Contrast media in diagnostic radiology

Positive contrast media

 

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.

History - mechanisms of toxicity

In 1895 Wilhelm Conrad Röntgen discovered X-rays. 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.

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

	Structure	Ratio	Viscosity		Osmolality	Generic name	Trade name
			20o	37o
Figure 2	ionic monomer	3:2=1.5	5+ 9++	3+ 5++	1500-1600	iothalamate metrizoate amidotrizoate ioxithalamate	Conray Vasoray Isopaque Urografin Angiografin Gastrografin Telebrix
Figure 3	ionic dimer	6:2=3	12	6	600	ioxaglate	Hexabrix
Figure 4	non-ionic monomer	3:1=3	11	6	500-700	iohexol iopamidol iopromide ioversol	Omnipaque lopamiro Ultravist Optiray
Figure 5	non-ionic dimer	6:1=6	25	10	300	iodixanol iotrolan	Visipaque 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).
	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-ioinic monomer was produced by the Norwegian contrast medium company, Nyegaard & Co (Today Nycomed Imaging AS).

Further factors that influence toxicity and water solubility are described below. Table 1 and Figures 2-5 show the most commonly us ed 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).

lonic 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:

1. 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.)

2. 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) (see also the section: "Osmolality ratio, below). 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.

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

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).

	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
	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

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 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

Different types of contrast media

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).
1. Ionic monomeric contrast media
2. Ionic dimeric contrast media
3. Non-ionic monomeric contrast media
4. 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 Inulin. 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. 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.

Hematological effects

When contrast medium is injected into the blood stream, it comes in contact with blood cells, endothelium and various proteins of the coagulation cascades.

The red blood cells are influenced by the osmotic effects of a large contrast medium bolus. This occurs particularly with the high osmotic ratio 1.5 media, which draw water out of the cells and deform them. Red blood cells thereby become rigid and lose their normal deformability, which tends to decrease their flow through small vessels, such as capillaries.

It is known that vascular endothelium may be injured by hyperosmolar solutions, such as solutions of ratio 1.5 contrast media. Damaged endothelium may elicit thrombus formation on it, particularly when a high osmotic contrast medium is used in those phlebographic techniques which cause prolonged contact between the medium and the endothelium. The new ratio 3 and ratio 6 contrast media have lower osmolality than the ratio 1.5 media and therefore cause less damage to the endothelium and are thereby less prone to promote thrombus formation on it. They are in this context less procoagulant than the ratio 1.5 media.

All contrast media when mixed with blood in a test tube or in an angiography catheter are anticoagulants. The old, more toxic ratio 1.5 contrast media are in this context stronger anticoagulants than the new, more biocompatible, less toxic ratio 3 and ratio 6 media. Inside an arteriography catheter with end- and side-holes, the anticoagulant effect of heparinized saline or solutions of ratio 1.5, ratio 3 or ratio 6 contrast media, becomes very small, because even a few seconds after the injection of contrast medium or heparinized saline into the catheter, the injected solution is already contaminated by blood. Therefore, catheters must be flushed at least every second minute so that blood does not stay within the catheter lumen or in the holes of the catheter and coagulate there, independent of what contrast medium or flushing fluid that has been used.

Lungs
When large intravenous bolus injections (urography, pulmonary angiography, intravenous contrast enhancement in computerized tomography, etc.) are performed, the lung is the first organ, after the heart, to be reached by the contrast medium bolus. When high-osmotic contrast medium is injected, there is a steep rise in pulmonary arterial pressure, and the higher the osmolality, the higher the increase in pressure due to the induced rigidity of the red cells. The increase in pressure has been shown to be particularly dangerous to patients with pulmonary hypertension and these patients should not have intravenous bolus injections of ionic ratio 1.5 media of high osmolality. Also patients with decreased lung function should have contrast media with low osmolality in order to reduce the adverse effects on the pulmonary circulation. Furthermore, the release of histamine and other vaso-active substances, when contrast media activate the large number of mast-cells in the lungs, is considered to be one of the explanations for the higher frequency of some adverse reactions (vomiting, urticaria) following intravenous injection of contrast media than following intra-arterial injections of the media. This is another reason to use low-osmotic contrast media when large intravenous doses of the media are considered.

Heart
In selective coronary arteriography high-osmolarity contrast media (ratio 1.5) induce a larger reduction of the contractile force of the heart than less hypertonic (ratio 3) or plasma-isotonic contrast media (ratio 6). If, in spite of this, ionic contrast media are chosen for coronary arteriography, those containing sodium ions in the same concentration as plasma should be used due to their lower risk of inducing ventricular fibrillation compared to the pure meglumine salts of the ionic media. It is also possible that adverse effects on the heart from the non-ionic media can be further reduced by using media with optimized electrolyte content and with oxygen saturation of the contrast medium solution.

Peripheral vascular bed
In femoral arteriography with a contrast medium concentration around 300 mg I/ml, the ratio 6 media are isotonic with plasma, while the ratio
1.5 media have 5 times the plasma osmolality (1500 mOsm/kg water) and the ratio 3 media have osmolalities in between. Some adverse effects of the media in femoral arteriography parallel their osmotoxicity so that ratio 1.5 media produce most pain, most feeling of warmth and most vasodilatation while the ratio 6 media produce least pain and vasodilatation and the ratio 3 media produce something in-between. Chemotoxicity is also involved in vasodilation, because sodium chloride solutions made isotonic with ratio 1.5, ratio 3 or ration 6 contrast media produce less vasodilation than these media.

Subarachnoid space
In the subarachnoid space only those contrast media should be used which do not contain carboxyl groups and furthermore have hydroxyl groups evenly distributed throughout the contrast medium molecule.

Animal experiments have shown that those media have the lowest risk of inducing seizures. You may find the media intended for subarachnoid use among the nonionic monomers and dimers. Please, look at the label of your contrast medium vial and DO NOT INJECT into the subarachnoid space those media which are NOT intended for subarachnoid use. By exchanging ionic monomers for non-ionic monomers the osmolality of the contrast medium solution was reduced by a factor of 2 while the total toxicity in the subarachnoid space of animals was reduced by a factor of 30. This decreased toxicity cannot be due to reduction in osmotoxicity alone; it must also be due to reduced chemotoxicity achieved by the elimination of carboxyl groups and by the introduction of hydroxyl groups. You may regard the non-ionic contrast media as surrounded by a cloud of water molecules which by electrostatic forces are attracted to the contrast medium molecules so that the body might recognize the latter as a cloud of water molecules with a low toxicity.

Kidneys
In urography there is a need for a high iodine concentration in the cortex (cortical nephrogram) in order to analyze cortical pathology and the size and margins of a kidney. A high iodine concentration in the renal pelvis and ureter (pyelogram) is desired to detect processes in the calyces, renal pelvis and ureters. Different mechanisms regulate the contrast medium concentration obtained during