1 Classification and Terminology Peter Aspelin, Marie-France Bellin, Jarl Å. Jakobsen,

Classifi cation and Terminology 1

1 Classification and Terminology

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

P. Aspelin, MD

Department of Radiology, Karolinska University Hospital, 14186 Stockholm, Sweden

M.-F. Bellin, MD

Department of Radiology, University Paris-Sud 11, Paul Brousse Hospital, AP-HP, 12–14 avenue. Paul Vaillant Couturier, 94804 Villejuif Cedex, France

J. Å. Jakobsen, MD

Department of Diagnostic Radiology, Rikshospitalet, 0017 Oslo, Norway

J. A. W. Webb, MD

Department of Diagnostic Imaging, St. Bartholomew’s Hospi- tal, West Smithfi eld, London EC1A 7BE, UK

several powers higher than audible sound which are reflected back from tissue interfaces in the body to generate the image.

Contrast media may be used with all of these imaging techniques to enhance the differences seen between the body tissues on the images. Contrast media alter the response of the tissues to the applied electromagnetic or ultrasound energy by a variety 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 have adverse effects.

This chapter deals with the classification of con- trast agents and the terminology used to describe them.

1.2

Radiographic Contrast Media

Radiographic contrast media are divided into posi- tive and negative contrast agents. The positive con- trast media attenuate X-rays more than do the body soft tissues and can be divided into water soluble iodine agents and non water soluble barium agents.

Negative contrast media attenuate X-rays less than do the body soft tissues. No negative contrast media are commercially available.

1.2.1

Iodine Agents

Water soluble iodinated contrast agents which dif- fuse throughout the extracellular space are prin- cipally used for angiography, during computed tomography (CT) and conventional radiography.

They can also be administered directly into the body cavities, for example the gastrointestinal tract and urinary tract.

CONTENTS

1.1 Introduction 1

1.2 Radiographic Contrast Media 1 1.2.1 Iodine Agents 1

1.2.2 Barium Contrast Media 2 1.3 MR Contrast Media 2

1.3.1 Paramagnetic Contrast Agents 2 1.3.2 Superparamagnetic Contrast Agents 3 1.4 Ultrasound Contrast Media 3 1.4.1 Classification 4

1.1

Introduction

Current radiological imaging uses either electro- 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 the body is detected either by analogue radiological film or by a variety of digital media. The radio- waves used in magnetic resonance imaging have a frequency and photon energy several powers lower than visible light. The radiowaves cause deflec- tion of protons in the body which have aligned in the magnetic field in the scanner and as the pro- tons relax back to their resting position, they emit radiowaves which are used to generate the image.

Ultrasound imaging uses sound (pressure) waves

2 P. Aspelin et al.

All of these contrast media are based on a ben- zene ring to which three iodine atoms are attached.

A monomer contains one tri-iodinated benzene ring and a dimer contains two tri-iodinated benzene rings.

Iodinated contrast media can be divided into two groups, ionic and nonionic based on their water solu- bility. The water in the body is polarised unevenly with positive poles around the hydrogen atoms and negative poles around oxygen atoms. Ionic contrast 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 water soluble by their polar OH groups. Electrical poles in the contrast medium OH groups are attracted to the electrical poles in the water molecules.

The osmolality of contrast media affects the inci- dence of side-effects. The early contrast media had very high osmolalities (1500–2000 mosm per kg) and subsequently agents of lower osmolality have been developed. Contrast media may be divided into high-, low- and iso-osmolar agents. An indica- 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 particles in solution:

1.2.2

Barium Contrast Media

Barium sulphate preparations used to visualize the gastrointestinal tract consist of a suspension of insoluble barium sulphate particles which are not absorbed from the gut. Differences between the dif- ferent commercially available agents are very minor and relate to the additives in the different barium sulphate preparations.

1.3

MR Contrast Media

Magnetic resonance (MR) imaging contrast agents contain paramagnetic or superparamagnetic metal ions which affect the MR signal properties of the sur- rounding tissues. They are used to enhance contrast, to characterize lesions and to evaluate perfusion and flow-related abnormalities. They can also provide functional and morphological information.

1.3.1

Paramagnetic Contrast Agents

Paramagnetic contrast agents are mainly posi- tive enhancers which reduce the T1 and T2 relax- ation times and increase tissue signal intensity on T1-weighted MR images.

n in solutio particles

of Number

atoms iodine of Number o

edium Rati

Contrast m =

Fig. 1.1. Classifi cation of iodinized contrast media

The higher osmolality agents have more particles per iodine atom and therefore have lower ratios.

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. iohexol, iopentol, ioxitol, iomeprol, ioversol, iopromide, iobitridol, iopamidol

4. Nonionic dimeric contrast media (iso-osmolar

contrast media, IOCM), e.g. iotrolan, iodixanol

Classifi cation and Terminology 3

The most widely used paramagnetic contrast agents are non-specific extracellular gadolinium chelates. Their active constituent is gadolinium, a paramagnetic metal in the lanthanide series, which is characterized by a high magnetic moment and a relatively slow electronic relaxation time. Non-spe- cific extracellular gadolinium chelates can be clas- sified by their chemical structure, macrocyclic or linear, and by whether they are ionic or nonionic (Fig. 1.2). They are excreted via the kidneys.

Paramagnetic contrast agents also include liver specific gadolinium based agents (gadobenate dimeglumine, Gd-BOPTA and gadoxetate, Gd-EOB- DTPA) and manganese-based preparations [man- ganese chelate (mangafodipir trisodium) and free manganese combined with vitamins and amino acids (to promote the uptake) for oral intake]. These hepatobiliary contrast agents are taken up by hepa- tocytes and then there is variable biliary excretion.

The gadolinium based liver specific contrast media are also excreted by the kidneys.

1.3.2

Superparamagnetic Contrast Agents

Superparamagnetic contrast agents include super- paramagnetic iron oxides (SPIOs) and ultra small superparamagnetic iron oxides (USPIOs). Two prep- arations of SPIOs are available: ferumoxides and fer- ucarbotran. These particulate agents are composed of an iron oxide core, 3–5 mm in diameter, covered by low molecular weight dextran for ferumoxides and by carbodextran for ferucarbotran. SPIOs are approved for liver imaging and USPIOs are under consideration for MR lymphography.

After injection, SPIO and USPIO particles are metabolised into a soluble, non superparamagnetic form of iron. Iron is incorporated into the body pool of iron (e.g. ferritin, hemosiderin and hemoglobin) within a few days.

1.4

Ultrasound Contrast Media

Ultrasound contrast agents produce their effect by increased back-scattering of sound compared to that from blood, other fluids and most tissues. On grey- scale images microbubble contrast agents change grey and dark areas to a brighter tone, when the con- trast enters in fluid or blood. The spectral Doppler

Fig. 1.2. Structures of the organic ligands of Gadolinium chelates approved for clinical use.

Non-ionic and cyclic gadobutrol

O O

-O -O -O

O

OH

OH OH

N N

N N H H

Gd3+

Ionic and linear Gd-BOPTA (gadobenate dimeglumine)

O N N N

BOPTA

COO- COO-

HO HO HO HO

HO COO-

COO- COO-

Gd³⁺

H₂N⁺ CH₃

2 Ionic and linear Gd-DTPA (gadopentetate dimeglumine) HOOC

HOOC

N N N

COOH COOH

COOH Gd³⁺

Non-ionic and cyclic Gd-HP-DO3A (gadoteridol) Gd⁺

HOOC

HOOC

COOH

N

N N

N

CH(CH₃)OH Non-ionic and linear Gd-DTPA–BMA (gadodiamide)

HOOC

COOH

N N N

COOH Gd³⁺

CONH(CH₃) (CH₃)NHCO

Ionic and cyclic Gd-DOTA (gadoterate meglumine) HOOC

HOOC

COOH

N

N N

N

COOH Gd³⁺

4 P. Aspelin et al.

intensity is also increased, with a brighter spectral waveform displayed and a stronger sound heard.

Using color Doppler technique, ultrasound contrast agents enhance the frequency or the power intensity giving rise to stronger color encoding. The level of enhancement of the Doppler signals may be in the order of up to 30 dB.

Ultrasound contrast agents can be used to enhance Doppler signals from most main arteries and veins.

They may be useful for imaging solid organs, e.g.

liver, kidney, breast, prostate and uterus. They can also be used to enhance cavities e.g. bladder, ureters, Fallopian tubes, abscesses.

1.4.1

Classification

Ultrasound contrast agents can be divided into five different classes: (1) Nonencapsulated gas micro- bubbles (e.g. agitated or sonicated), (2) stabilised gas microbubbles (e.g. with sugar particles), (3) encapsu- lated gas microbubbles (e.g. by protein, liposomes or in polymers), (4) microparticle suspensions or emul-

sions [perfluorooctyl bromide (PFOB), phase-shift], and (5) gastrointestinal (for ingestion). Products are not commercially available from all classes.

Ultrasound contrast agents (USCA) can also be classified based on their pharmacokinetic properties and efficacy: (1) Non-transpulmonary USCAs which do not pass the capillary bed of the lungs following a peripheral intravenous injection, show on B-mode only in the right ventricle, and have a short dura- tion effect, (2) transpulmonary blood pool USCAs with a short half-life (< 5 min after an intravenous bolus injection), which produce low signals using 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 produce high signals using harmonic imaging at low acoustic power, (4) transpulmonary USCAs with a specific liver and spleen phase which can be short- or long-lived. They lodge in the small vessels of the liver or spleen, or are taken up by either the reticulo- endothelial system or by the hepatocytes.

Agents which are currently available commer- cially or are close to being available commercially 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

Definity^TM (DMP 115) Fluorocarbon gas in liposomes

SonoVue® (BR1) Sulphur hexa fluoride gas in polymer with phospholipid Optison^TM (FS069) Octafluoropropane-filled albumin microspheres Sonazoid^TM (NC100100) Perfluorinated gas-containing microbubbles Levovist® (SHU 508A) Galactose-based, palmitic acid stabilised air-bubbles