Extracellular Contrast Media in Perfusion Imaging

Stacul Fulvio, MD

Henrik S. Thomsen, MD

▪ Introduction

In all aspects of radiology (ultrasound, conventional radiography, computed tomography [CT] scanning, and magnetic resonance imaging [MRI]), medical imaging contrast-enhancing agents have been developed. They are used to enhance contrast, to characterize lesions, and to evaluate perfusion and flow-related abnormalities. They can also provide functional and morphologic information.

▪ Classification

Iodine-Based Contrast Media

These agents are mainly used for CT and for angiography. They contain one or two triiodinated benzene rings (monomeric or dimeric agents) and may have electrical charges in their structure or not (ionic or nonionic agents) (Table 11.1). Ionic agents include one anion and one cation in each molecule.¹ These ions attract the negative and positive poles of the water molecules, and thus these agents are water soluble. Nonionic agents do not contain ions, but they are water soluble as well, thanks to their OH groups.

Therefore, we can classify iodine-based contrast media into four categories:

Ionic monomers
Ionic dimers
Nonionic monomers
Nonionic dimers

The monomers contain three atoms of iodine and the dimers contain six. Each molecule of ionic agents contains two particles in solution (one anion and one cation), while each molecule of the nonionic agent contains one particle in solution.² Therefore, the ratio between the number of iodine atoms and the number of particles in solution is as follows:

Ionic monomers 1.5 (3:2)
Ionic dimers 3 (6:2)
Nonionic monomers 3 (3:1)
Nonionic dimers 6 (6:1)

The ratio is closely related to the osmolality of the contrast materials because the osmolality of a solution is proportional to the sum of the concentrations of the different molecular or ionic particles contained in the solution. Indeed, the osmolality of ionic monomers is about five to seven times the osmolality of plasma (1,500 to 2,000 mOsm/kg) when considering iodine concentrations that are usually employed in CT or angiography. The osmolality of nonionic monomers and ionic dimers is two to three times the osmolality of the plasma, while nonionic dimers are isoosmolar to plasma at any concentration (Table 11.2). Therefore, contrast media may be divided into high-osmolar agents (ionic monomers), low-osmolar agents (nonionic monomers and ionic dimers), and iso-osmolar agents (nonionic dimers).² It is interesting that nonionic monomers and ionic dimers are called lowosmolality agents even if their osmolality is still higher than the plasma osmolality.

The viscosity of the solution is another important parameter, although not as important as in the past, thanks to the use of modern injectors. Viscosity is affected by iodine concentration (the higher iodine concentration, the higher viscosity) and by the temperature (the higher temperature, the lower viscosity). Considering ionic monomers, their meglumine salts have a higher viscosity than sodium salts, but these agents generally have lower viscosities than nonionic monomers (Table 11.2). Additionally, the dimers usually display a higher viscosity than the monomers. Therefore, warming nonionic contrast media to body temperature to lower viscosity before their administration is advisable, particularly when nonionic dimers are used.

Iodine-based contrast media are in most cases given by bolus injection. Their pharmacokinetics is similar to those of extracellular gadolinium-based contrast media, whereas they differ regarding the protein binders used for MRI.¹ They are described according to a two-compartment model, the two compartments being the intravascular plasma space and the interstitial space. The agents do not enter cells significantly in or outside of the circulation. On injection into the circulating blood, they are simultaneously diluted in the circulating plasma volume and immediately begin to pass out of the circulation into the interstitium. At some point, varying among tissues, an “equilibrium point” is reached at which falling plasma levels and rising interstitial concentrations are transiently equal. After this point, as the contrast agents are continuously removed from blood via renal filtration, there is a reversal of movement and the contrast agents begin to come out of the interstitium and back into the plasma. Iodine-based contrast agents are excreted almost solely by the normal kidney by passive glomerular filtration with no significant active tubular involvement.

TABLE 11.1 Structures, Types, and Names of Commercial Iodine-Based Contrast Media

All agents are distributed into extracellular space and are predominantly renally excreted. Very little, if any, protein binding exists.

Trade names are protected by copyright, and other trade names may exist.

Reprinted with permission from Thomsen HS, Dawson P, Tweedle M. MR and CT contrast agents for perfusion imaging and regulatory issues.

In: Bammer R, ed. MR & CT perfusion imaging: clinical applications and theoretical principles. Philadelphia, PA: Lippincott Williams & Wilkins; 2015: Chapter 11 .

TABLE 11.2 Physical Data for Commercial Iodine-Based Contrast Media

Name	Structure	Charge	Maximum^a g-Iodine/mL	Osmolality, mOsmol/kg	Viscosity, mPa/s	Comparison, g-Iodine/mL	Osmolality, mOsmol/kg	Viscosity, mPa/s
Diatrizoate^b Na Monomer		Ionic	300	1,550	2.4	300	1,550	2.4
Diatrizoate
NMG	Monomer	Ionic	358	1,980	9.2	282	1,500	4.0
Diatrizoate
Na/NMG	Monomer	Ionic	370	2,100	8.4	292	1,420	4.0
Iothalamate	Monomer	Ionic	370	2,400	9.0	325	1,700	3.0
Ioxitalamate	Monomer	Ionic	350	2,130	7.5	300	1,500	5.2
Ioxaglate	Dimer	Ionic	320	600	7.5	320	600	7.5
Iopamidol	Monomer	Nonionic	370	796	9.4	300	616	4.7
Iohexol	Monomer	Nonionic	350	862	11.2	300	709	6.8
Iomeprol	Monomer	Nonionic	400	726	12.6	300	521	4.5
Ioxilan	Monomer	Nonionic	350	695	8.1	300	585	5.1
Ioversol	Monomer	Nonionic	350	792	9.0	300	651	5.5
Iopromide	Monomer	Nonionic	370	774	10	300	607	4.9
Iobitridol	Monomer	Nonionic	350	915	10	300	695	6
Iopentol	Monomer	Nonionic	300	683	6.5	300	683	6.5
Iotrolan	Dimer	Nonionic	320	317	11.6	300	291	8.4
Iodixanol	Dimer	Nonionic	320	290	11.8	270	290	6.3
Data at 37°C. Formulations frequently contain small quantities of excipients (e.g., Tris buffer) and can differ by geographic region. Multiple generic formulations exist for ionic monomers with slightly different data. ^aSome ultrahigh concentrations of ionic monomers were marketed at up to 460-480 mg I/mL with osmolalities of ˜3,000 and viscosities >19.^bSodium, NMG (Meglumine), and mixed counterion formulations have somewhat different colligative properties. Diatrizoate, as an example, is shown in Na and NMG formulations to exemplify the expected range. NMG salts are more viscous. Reprinted with permission from Thomsen HS, Dawson P, Tweedle M. MR and CT contrast agents for perfusion imaging and regulatory issues. In: Bammer R, ed. MR & CT perfusion imaging: clinical applications and theoretical principles. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Chapter 11 .

Gadolinium-Based Contrast Media

MRI contrast agents can be classified according to¹

The metal ion
Whether the ion is paramagnetic or superparamagnetic
Naturally occurring ion in the body (yes or no)
Ionicity (ionic or nonionic)
Chelate (macrocyclic or linear)
The capability to hold the metal ion, in particular gadolinium (low, intermediate, or high stability)
Protein binding (yes or no)
Distribution in the body (extracellular or organ specific)

Today, the most used agents are based on a paramagnetic metal ion (gadolinium), which does not appear naturally in the human body. The agent may be either ionic or nonionic. High-stability agents based on a macrocyclic chelate are preferred more and more. In some countries, for example, Denmark, the low-stability agents are no longer used. The most used agents are extracellular with no protein binding.

Paramagnetic contrast agents (e.g., gadolinium, manganese) are mainly positive enhancers that reduce T1 and T2 relaxation times and increase signal intensity on T1-weighted MR images.² Gadolinium is a paramagnetic metal ion in the lanthanide series of the periodic table. It has a high magnetic moment and a relatively slow electronic relaxation time, and it is very toxic. Manganese has similar relaxivity properties to gadolinium but, unlike gadolinium, occurs naturally in the body. It is one of the least toxic metal ions and is excreted by the hepatobiliary system.³ Agents containing manganese are no longer commercially available in Europe and the United States.

Superparamagnetic agents (e.g., iron) are extremely effective T2 relaxation agents, which produce signal loss on T2- and T2^★-weighted images. They also have a T1 effect, which is substantially less than their T2 effect.⁴ However, superparamagnetic agents are no longer registered in most countries. Iron was used as the active ion in many agents. The iron agents were metabolized by the macrophages and the iron entered the body iron pool. Ferumoxytol is approved for intravenous treatment of patients with iron deficiency. Currently, it is studied whether it can be used for angiography and perfusion studies.⁵ However, the MR use is off-label.

Gadolinium is a heavy metal, which in its free form is very toxic and may cause liver necrosis, hematologic changes, etc. A human being would not survive 0.1 mmol/kg free gadolinium injected into the circulation.¹ Therefore, the gadolinium ion is bound to a ligand in order to minimize its toxicity. For gadolinium-based contrast
agents, the choice of chelate structure influences the compound’s chemical and biologic stability and the colligative properties of its formulations, both of which in turn influence tolerance, pharmacokinetics, clinical uses, and contraindications. Two fundamental structural types are in use:

Linear seven-ring structures derived from diethylene triamine pentaacetate (DTPA)
Macrocyclic eight-ring structures derived from dodecane tetraacetic acid (DOTA).

The fundamental difference between these structural types is that the chain of nitrogen and carbon atoms constituting the backbone of the chelating agent is open on both ends in linear agents and closed into a single loop in macrocycles. The macrocyclic chelate has much better grip on the toxic gadolinium than the linear chelate.⁶ The ligands may be ionic, which have a charge in solution, or nonionic. In order to reduce the osmolality, the two carboxyl groups in the ionic linear chelate have been replaced by two amide bindings, which have a weaker binding grip on the gadolinium ion than the carboxyl groups.

Gadolinium-based contrast agents may be classified in two categories: (a) nonspecific extracellular gadolinium chelates and (b) high-relaxivity agents/organ-specific agents/protein-bound agents (protein binders).¹,² The nonspecific extracellular gadolinium chelates do not bind to proteins and are excreted by the kidney only, while the high-relaxivity agents show protein binding and are excreted to a varying extent through the bile as well as by the kidney. Nine gadolinium-based contrast agents are currently commercially available (Table 11.3).

The osmolality of the gadolinium-based contrast agents varies between 600 and 2,000 mOsmol/kg (Table 11.4). Unlike iodinebased contrast agents, high-osmolality gadolinium-based agents do not cause more acute nonrenal adverse reactions and discomfort than low-osmolality agents. This is probably because the molar amounts of gadolinium-based contrast agents used for the MR examinations are significantly less than the molar amounts of iodine-based agents used for radiography including CT.

The stability of gadolinium-based contrast agents depends on their kinetics, thermodynamics, and conditional stability (Table 11.4). Although these parameters do not directly relate to molecular structure,¹,⁶ the contrast agents with cyclic ligands, in which gadolinium is caged in a preorganized cavity, are more stable than those with linear ligands.

The relaxivity (r₁ and r₂) of the extracellular gadolinium-based agents is almost identical at both 1.5 and 3 T, since the change in field strength does not affect the relaxivity (Table 11.4). Protein binding increases the r₁ relaxivity of gadolinium-based agents, particularly at 1.5 T, but the relaxivity decreases more the higher the protein binding is when one moves from 1 to 3 T (Table 11.4).

The pharmacokinetics of extracellular nonspecific gadoliniumbased contrast agents are similar to those of iodine-based radiographic contrast agents (two-compartment model: the two compartments being the intravascular plasma space and the interstitial space).¹ They do not enter cells significantly in or outside of the circulation. After the extracellular gadolinium-based contrast medium has been injected into the circulating blood, it is diluted in the circulating plasma volume. Straightaway, it begins to enter the interstitium, leaving the circulation, and at some point, it will reach an “equilibrium point.” This point can vary from tissue to tissue. The “equilibrium point” is the point when the level of falling plasma and rising interstitial concentrations are the same. Hereafter, the extracellular contrast medium is continuously removed from the blood by means of excretion, and subsequently, the contrast medium begins to leave the interstitium and go back to the plasma, thereby revising its movement. The extracellular gadolinium-based contrast medium is excreted nearly by the normal kidney only by means of passive glomerular filtration without significant active tubular involvement.

High-relaxivity gadolinium-based contrast agents or protein binders behave similarly to the extracellular nonspecific agents immediately after intravascular injection.⁷ However, because of their protein binding and biliary excretion, their pharmacokinetics differs and the liver uptake phase may be used for liver imaging. Of the available protein binders, gadobenate is used mainly as an extracellular agent, gadofosveset was specifically designed for MR angiography, and gadoxetate, which has the greatest biliary excretion, is mainly used for liver imaging. Protein binding, predominantly serum albumin binding, can produce (a) variable hepatobiliary versus renal excretion, (b) greater relaxivity where albumin is present, and (c) extended plasma half-life versus both excretion and leakage into extracellular space. All the currently available protein binders are based on the linear chelate (DTPA) and are ionic. Under similar conditions, gadobenate binds only slightly, approximately 5% to albumin; gadoxetate binds approximately 10%; and gadofosveset binds approximately 90%. These values are approximates for comparison and highly dependent on conditions of the measurement, including gadolinium concentration, which changes with time after injection, and also are complicated by binding of multiple gadolinium-based contrast agents to each albumin molecule. Gadobenate is excreted mostly into the urine at rate indistinguishable from the non-protein-binding agents, with only approximately 4% hepatobiliary excretion in man; in rats, it is much higher. The consequence of the added lipophilicity in gadoxetate is approximately 10% albumin binding along with very rapid hepatic uptake and then hepatobiliary excretion, approximately 50%, accompanied by relatively rapid renal excretion. In gadofosveset, the hepatobiliary excretion is 5%; due to the protein binding, its T1/2 is 18 hours or 12 times longer than that of the extracellular gadolinium-based contrast agents.

▪ Dosage

Iodine-Based Contrast Media

This issue is addressed considering different procedures requiring administration of iodine-based agents separately.

Intravenous urography was largely replaced by CT urography, but nevertheless it is still popular in some countries. The typical recommended dose is 300 mg I/kg for an adult patient.⁸ A dose of approximately 22 g of iodine is considered optimal for both lowosmolality and high-osmolality contrast media, although adjustments can be made for extremely small or large patients.⁹

Digital subtraction angiography (DSA) requires contrast administration through catheters, which are selectively placed into different vessels. Injection can be performed manually or taking benefit of power injectors. The contrast volume is related to the vessel size and tables suggesting the optimal amount and the optimal injection rate for each vessel when performing conventional angiography were available.⁹ When DSA was introduced 30 years ago, its higher contrast resolution allowed for injection of lower iodine doses and thus injecting lower volumes or more diluted agents. Practical purposes usually favored the former approach.

When considering CT, dosage is a difficult issue and the type of scheduled procedure, that is, CT angiography or CT for tumor staging, should be considered. The peak of the aortic enhancement depends on the contrast concentration, on the injection rate, and, to a lesser extent, on the total contrast volume. The availability of faster scanners allowed shorter acquisition times and therefore to decrease the contrast dosage of CT angiographic studies. This is not the case when considering the hepatic enhancement, which is closely related to the iodine load delivered with the contrast injection. Therefore, faster scanners did not allow decreasing iodine dosage in an oncologic setting.

TABLE 11.3 Structures, Types, Names, and Excretion of Commercial Gadolinium-Based Contrast Media Used for MRI

In solution, each structure also coordinates one water molecule. All agents distribute to extracellular space.

The figures shown apply to human beings. Protein binding and excretion vary with species.

Trade names are protected by copyright.

Reprinted with permission from Thomsen HS, Dawson P, Tweedle M. MR and CT contrast agents for perfusion imaging and regulatory issues. In: Bammer R, ed. MR & CT perfusion imaging: clinical applications and theoretical principles. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Chapter 11 .

TABLE 11.4 Physical Data for Commercial Gadolinium-Based Contrast Media for MRI at 37°C (Except Where Noted)

Structure Type	Linear						Macrocyclic
Charge type	Ionic				Nonionic		Ionic	Nonionic
Trade name	Magnevist	MultiHance	Eovist Primovist	Ablavar	Omniscan	OptiMARK	Dotarem Magnescope	ProHance	Gadovist Gadavist
[Gd] in M (commercial preparations)	0.5	0.5	0.25	0.25	0.5	0.5	0.5	0.5	1.0
Osmolality, mOsm/kg	1,960	1,970	688	825	789	1,110	1,350	630	1,603
Viscosity, mPa/s	2.9	5.3	1.2	2.1	1.4	2.0	2.0	1.3	5.0
Relaxivity, Plasma
r₁—1.5 T/mM/s	3.9-4.1	6.3-7.9	6.9	19	4.3	4.7	3.6	4.1	4.7-5.2
r₂—1.5 T/mM/s	4.6-5.3	8.7-18.9	8.7	34	5.2	5.2	4.3	5.0	6.1-7.5
r₁—3 T/mM/s	3.7-3.9	5.5-5.9	6.2	9.9	4.0	4.5	3.5	3.7	4.5-5.0
r₂—3 T/mM/s	5.2	11.0-17.5	11.0	60	5.6	5.9	4.9	5.7	6.3-7.1
Stability Constants
Log K_eq, M-¹^a	22.5	22.6	23.5	22.1	16.9	16.6	25.6	23.8	21.8
Log K_eq‘, pH 7^a	18.4	18.4	18.7	18.9	14.9	15.0	19.3	17.1	15.5
T_½ dissociation pH 1	<5 s^a	<s^a	<5 s^a	<5 s^a	<5 s^a	<5 s^a	26 h	2.0 h	7.9 h
Risk of NSF^b	High	Intermediate	Intermediate	Intermediate	High	High	Low	Low	Low
^a25°C. ^bAccording to the classification approved by the European Medicines Agency (EMA). High-risk agents are contraindicated in patients with a glomerular filtration rate (GFR) < 30 mL/min × 1.73 m² and should be used with caution in patients with a GFR between 30 and 60 mL/min × 1.73 m² (ESUR guidelines on Contrast Media version 8.1—http://www.esur.org (Jan 2014)). Reprinted with permission from Thomsen HS, Dawson P, Tweedle M. MR and CT contrast agents for perfusion imaging and regulatory issues. In: Bammer R, ed. MR & CT perfusion imaging: clinical applications and theoretical principles. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Chapter 11 .