MIS 206 MEDICAL IMAGING METHODS 2008

Iodine Based Contrast Media

Introduction

In medical terminology contrast media is defined as exogenous substance used to

enhance the visibility of structures or fluids within the body. These exogenous substances
alter the contrast in X-ray imaging by affecting the attenuation of X-rays, thus enabling
visualization of not easily seen anatomical structures e.g. blood vessels, kidneys,
billary/hepatic ducts etc. The ability of contrast media to attenuate x-rays arises from the
basic fact that that the substance which has been introduced into the body has either a
higher or lower atomic number than that of the surrounding tissue (It is the atomic
number of any substance which determines as to what degree the radiation will be
attenuated).
Historically as early as 1986 the first arteriography was performed in an amputated hand.
A contrast medium consisting of a suspension of chalk in water was injected into the
arteries. The first water soluble iodine contrast medium was used in 1920 and was
discovered because patients with syphilis in those days were treated with sodium iodide.
The sodium iodide was observed in an image of the abdomen as an "increased density" of
the kidneys. Sodium iodide, however, had a high toxicity when used as contrast medium.

Why the need for Contrast Media in Medical Imaging?

Different tissues within the body attenuate the beam of X-rays to different degrees.
The degree of attenuation of an X-ray beam by an element is complex, but one of the
major variables is the number of electrons in the path of the beam with which it can
interact. The number of electrons in the path of the beam is dependent upon three factors:
• The thickness of the substance being studied
• Its density
• The number of electrons per atom of the element (which is equal to its atomic
number)
In a complex mixture of elements, which is of course what we are concerned with in the
organs of a patient, the degree of attenuation is particularly influenced by the average of
the atomic numbers of all the atoms involved.

Where there is a considerable difference between the densities of two organs, such as
between the solid muscle of the heart and the air in the lungs, then the outlines of the
structures can be visualized on a radiograph because of the natural contrast that exists.
Similarly, if there is a difference between the average atomic numbers of two tissues,
such as between soft tissues, which are composed of elements of low atomic number, and
bone, which is partly composed of the element calcium, with a rather higher atomic
number, then the outlines of the different structures can be seen by natural contrast.

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However, if the two organs have similar densities and similar average atomic numbers,
then it is not possible to distinguish them on a radiograph, because no natural contrast
exists. This situation commonly occurs in diagnostic radiography, so that, for example, it
is not possible to identify blood vessels within an organ, or to demonstrate the internal
structures of the kidney, without artificially altering one of the factors mentioned earlier.

Types of Contrast Media

Contrast media can be broadly grouped into two categories, they are either

(i) Positive or
(ii) Negative contrast media.

In general positive contrast media are those which have an increased

absorption(increased attenuation) of x-rays and show up as white/grey areas whereas
negative contrast are those which have less absorption(lowered attenuation) of x-rays and
show up as dark/grey areas.

Positive Contrast Media

As mentioned above these substances once introduced into hollow structures of the body
will show up as white/grey areas. This is by far the largest sub-group of contrast media.
Positive contrast media can also be further be classified into the following sub-
categories:

(i) Iodine Based

(ii) Non Iodine Based
(iii) Other

Iodine Based Contrast Media

Iodine based or iodinated contrast media may be divided into

• Water-soluble,
• Water-insoluble, and
• Oily contrast media.

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• LOCM-Low Osmolar Contrast Medium.

• HOCM-High Osmolar Contrast Medium.

Water-insoluble contrast media include aqueous suspension of propyliodone (Dionosil),

used in bronchography. Oily contrast media include Lipiodol, a stable compound of 40%
iodine in poppy seed oil, introduced in the 1920s, and later replaced by Lipiodol Ultra
Fluid and Ethiodol, ethyl esters of iodinated fatty acids of poppy seed oil containing 48%
and 37% iodine, respectively. These oils are still to some extent used for lymphography,
and by some also for hysterosalpingography. Iodophenylundecylic acid (iophendylate)
was introduced in 1944 as a contrast medium for oil myelography (brand names:
Pantopaque, Myodil).

Water Soluble Iodine Contrast Media for the Extracellular Space

These contrast media are used for intravenous urography, angiography and for contrast
enhancement in computerized tomography. Water soluble contrast media can be further
sub-categorized into either
(i) Ionic,
(ii) Non ionic contrast media.

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Table 1. Different contrast media - their structure, ratio, viscosity, osmolality

and name

Structure Ratio Viscosity Osmolality Generic name Trade name

20
37 ̊

iothalamate Conray
Figure 2 ionic 1500-1600 Vasoray
3:2=1.5 5+ 3+
monomer metrizoate amidotrizoate Isopaque
9++ 5++
Urografin
Angiografin
Gastrografin
ioxithalamate Telebrix
ionic
Figure 3 6:2=3 12 6 600 Ioxaglate Hexabrix
dimer
iohexol Omnipaque
Figure 4 non-ionic 3:1=3 11 6 500-700 iopamidol lopamiro
monomer iopromide Ultravist
ioversol Optiray
non-ionic iodixanol Visipaque
Figure 5 6:1=6 25 10 300
dimer iotrolan Isovist

Values of viscosity (cP) and osmolality (mOsm/kg H2O) have been approximated to an
iodine concentration of 300 mg I/ml.
+ are viscosity values for sodium salts.
++ are viscosity values for meglumine salts.

Figure 1.
Transformation of an ionic monomer (above) to a
non-ionic monomer (below).

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Figure2.
Ionic monomer (ratio1.5).
2 ions in solution per 3 iodine atoms
3 iodine atoms per molecule
1 carboxyl group (-COO-) per molecule
No hydroxyl group (-OH) except ioxithalamate
with one OH/molecule
Intravenous LD50 for mouse
5-10 g I/kg mouse

The efforts to design less toxic contrast media were started in the 1920s and are still
continuing. A major development occurred in the beginning of the 1950s when it was
found that contrast media with three iodine atoms bound to a benzene ring had low
toxicity (amidotrizoate Table 1, Fig. 2). A benzene ring with three iodine atoms is in
contrast medium research defined as a "mer". A monomer, for example, contains one such
three- iodinated benzene ring, while a dimer contains two such structures. In the 1960s a
radiologist, T. Almen, proposed the synthesis of monomers and oligomers of non-ionic,
tri-iodinated contrast media (Fig. 1).The first non-ionic monomer was produced by the
Norwegian contrast medium company, Nyegaard & Co

Further factors that influence toxicity and water solubility are described below. Table 1
and Figures 2-5 show the most commonly used contrast media, their names, chemical
structures, osmolality, viscosity and ratio between number of iodine atoms and number of
contrast medium particles in an ideal solution.

Water Solubility and Toxicology

Water is the most common molecule in the human body, both inside and outside the cells.
In order to enable a high contrast medium concentration in extracellular water, high water
solubility is necessary for contrast media in urography, angiography, etc. This water
solubility is achieved in different ways by ionic and by non-ionic contrast media. Water is
a polar solvent; the water molecules are electrically neutral (equal numbers of positive
and negative unit charges within the water molecule), but the positive and negative
charges are distributed so that there is a surplus of positive charges (lack of electrons) at
the site of the hydrogen atoms (which form positive poles) and a surplus of negative
charges (excess of electrons) around the oxygen atom (which forms a negative pole).

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Ionic contrast media dissociate in water into electrically charged particles named ions.
The positively charged ion may be a sodium ion or a meglumine ion. The negatively
charged ion is the benzene derivative with three iodine atoms and a negatively charged
carboxyl group. The ionic contrast media are water soluble because the positive and
negative ions are attracted to the negative and positive poles of the water molecules.

Non-ionic contrast media are electrically neutral like the water molecules. The nonionic
contrast media are water soluble because they contain polar groups (OH-groups, hydroxyl
groups) which have an uneven distribution of electrical charges with excess electrons
around the oxygen atoms (forming negative poles) and a deficit of electrons around the
hydrogen atoms (forming positive poles). The electrical poles in the OH-groups of the
contrast media are attracted to the electrical poles in the water molecules - thus achieving
water solubility.

The only desirable effect of a contrast medium is to attenuate radiation. All other effects
of the contrast medium in the body, regardless whether they cause clinical symptoms or
not, are not desired. When these effects cause changes observable in laboratory tests or
clinical symptoms they are deemed to be adverse effects. Different chemical structures
have been designed to achieve high water solubility and this has resulted in contrast
media with different toxicity.

The total toxicity of a contrast medium solution is the sum of the chemotoxicity of the
contrast medium molecules, the osmotoxicity of the contrast medium solution and the ion
toxicity - a surplus or deficit of various ions in the solution:

(i) The chemotoxicity of a contrast medium molecule may depend on its effects
on proteins in the extracellular space and/or in the cell membrane, and effects
on cell organelles and enzymes by the small numbers of contrast medium
molecules which go intracellularly. (The carboxyl ion in ionic contrast media
is an example of a chemical structure with high neurotoxicity in the
subarachnoid space. Therefore, ionic contrast media must not be used in
myelography.)

(ii) Osmotoxicity. Ionic contrast media have a high osmolality per amount of
iodine, because the iodinated and negatively charged ions (diatrizote,
iothalamate, metrizoate) are accompanied by the non- iodinated positively
charged ions (sodium ions, meglumine ions) .The hypertonicity of the contrast
medium solution causes fluid shifts from erythrocytes, endothelial cells and
other structures. This induces pain in arteriography, dilatation of blood vessels
with a fall in blood pressure and viscosity changes of the blood.

(iii) Ion-imbalance. When contrast medium instead of blood flows through blood
vessels, a too high or too low concentration of different ions produces side-
effects (ventricular fibrillation at coronary arteriography, influence on
plasma proteins).

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Osmolality and the Ratio Concept

The ionic monomeric contrast media are highly hypertonic compared to blood. Blood has
an osmolality of 300 mosmol/kg water and the ionic contrast media used in angiography
have an osmolality of 1500-2000 mosmol/kg. The osmolality is proportional to the
number of particles in a solution. The "ratio" of a contrast medium describes the
proportions between its ability of being a "good" contrast medium (by attenuating X
-rays) and its tendency to induce side-effects (by its osmotoxicity). You can calculate a
theoretical ratio of a contrast medium as "the number of iodine atoms per volume contrast
medium" divided by "the number of particles (contrast medium ions or contrast medium
molecules) per volume contrast medium solution”.

The ionic monomeric contrast media have a ratio of 1.5 (3/2 = 1.5) (three iodine atoms
per two water soluble particles [ions]). When there was a need to decrease the osmotic
effects per amount of iodine, it was done by increasing the ratio, e.g. the number of
iodine atoms/number of particles (Figs. 1 and 2).
A non-ionic monomeric contrast medium that does not dissociate in water, has three
iodine atoms per water soluble molecule and therefore ratio 3 (3/1 = 3) (Fig. 4).
The evolution of contrast media has continued and one of its goals has been to further
reduce the osmolality of both the ionic and non-ionic media by making dimers of them.
First the synthesis of a dimeric, ionic contrast medium, which has the ratio 3 (6/2 = 3)
was made (Fig. 3).Later, in the 1980s and 1990s, dimeric non-ionic contrast media have
been explored and these contrast media have such low osmolalities that electrolytes have
to be added in order to make them iso-osmotic with blood (Fig. 5).They have a ratio of 6
(6/1 = 6).

Figure 3. Ionic dimer (ratio 3).

2 ions in solution per 6 iodine atoms
6 iodine atoms per molecule
1 carboxyl group (-COO-) per molecule
1 hydroxyl group (-OH) per molecule
Intravenous LD50mouse 10-15 g I/kg mouse

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Figure 4. Non-ionic monomer (ratio 3).

1 molecule in solution per 3 iodine atoms
3 iodine atoms per molecule No carboxyl group
(-COO-)
4-6 hydroxyl groups (-OH) per molecule
Intravenous LD 50 mouse 15-20 g I/kg mouse

Figure 5. Non-ionic dimer (ratio 6).

1 molecule in solution per 6 iodine atoms 6 iodine
atoms per molecule
No carboxyl group (-COO-)
More than 8 hydroxyl groups (-OH) per molecule
lntravenous LD50 mouse 20 g I/kg mouse

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Different types of Contrast Media (Ionic & Non ionic)

The strategies above about handling water solubility; chemo- and osmotoxicity have led
to four different types of iodine contrast media for urography, angiography and
computerized tomography (Figures 2-5).

(i) Ionic monomeric contrast media.

(ii) Ionic dimeric contrast media.
(iii) Non-ionic monomeric contrast media.
(iv) Non-ionic dimeric contrast media.

As the ability of the iodine atom to attenuate X -rays is independent of the organic
molecule in which it is chemically bound, a comparison between side-effects, toxicity,
osmolality, viscosity or price of different contrast media must always be made in iodine
equivalent amounts and concentrations. (It is thus important to relate adverse effects,
price, etc., to the desired effect of a contrast medium, i.e. its attenuation of X-rays, which
is proportional to the amount of iodine.)

Contrast Media Kinetics

The four contrast medium groups above have all high water solubility, low plasma
protein binding, almost exclusive distribution to the extracellular space and minor
intracellular distribution. The size of the molecules enables them to pass through the
glomerular basement membrane. They are to a very small extent reabsorbed or excreted
by the tubular cells and are quantitatively handled by the kidneys like Insulin. The media
can therefore be used to determine glomerular filtration rate (GFR). Their half-life in
plasma is dependent on the GFR. At normal GFR they have a half-life of 1.5-2 h. If GFR
is decreased by a factor 2 or 4, their plasma half-life increases by a factor 2 or 4, etc.
A small amount (at normal GFR less than 2 %) of these contrast media is excreted via the
biliary system. The high-osmolar media (ratio 1.5) give in iodine equivalent doses a
larger osmotic diuresis than the ratio 3 and ratio 6 media. Therefore, the ratio 1.5 media
have a lower urinary concentration than the ratio 3 and 6 media.

After a rapid intravenous bolus injection of contrast medium an almost undiluted volume
of contrast medium reaches the heart where it is mixed with blood and this "blood-
contrast medium bolus" passes through the pulmonary vascular bed and reaches the left
side of the heart and the aorta and its branches. There is rapid contrast medium diffusion
through most capillary membranes from the blood mainly into the extracellular space as
the media have very low binding to plasma proteins and a very small intracellular
distribution.

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For only a few minutes after a bolus injection, the media may be regarded as representing
the distribution of the blood and blood vessels in the body. This fact makes it possible to
detect necrotic tumors and cysts which are not vascularized and therefore contain less
contrast medium-filled blood than the surrounding normal tissue. Likewise, it is possible
during the same period to detect tumors or inflammatory processes that are
hypervascularized because they contain more contrast medium filled blood than the
surrounding normal, less vascularized tissues.

In the brain, the normal blood-brain-barrier prevents the contrast media from escaping
from the blood out into the brain parenchyma. In areas where the blood-brain barrier is
damaged due to a tumor or an inflammatory process, contrast media may leak from the
blood into the brain parenchyma. Regions with an injured blood-brain-barrier may thus
be detected at contrast medium enhanced computerized tomography due to the higher
contrast medium concentration in those regions than in the surrounding normal brain
parenchyma.

Unpredictable/Acute Reactions

Unpredictable reactions to contrast media and other pharmaceuticals may occur on one
occasion, but not on another occasion, despite injection of the same substance in the same
dose in the same patient. The symptoms may be those of an allergic type I reaction. The
majority of the contrast medium reactions are not caused by an antigen-antibody reaction
and they often occur without previous exposure to the contrast medium. In fact, there are
only three reports of antibodies to contrast media.
The majority of contrast medium reactions are called "pseudoallergic" because they
cause exactly the same clinical symptoms and require the same symptomatic treatment as
true allergic reactions, but they are not initiated by an antigen-antibody reaction. Instead
they occur by activation of immunologic effectors through other mechanisms. Reactions
with minor symptoms are named pseudo-allergic or allergoid and those with more serious
symptoms pseudo-anaphylactic or anaphylactic.

Contrast media may by chemotoxicity, hypertonicity or ion toxicity trigger immunologic

effects by at least two mechanisms:
(i) Interaction with cell membranes releases vasoactive substances such as
histamine and platelet activating factor (mast cells), serotonin (platelets),
leucotrienes (mast cells, leukocytes), thromboxane A2 (platelets, leukocytes )
and prostaglandins (endothelium).
(ii) Interactions with biomolecules of the complement, kinin, coagulative or
fibrinolytic systems may activate these systems creating bradykinin, other
vasoactive substances and anaphylatoxins and macroproteins which form
channels through cell membranes causing cell lysis. Erythrocytes, leukocytes,
lymphocytes and mast cells all contain complement receptors so that products
of the activated complement system can cause cell membranes to release
substances according to mechanism 1.
The release or creation of vaso-active substances according to mechanisms (i) and (ii),
may cause the same acute symptoms as those seen after a true allergic type-I-reaction

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when the release of vaso-active substances is caused by an antigen-antibody reaction.

Whether the patient's re action is of pseudo-allergic (common) type or true allergic
(uncommon) type does not matter because in the acute situation the treatment of the two
types of re action is the same.

Contrast medium reactions can be divided into

(i) mild (no treatment necessary)
(ii) moderate (treatment necessary, but no intensive care)
(iii) severe (life-threatening, intensive care necessary)

The ratio 1.5 contrast media cause mild adverse reactions in up to 10% of the patients and
severe reactions in a frequency of 1 :900-1 :3000 and a mortality rate of approximate
magnitude 1:50 000-1:100000. The new low-osmolar contrast media, especially the non-
ionic’s, have a lower risk of pseudo-allergic reaction. In conclusion, the mechanisms
behind these contrast medium reactions are not known. The present opinions are that they
are, in the majority of cases, not caused by an antigen-antibody reaction, not caused by
the presence of iodine atoms in the contrast medium molecules and not caused by shell
fish allergy.

Risk Factors

The statistical chance of a pseudoallergic reaction to a planned contrast medium injection

increases in the presence of the following risk factors: an earlier pseudo-allergic reaction
to contrast media or other pharmaceuticals, bronchial asthma, cardiac disease, the
presence of any type of allergy (including shell fish allergy). The larger the dose of
contrast medium, the larger the risk of an acute reaction. The larger the number of risk
factors, the greater the readiness for immediate treatment of an acute reaction should be.

Advantages of Non-ionic versus Ionic Contrast Agents

(i) Reduced tonicity: since most side effects are related to hypertonicity, the
change to nearly isotonic has significantly decreased reactions in man - some
studies report dramatic decrease in side effects and discomfort largely due to
reduction in vasodilation and resultant sensations of heat and flushing
(ii) Myelography: cannot use ionic contrast media for myelogrphy so discovery of
non-ionic in 1974 (metrizamide) revolutionized this procedure. Newer agents
(iopamidol and iohexol) have even lower neurotoxicity
(iii) Chemical toxicity: molecules are more hydrophilic due to longer sidechains,
shields the hydrophobic I atoms, no sodium ions, decreased damage to BBB.
Increased hydrophilia means less tendency to cross cell membranes

Decreased hypersensitivity reactions: fatal reactions in man reported - 1/80,000 -

probably most from decreased osmolality and decreased cardiotoxicity.

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