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Home , Iodinated contrast, Iomeprol, Mangafodipir

Classifi cation and Terminology 1 1 Classification and Terminology

Peter Aspelin, Marie-France Bellin, Jarl Å. Jakobsen, and Judith A. W. Webb

CONTENTS several powers higher than audible sound which are reflected back from tissue interfaces in the body to 1.1 Introduction 1 generate the image. 1.2 Radiographic Contrast Media 1 1.2.1 Agents 1 Contrast media may be used with all of these 1.2.2 Barium Contrast Media 2 imaging techniques to enhance the differences seen 1.3 MR Contrast Media 2 between the body tissues on the images. Contrast 1.3.1 Paramagnetic Contrast Agents 2 media alter the response of the tissues to the applied 1.3.2 Superparamagnetic Contrast Agents 3 electromagnetic or ultrasound energy by a variety 1.4 Ultrasound Contrast Media 3 1.4.1 Classification 4 of mechanisms. The ideal contrast medium would achieve a very high concentration in the tissues with- out producing any adverse effects. Unfortunately, so far this has not been possible and all contrast media 1.1 have adverse effects. Introduction This chapter deals with the classification of con- trast agents and the terminology used to describe Current radiological imaging uses either electro- them. magnetic radiation (X-rays or radiowaves) or ultra- sound. X-rays have a frequency and photon energy several powers higher than visible light and can pen- etrate the body. The radiation which emerges from 1.2 the body is detected either by analogue radiological Radiographic Contrast Media film or by a variety of digital media. The radio- waves used in magnetic resonance imaging have a Radiographic contrast media are divided into posi- frequency and photon energy several powers lower tive and negative contrast agents. The positive con- than visible light. The radiowaves cause deflec- trast media attenuate X-rays more than do the body tion of protons in the body which have aligned in soft tissues and can be divided into water soluble the magnetic field in the scanner and as the pro- iodine agents and non water soluble barium agents. tons relax back to their resting position, they emit Negative contrast media attenuate X-rays less than radiowaves which are used to generate the image. do the body soft tissues. No negative contrast media Ultrasound imaging uses sound (pressure) waves are commercially available.

P. Aspelin, MD Department of Radiology, Karolinska University Hospital, 1.2.1 14186 Stockholm, Sweden Iodine Agents M.-F. Bellin, MD Department of Radiology, University Paris-Sud 11, Paul Brousse Hospital, AP-HP, 12–14 avenue. Paul Vaillant Couturier, Water soluble agents which dif- 94804 Villejuif Cedex, France fuse throughout the extracellular space are prin- J. Å. Jakobsen, MD cipally used for , during computed Department of Diagnostic Radiology, Rikshospitalet, 0017 tomography (CT) and conventional . Oslo, Norway J. A. W. Webb, MD They can also be administered directly into the body Department of Diagnostic Imaging, St. Bartholomew’s Hospi- cavities, for example the gastrointestinal tract and tal, West Smithfi eld, London EC1A 7BE, UK urinary tract. 2 P. Aspelin et al.

All of these contrast media are based on a ben- 1.2.2 zene ring to which three iodine atoms are attached. Barium Contrast Media A monomer contains one tri-iodinated benzene ring and a dimer contains two tri-iodinated benzene Barium sulphate preparations used to visualize rings. the gastrointestinal tract consist of a suspension of Iodinated contrast media can be divided into two insoluble barium sulphate particles which are not groups, ionic and nonionic based on their water solu- absorbed from the gut. Differences between the dif- bility. The water in the body is polarised unevenly ferent commercially available agents are very minor with positive poles around the hydrogen atoms and and relate to the additives in the different barium negative poles around oxygen atoms. Ionic contrast sulphate preparations. media are water soluble because they dissociate into negative and positive ions which attract the negative and positive poles of the water molecules. Nonionic contrast media do not dissociate and are rendered 1.3 water soluble by their polar OH groups. Electrical MR Contrast Media poles in the contrast medium OH groups are attracted to the electrical poles in the water molecules. Magnetic resonance (MR) imaging contrast agents The osmolality of contrast media affects the inci- contain paramagnetic or superparamagnetic metal dence of side-effects. The early contrast media had ions which affect the MR signal properties of the sur- very high osmolalities (1500–2000 mosm per kg) rounding tissues. They are used to enhance contrast, and subsequently agents of lower osmolality have to characterize lesions and to evaluate perfusion and been developed. Contrast media may be divided flow-related abnormalities. They can also provide into high-, low- and iso-osmolar agents. An indica- functional and morphological information. tion of the osmolality of an agent is given by the con- trast medium ratio which is derived by dividing the number of iodine atoms in solution by the number of 1.3.1 particles in solution: Paramagnetic Contrast Agents Number of iodine atoms Contrast medium Ratio = Number of particles in solution Paramagnetic contrast agents are mainly posi- tive enhancers which reduce the T1 and T2 relax- The higher osmolality agents have more particles ation times and increase tissue signal intensity on per iodine atom and therefore have lower ratios. T1-weighted MR images. Thus the ionic monomers have a ratio of 1.5 (three iodine atoms per two particles in solution), the non- ionic monomers and the ionic dimers have a ratio of 3 (three iodine atoms per particle in solution) and the nonionic dimers have a ratio of 6 (six iodine atoms per particle in solution) (Fig. 1.1). The non- ionic dimers are iso-osmolar with blood (300 mosm per kg) at all concentrations. Using these properties four different classes of iodinated contrast may be defined (Fig. 1.1): 1. Ionic monomeric contrast media (high-osmo- lar contrast media, HOCM), e.g. amidotrizoate, iothalamate, ioxithalamate 2. Ionic dimeric contrast media (low-osmolar con- trast media, LOCM), e.g. ioxaglate 3. Nonionic monomeric contrast media (low-osmo- lar contrast media, LOCM), e.g. , , ioxitol, , , , , 4. Nonionic dimeric contrast media (iso-osmolar contrast media, IOCM), e.g. , Fig. 1.1. Classifi cation of iodinized contrast media Classifi cation and Terminology 3

The most widely used paramagnetic contrast Gd3+ COOH agents are non-specific extracellular HOOC chelates. Their active constituent is gadolinium, a N N N paramagnetic metal in the lanthanide series, which HOOC COOH is characterized by a high magnetic moment and a relatively slow electronic relaxation time. Non-spe- COOH cific extracellular gadolinium chelates can be clas- Ionic and linear Gd-DTPA (gadopentetate dimeglumine) sified by their chemical structure, macrocyclic or linear, and by whether they are ionic or nonionic Gd3+ (Fig. 1.2). They are excreted via the kidneys. (CH )NHCO CONH(CH ) Paramagnetic contrast agents also include liver 3 3 specific gadolinium based agents (gadobenate N N N dimeglumine, Gd-BOPTA and gadoxetate, Gd-EOB- HOOC COOH DTPA) and manganese-based preparations [man- COOH ganese chelate ( trisodium) and free Non-ionic and linear Gd-DTPA–BMA () manganese combined with vitamins and amino acids (to promote the uptake) for oral intake]. These HOOC COOH hepatobiliary contrast agents are taken up by hepa- tocytes and then there is variable biliary . N N The gadolinium based liver specific contrast media Gd3+ are also excreted by the kidneys. N N HOOC COOH Ionic and cyclic Gd-DOTA (gadoterate meglumine) 1.3.2 Superparamagnetic Contrast Agents HOOC COOH Superparamagnetic contrast agents include super- N N paramagnetic iron oxides (SPIOs) and ultra small Gd + superparamagnetic iron oxides (USPIOs). Two prep- arations of SPIOs are available: ferumoxides and fer- N N ucarbotran. These particulate agents are composed HOOC CH(CH3)OH of an iron oxide core, 3–5 mm in diameter, covered Non-ionic and cyclic Gd-HP-DO3A () by low molecular weight dextran for ferumoxides and by carbodextran for ferucarbotran. SPIOs are O O approved for liver imaging and USPIOs are under consideration for MR lymphography. - N N - O 3+ O After injection, SPIO and USPIO particles are Gd metabolised into a soluble, non superparamagnetic - O N form of iron. Iron is incorporated into the body pool N H H OH of iron (e.g. ferritin, hemosiderin and hemoglobin) O within a few days. OH OH

Non-ionic and cyclic CH3 + H2N - - 1.4 COO COO HO Ultrasound Contrast Media 2 HO N N - O N COO HO HO - Ultrasound contrast agents produce their effect by COO COO- increased back-scattering of sound compared to that BOPTA Gd3+ HO from blood, other fluids and most tissues. On grey- scale images microbubble contrast agents change Ionic and linear Gd-BOPTA (gadobenate dimeglumine) grey and dark areas to a brighter tone, when the con- Fig. 1.2. Structures of the organic ligands of Gadolinium trast enters in fluid or blood. The spectral Doppler chelates approved for clinical use. 4 P. Aspelin et al. intensity is also increased, with a brighter spectral sions [perfluorooctyl bromide (PFOB), phase-shift], waveform displayed and a stronger sound heard. and (5) gastrointestinal (for ingestion). Products are Using color Doppler technique, ultrasound contrast not commercially available from all classes. agents enhance the frequency or the power intensity Ultrasound contrast agents (USCA) can also be giving rise to stronger color encoding. The level of classified based on their pharmacokinetic properties enhancement of the Doppler signals may be in the and efficacy: (1) Non-transpulmonary USCAs which order of up to 30 dB. do not pass the capillary bed of the lungs following U lt r a sou nd cont r a st a gent s c a n be u se d to en ha nce a peripheral intravenous injection, show on B-mode Doppler signals from most main arteries and veins. only in the right ventricle, and have a short dura- They may be useful for imaging solid organs, e.g. tion effect, (2) transpulmonary blood pool USCAs liver, kidney, breast, prostate and uterus. They can with a short half-life (< 5 min after an intravenous also be used to enhance cavities e.g. bladder, ureters, bolus injection), which produce low signals using Fallopian tubes, abscesses. harmonic imaging at low acoustic power, (3) trans- pulmonary blood pool USCAs with a longer half-life (> 5 min after an intravenous bolus injection), which 1.4.1 produce high signals using harmonic imaging at low Classification acoustic power, (4) transpulmonary USCAs with a specific liver and spleen phase which can be short- Ultrasound contrast agents can be divided into five or long-lived. They lodge in the small vessels of the different classes: (1) Nonencapsulated gas micro- liver or spleen, or are taken up by either the reticulo- bubbles (e.g. agitated or sonicated), (2) stabilised gas endothelial system or by the hepatocytes. microbubbles (e.g. with sugar particles), (3) encapsu- Agents which are currently available commer- lated gas microbubbles (e.g. by protein, liposomes or cially or are close to being available commercially in polymers), (4) microparticle suspensions or emul- are listed in Table 1.1.

Table 1.1. Some ultrasound contrast agents on or close to the market in various parts of the world (officially available data per April, 2005) Product name Some properties DefinityTM (DMP 115) Fluorocarbon gas in liposomes SonoVue® (BR1) Sulphur hexa fluoride gas in polymer with phospholipid OptisonTM (FS069) Octafluoropropane-filled albumin microspheres SonazoidTM (NC100100) Perfluorinated gas-containing microbubbles Levovist® (SHU 508A) -based, palmitic acid stabilised air-bubbles