contrast media

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 D

Figure 2 ionic monomer

3:2=1.5 5+9++

3+5++

1500-1600iothalamate

metrizoate amidotrizoate

ioxithalamate

ConrayVasorayIsopaqueUrografinAngiografinGastrografinTelebrix

Figure 3 ionic dimer

6:2=3 12 6 600 Ioxaglate Hexabrix

Figure 4 non-ionic monomer

3:1=3 11 6 500-700iohexol iopamidol iopromide ioversol

OmnipaquelopamiroUltravistOptiray

Figure 5non-ionic dimer

6:1=6 25 10 300iodixanol iotrolan

VisipaqueIsovist

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 atoms3 iodine atoms per molecule1 carboxyl group (-COO-) per moleculeNo hydroxyl group (-OH) except ioxithalamate with one OH/moleculeIntravenous 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 atoms6 iodine atoms per molecule1 carboxyl group (-COO-) per molecule1 hydroxyl group (-OH) per moleculeIntravenous 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 atoms3 iodine atoms per molecule No carboxyl group (-COO-)4-6 hydroxyl groups (-OH) per moleculeIntravenous 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 moleculeNo carboxyl group (-COO-)More than 8 hydroxyl groups (-OH) per moleculelntravenous 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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contrast media

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