osmolality is the number of moles of osmotically active particles that are present in the solution per kilogram of solvent. The currently available MR agents have an osmolality ranging between 630 and 1970 mOsm/kg. All of these agents are hypertonic when compared to the average plasma osmolality of 285 mOsm/kg.
As already discussed, local calcium binding and iconicity can explain the effect of reversible cardiodepression; however, in some instances, a second category of longer-lived cardiovascular effects can occur over the course of minutes. Fluid shifts, changes in vascular resistance and cardiac adaptation are some of these likely effects that are often attributed to osmolality. The first study that was performed to elicit these effects was performed by Kuhtz-Bushbeck et al. They injected high dose Gd-DTPA, iopamidol, diatrizoate and saline into pigs. They surmised that Magnevist and the non-ionic radiographic agent iopamidol caused a 10– 15% uptick in mean aortic and pulmonary arterial pressure, cardiac output, stroke volume, and contractility. Vasodilation causing decreased pulmonary vascular resistance along with a reduction in systemic vascular resistance. These effects returned to pre injection levels, within 10 minutes, and were found to be greater than those observed with saline injection alone. The similarity between Magnevist and iopamidol suggests that iconicity has no bearing in terms of these longer-lived hemodynamic effects. The difference between Magnevist and diatrizoate, which have similar iconicity and high osmolality, points toward the fact that osmolality is not the primary factor in potentiating these effects either. This result supports the notion that these effects are not potentiated by ionicity or osmolality.
Viscosity: The amount of internal friction within a fluid is known as viscosity. With an increase in internal friction, less deformation occurs with a given shear stress, resulting in increased resistance to flow. The unit of measurement for viscosity is Pascal seconds (Pa-s). Contrast agents and their viscosity is generally denoted by centiPoise (cP). Water has a viscosity of 1cP at 20 degree Celsius. Plasma has a viscosity 1.5cP and whole blood has a viscosity of 3cP at 37 deg Celsius. The first generation Gd agents have viscosity ranging between 1.3 to 2.9cP at 37 deg Celsius.
The current Gd chelates have a viscosity that is not a significant concern at the injection rates and standard doses. However, when dealing with high-flowrate applications and small catheters, the radiologist should be aware of the limits of the system. Since catheter radius is the predominant factor affecting flow rate, increasing catheter size is the simplest solution to a flow-limit problem. Another solution is to take advantage of differences in viscosity between agents. Viscosity of the contrast agents can also be changed by warming the agent to body temperature prior to injection (Non FDA approved practice).
Nephrotoxicity: One of the more accepted theories regarding contrast-induced nephropathy (CIN) with iodinated contrast agents is that free radical formation triggers and causes renal tubular damage. Hyperosmolar stress triggers the generation of free radicals, which is aggravated by the acidic environment of tubular urine. The above hypothesis gains more importance due to the nephro-protective effects seen with N-acetylcysteine (A free radical scavenger) and sodium bicarbonate treatments. A study performed by Thomsen et al measure the degree of albuminuria and enzymuria caused by both iodinated and Gd based contrast agents. The effect of osmolality exerted on the renal tubules was directly correlated to the degree of albuminuria, presumably due to an osmotic effect on the glomerular filter. Both iodinated and Gd based contrast agents stimulated the release of tubular and cytoplasmic brush border enzymes.
Nephrogenic systemic fibrosis (19)
There are the several reports that have associated intravenous Gd administration with a rare and relatively unheard of systemic condition that is deemed idiopathic, initially called as Nephrogenic fibrosing dermopathy (NFD). This condition was initially diagnosed as a dermatologic disorder, but it was soon learned that internal organs could and can be affected too. This condition is now more commonly referred to as Nephrogenic Systemic Fibrosis (NSF). This condition is more commonly seen in individuals with renal issues such as kidney disease and is also strongly associated with previous IV Gd exposure. NSF occurs in patients who have had a prior history of vascular procedure, recent major surgery or thrombotic event resulting in an inflammatory states with high levels of circulating fibrocytes. These fibrocytes appear to induce fibrosis in normal tissue.
Thickening, induration and tightening of the skin as well as subcutaneous edema are some of the salient features of this condition; that develops a few days to months after intravenous Gd injection. Distal extremities are the most common site to be affected but there are cases wherein the trunk has been affected as well. The changes might and could lead to joint contracture along with severe limited range of motion and mobility. In addition to skin manifestations, NSF can also involve the lungs, liver, heart, diaphragm and skeletal muscles along with the kidney and other organs as well.
Other instances wherein iodinated and intravenous Gd use should be limited/reconsidered:
1. Pregnancy (1)
2. Lactation (2004 edition of the ACR Manual on Contrast Media states that “the available data suggest that it is safe for the mother and infant to continue breast-feeding after receiving such an agent”. A similar conclusion was reached by the Contrast Media Safety Committee of the European Society of Urogenital Radiology in 2005. Ultimately, an informed decision to disrupt breast-feeding should be left up to the mother, who should be assured that this disruption need not last longer than 24 hours (assuming normal renal function) (21)
3. Pediatric patient groups. (20)
4. Patients with GFR
