Contrast

Agents
/ Preface Radiology covers also topics of the postgraduate levels
of the European Training Curriculum for Radiology, thus
addressing postgraduate educational needs of residents.
/ Contrast
Agents
Modern Radiology is a free educational resource for In addition, it reflects feedback from medical professionals CHAPTER OUTLINE:

radiology published online by the European Society of worldwide who wish to update their knowledge in specific Contrast Agents
Radiology (ESR). The title of this second, rebranded ver- areas of medical imaging and who have already appreci-
X-Ray Contrast Media
sion reflects the novel didactic concept of the ESR eBook ated the depth and clarity of the ESR eBook across the (RCM)
with its unique blend of text, images, and schematics in the basic and more advanced educational levels.
Magnetic Resonance
form of succinct pages, supplemented by clinical imaging Contrast Agents
cases, Q&A sections and hyperlinks allowing to switch I would like to express my heartfelt thanks to all authors who
quickly between the different sections of organ-based and contributed their time and expertise to this voluntary, non- Ultrasound Contrast
Agents
more technical chapters, summaries and references. profit endeavour as well as Carlo Catalano, Andrea Laghi
and András Palkó, who had the initial idea to create an ESR Take-Home Messages
Its chapters are based on the contributions of over 100 rec- eBook, and - finally - to the ESR Office for their technical References
ognised European experts, referring to both general tech- and administrative support.
Test Your Knowledge
nical and organ-based clinical imaging topics. The new
graphical look showing Asklepios with fashionable glasses, Modern Radiology embodies a collaborative spirit and
symbolises the combination of classical medical teaching unwavering commitment to this fascinating medical disci-
with contemporary style education. pline which is indispensable for modern patient care. I hope
that this educational tool may encourage curiosity and crit-
Although the initial version of the ESR eBook was cre- ical thinking, contributing to the appreciation of the art and
ated to provide basic knowledge for medical students science of radiology across Europe and beyond.
and teachers of undergraduate courses, it has gradually
expanded its scope to include more advanced knowledge Minerva Becker, Editor
for readers who wish to ‘dig deeper’. As a result, Modern Professor of Radiology, University of Geneva, Switzerland 2
/ Copyright and Terms of Use / Contrast
Agents
CHAPTER OUTLINE:

This work is licensed under a ­Creative ­Commons Attribution-NonCommercial-­NoDerivatives 4.0 International License. Contrast Agents

X-Ray Contrast Media

You are free to: (RCM)
Share, copy and redistribute the material in any medium or format Magnetic Resonance
Contrast Agents

Ultrasound Contrast
Under the following terms: How to cite this work: Agents

Take-Home Messages
/ You must give appropriate
AT T R I B U T I O N – European Society of Radiology,
credit, provide a link to the license, and indicate if Johannes Fröhlich, Gabriella Hänggi (2025) References
changes were made. You may do so in any rea- ESR Modern Radiology eBook: Test Your Knowledge
sonable manner, but not in any way that suggests
the licensor endorses you or your use.
/ Contrast Agents.
/ NONCOMMERCIAL – You may not use the DOI 10.26044/esr-modern-radiology-07
material for commercial purposes.

/ If you remix, transform,

N O D E R I VAT I V E S –
or build upon the material, you may not dis-
tribute the modified material. 3
/ Signage / Contrast
Agents
CHAPTER OUTLINE:

Contrast Agents
<•> CORE KNOWLEDGE <!> AT T E N T I O N <↑> HYPERLINKS
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Contrast Agents
>•< FURTHER KNOWLEDGE >|< C O M PA R E <∞> REFERENCES
Ultrasound Contrast
Agents

Take-Home Messages

<?> QUESTIONS References

Test Your Knowledge

4
 Based on
the ESR
Curriculum for
Radiological
Education
/ Contrast
Agents
CHAPTER OUTLINE:

Contrast Agents

Contrast
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast

Agents
Agents

Take-Home Messages

References

Test Your Knowledge

AUTHORS

Johannes Fröhlich | Gabriella Hänggi

<↑> HYPERLINK
A F F I L I AT I O N

KlusLab, Consultant for various pharma companies [email protected] 5

 / Blood Pool Agents

/ Chapter Outline / Organ-specific Gd-Based

Contrast Agents
/ Tissue Specific
Reticuloendothelial and
/ Contrast
Agents
/ Contrast Agents Application Lymph Node Agents CHAPTER OUTLINE:
/ Intravenous RCM / Direct MR Arthrography
/ X-Ray Contrast Media Injection / Adverse Reactions Contrast Agents
(RCM) / Intraarterial RCM Injection / Nephrogenic System
/ Classification / Oral and Rectal RCM Fibrosis (NSF)
Applications X-Ray Contrast Media
/ Positive RCM / Gadolinium Retention in the (RCM)
/ Negative RCM / Adverse Reactions to RCM Brain
/ Iodinated RCM / Acute Adverse Reactions / Safety Recommendation Magnetic Resonance
/ Oily Lipophilic Iodinated / Delayed Adverse Contrast Agents
RCM Reactions / Ultrasound Contrast
/ Water Soluble Hydrophilic / Thyrotoxicosis Agents Ultrasound Contrast
RCM / Renal Adverse Reactions
/ Microbubbles Agents
/ Gallbladder-Specific RCM / Extravasation
/ Ultrasound Echo
/ Physicochemical Properties / Magnetic Resonance Enhancement by Take-Home Messages
of Iodinated RCM Contrast Agents Microbubbles
/ Iodine Concentration / Paramagnetic Contrast / Biodistribution and References
/ Osmolality Agents Elimination
/ Viscosity Test Your Knowledge
/ Hydrophilicity / Gadolinium-Based Contrast / Administration of Ultrasound
Agents Contrast Agents
/ Pharmacokinetics of
Iodinated RCM / Structure of the Gd / Indications
Complexes / Cardivascular Imaging
/ Two-Compartment Model / Stability of the Gd
/ Pharmacokinetics and / Vascular Imaging
Complexes / Liver Lesions
Imaging / Transmetallation / Further Indications
/ Opacification modes of RCM / Biodistribution
/ Adverse Reactions
/ Direct Luminal Filling / Superparamagnetic
/ Functional organ Imaging Contrast Agents / Take-Home Messages
/ Parenchymal / Indications
Enhancement
/ Non-specific Extracellular
/ References
/ Angiography
Contrast Agents / Test Your Knowledge
/ Indications of RCM 6
 / Contrast
Agents
CHAPTER OUTLINE:

Contrast Agents

/ Contrast
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast

Agents
Agents

Take-Home Messages

References

Test Your Knowledge

7
<•> CORE KNOWLEDGE

/ Contrast Agents / Contrast

Agents
CHAPTER OUTLINE:

Contrast agents are used to improve visualisa- electromagnetic or ultrasound energy. They are
Contrast Agents
tion of an organ, tissue, or pathologic condition in substances used for diagnostic purposes only, with-
diagnostic imaging by altering the attenuation of out any pharmacodynamic activity, and are gen- X-Ray Contrast Media
(RCM)
X-rays or by changing the response to the applied erally eliminated rapidly without metabolisation.
Magnetic Resonance
Contrast Agents
A B
Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

F igure 1

Brain MR-image pre-

contrast (A) and after iv.
administration of contrast (B). 8
 / Contrast
Agents

/ X-Ray CHAPTER OUTLINE:

Contrast Agents

­Contrast
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast

Media
Agents

Take-Home Messages

References

Test Your Knowledge

(RCM)
9
<•> CORE KNOWLEDGE

/ Classification / Contrast
Agents
CHAPTER OUTLINE:
X-ray contrast media, also called radiographic contrast media (RCM), enhance image
contrast by locally inducing a change in X-ray absorptivity, which can be stronger Contrast Agents

(positive RCM) or weaker (negative RCM) than in the adjacent normal tissue. X-Ray Contrast Media
(RCM)

Magnetic Resonance
Positive RCM Negative RCM Contrast Agents

Ultrasound Contrast
Agents
Substances with a high Substances
radiodensity, contain- with a low Take-Home Messages
ing atoms with a high density, such References
atomic number such as CO2, Xe
Test Your Knowledge
as Barium (56Ba2+), and air, lead
Iodine (53I-) or gadolin- to reduced
ium (64Gd3+) (off-label), absorption
lead to enhanced of X-rays.
absorption of X-rays.

F igure 3
F igure 2
Air in the lungs appears black because of less
Positive contrast due to the bones. absorption of the X-rays: negative contrast. 10
<•> CORE KNOWLEDGE

/ Iodinated RCM / Contrast

Agents
CHAPTER OUTLINE:
Iodinated RCM are available as water
soluble, hydrophilic RCM or as oily, Contrast Agents

lipophilic RCM. X-Ray Contrast Media

(RCM)

Magnetic Resonance
Contrast Agents
Oily, Lipophilic Iodinated RCM
Ultrasound Contrast
Agents
Lipiodol is an oily lipophilic iodinated RCM,
Take-Home Messages
which is made of poppy seed oil whose unsatu-
rated fatty acids were substituted with iodine. It References
is used for visualisation of fine structures in: Test Your Knowledge

/ direct lymphography (imag-

ing of the lymphatic system)

/ transarterial chemoembolisation of hepa-

tocellular carcinoma (Fig. 4) F igure 4

Control CT image obtained after transarterial chemoembolisation of a

/ some countries for hysterosalpingogra- hepatocellular carcinoma (HCC) with Doxorubicine/Lipiodol and portal vein
embolisation with Lipiodol/bucrylate (to induce left liver lobe hypertrophy).
phy (to determine tubal patency)
Residual Lipiodol in HCC (red arrow) and in the embolised portal branches
(yellow arrows). Image courtesy: Christoph Becker, MD, University of Geneva. 11
<•> CORE KNOWLEDGE

Positive RCM Negative RCM

CO2, air, xenon
/ Contrast
Agents
CHAPTER OUTLINE:

Barium sulfate Iodinated RCM Contrast Agents

X-Ray Contrast Media

(RCM)

Magnetic Resonance
Water soluble, hydrophilic RCM Oily, lipophilic RCM Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages
Nephrotropic RCM Gall bladder specific RCM
References
Uro-Angiographics Cholegraphics
Test Your Knowledge

Monomers Monomers
Ionic Non-ionic Ionic Non-ionic
High-osmolal Low-osmolal High-osmolal Low-osmolal

F igure 5

Classification of X-ray contrast media. 12

<•> CORE KNOWLEDGE

Water Soluble, Hydrophilic Iodinated RCM

The water soluble, hydrophilic RCM comprise

/ Contrast
Agents
nephrotropic RCM, which are employed for uro-an- CHAPTER OUTLINE:

giographics, and gallbladder specific RCM, which Contrast Agents

were used for intravenous cholangiography.
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Structure of Water soluble, Iodinated RCM Contrast Agents

The basic structure of water-soluble iodinated RCM Ultrasound Contrast

Agents
is a benzene ring, which is symmetrically substi-
tuted with three covalently bound iodine atoms: Take-Home Messages

References
/ the presence of three iodine atoms in one mol-
Test Your Knowledge
ecule provides a high X-ray absorptivity with
correspondingly high contrast density

/ the covalent binding ensures a strong chem-

ical bond of iodine and thus reduces the risk
of toxic effects from released free iodide

/ the remaining three, non-iodinated carbons of

the benzene ring are substituted with respec-
F igure 6
tive chemical side-groups R1, R2 and R3 Basic structure of iodinated RCM. 13
>•< FURTHER KNOWLEDGE

Classification of the Nephrotropic RCM

Two major chemical variations, namely, monomeric versus dimeric and ionic ver-
/ Contrast
Agents
sus non-ionic, result in four classes of RCM (Fig. 7): CHAPTER OUTLINE:

Contrast Agents
Ionic monomeric RCM: one triiodinated ben- Non-ionic monomeric RCM: one triiodin-
X-Ray Contrast Media
zene ring with a carboxylate functional group ated benzene ring without -COO- functional (RCM)
(-COO-) in one of the substituent groups group, e.g., having an amide (-CO-NH-R) group
Magnetic Resonance
instead of the -COO- functional group Contrast Agents
Ionic dimeric RCM: two triiodinated benzene rings
Ultrasound Contrast
linked by an organic bridging group with at least Non-ionic dimeric RCM: two triiodinated benzene Agents
one carboxylate functional group (-COO-) in one of rings without -COO- functional group, e.g., having an
Take-Home Messages
the substituent groups (not marketed anymore). amide (-CO-NH-R) group instead of the -COO- func-
tional group, linked by an organic bridging group References

Test Your Knowledge

14
>•< FURTHER KNOWLEDGE

COO Na+/meglumine+ R3 COO Na+/meglumine+ / Contrast

Agents
I I I I I I
CHAPTER OUTLINE:

Contrast Agents
R1 R2 R1 R' R2
X-Ray Contrast Media
I I I (RCM)

Magnetic Resonance
Ionic monomeric high osmolar RCA Ionic dimeric low osmolar RCA Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages
CO-NH-R R3 R4
References
I I I I I I
Test Your Knowledge

R1 R2 R1 R' R2
I I I

Non-ionic low osmolar monomeric RCA Non-ionic isoosmotic dimeric RCA

F igure 7

Structure of the 4 classes of nephrotropic RCM. 15

>•< FURTHER KNOWLEDGE

Ionic contrast agent – once dissolved, there‘s a dissociation into an anion and cation in the
aqueous solution. / Contrast
Agents
In the ionic RCM, the presence of a carboxylate group The other substituents may further improve CHAPTER OUTLINE:

contributes to a net negative charge to the molecule, water solubility, influence the pharmacokinet- Contrast Agents
which is made available in neutral form, usually as a ics and safety properties, defining the elimination
X-Ray Contrast Media
salt of sodium, calcium or methylglucamine cations. pathway, protein binding and/or tolerability. (RCM)

Magnetic Resonance
The dissociation into negative and positive ions Contrast Agents
in ionic RCM ensures water solubility, while in
Ultrasound Contrast
non-ionic RCM any polar groups of the sub- Agents
stituents R1, R2 and R3, particularly hydroxyl
Take-Home Messages
groups, are responsible for the water solubility.
References

Test Your Knowledge

16
>•< FURTHER KNOWLEDGE

Gallbladder Specific RCM

An intravenous gallbladder specific RCM available as a delayed glomerular filtration leading to excretion in
/ Contrast
Agents
a salt of meglumine has a dimeric structure with two the bile without chemically modifying the molecule. CHAPTER OUTLINE:

triiodinated benzene rings linked by an organic bridging Contrast Agents

group. This cholegraphic RCM comprises a carbox- However, the cholegraphic RCM have shown a higher
X-Ray Contrast Media
ylate functional group at each benzene ring with no incidence of adverse effects than the nephrotropic (RCM)
further side chains. The unsubstituted position in each explaining the non-availability of these RCMs.
Magnetic Resonance
benzene ring promotes plasma protein binding and Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

F igure 8

Structure of the gallbladder specific RCM. 17

<•> CORE KNOWLEDGE

/ Physicochemical Properties of Iodinated RCM / Contrast

Agents
CHAPTER OUTLINE:
The most important physicochemical properties of iodinated RCM which affect clini-
cal practice are iodine concentration, osmolality, viscosity and hydrophilicity. Contrast Agents

X-Ray Contrast Media

(RCM)
Iodine Concentration Magnetic Resonance
Contrast Agents
The contrast enhancement is directly related to Intravenous iodinated RCM are available in con- Ultrasound Contrast
the local iodine concentration in the tissue. centrations from 200 to 400 mg of iodine per Agents
millilitre of the contrast solution, with a dosage of Take-Home Messages
300 mg/ml being clinically used in most cases.
References

The choice of the appropriate iodine concen- Test Your Knowledge

tration depends on the type of investigation, the
disease and the diagnostic device used.

F igure 9

Example of a iodinated contrast

agent: 300 mg/mL = 30% of iodine. 18
<•> CORE KNOWLEDGE

Osmolality

Osmolality is a measure of the number of dis- For a given iodinated RCM, osmolality increases
/ Contrast
Agents
solved active particles per kilogram of solvent, i.e., linearly with iodine concentration. CHAPTER OUTLINE:

water, expressed in mOsm/kg H2O at 20°C. Contrast Agents

X-Ray Contrast Media

The osmolality of blood is 300 mOsm/kg H2O, and the (RCM)
>•< FURTHER KNOWLEDGE
osmolality of the pain threshold is 600 mOsm/kg H2O.
Magnetic Resonance
High-osmolality agents include Contrast Agents
ionic monomers, which for
every 3 iodine atoms generate Ultrasound Contrast
2 solute particles; with the Agents
resultant osmolality being 5-8
Take-Home Messages
times that of blood.
Low-osmolality agents include References
ionic dimers and non-ionic
Test Your Knowledge
monomers, which for every 3
iodine atoms generate 1 solute
particle; with the resultant
osmolality being 1-3 times that
of blood.
Iso-osmolal agents include
non-ionic dimers, which for
every 6 iodine atoms generate
1 solute particle; with the
F igure 10 resultant osmolality being
Osmolality as function of the iodine concentration. Osmolality, approximately equal to that of
e.g., influences the pain sensation of the patient. blood. 19
<•> CORE KNOWLEDGE

<!> AT T E N T I O N
Administration of a RCM with
a high osmolality stimulates an
inflow of water from the interstitial
/ Contrast
Agents
ST R U CT U R E OSMOLALITY VISCOSITY
spaces into the vascular compart- CHAPTER OUTLINE:

ment, leading to hypervolaemia, Contrast Agents

High-osmolality ionic momomeres 1500 - 2100 mOsm/kg H2O +
vasodilatation, an increased car-
X-Ray Contrast Media
dio-vascular charge, bradycardia, (RCM)
Low-osmolality non-ionic monomers 500 - 900 mOsm/kg H2O ++ a reflectoric drop in blood pres-
Magnetic Resonance
sure, pulmonary hypertension Contrast Agents
and possibly endothelial damage.
Low-osmolality ionic dimers 600 mOsm/kg H2O + Ultrasound Contrast
Agents
Adverse effects attributable to
Take-Home Messages
Iso-osmolal non-ionic dimers 300 mOsm/kg H2O +++ high osmolality include vascular
pain, flushing, discomfort, nau- References

Table 1
sea, vomiting and an increase Test Your Knowledge
Osmolality and viscosity of iodinated contrast media. of diuresis and dehydration.

20
<•> CORE KNOWLEDGE

Viscosity

Viscosity describes the flow properties of the con- Viscosity increases disproportionately with
/ Contrast
Agents
trast agent solution and is expressed in mPa.s. iodine concentration and it decreases sig- CHAPTER OUTLINE:

nificantly with increasing temperature. Contrast Agents

X-Ray Contrast Media

(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast
<!> AT T E N T I O N Agents

Take-Home Messages
The viscosity of a contrast medium
has an impact on the maximum References
possible injection rate and on the
mixing behavior in the blood vessels. Test Your Knowledge
Warming contrast medium to a
temperature of 37°C reduces its
viscosity and increases the efficiency
of delivering high-viscosity agents in
case of fast injection and/or passage
through tiny catheters.
F igure 11
Viscosity plays an important role in
Viscosity in
relation to the
renal tolerance of RCM, with near-
temperature serum viscosity reducing the risk
and iodine of contrast-induced nephrotoxicity
concentration. associated with iodinated RCM. 21
<•> CORE KNOWLEDGE

Hydrophilicity

Hydrophilicity refers to an affinity for water, The increased water solubility of highly hydro-
/ Contrast
Agents
e.g., to the tendency of a substance to dis- philic RCM reduces the binding to plasma proteins, CHAPTER OUTLINE:

solve in water, and can be expressed as log thereby slowing down intracellular distribution Contrast Agents
P (octanol-water distribution coefficient). of the RCM, accelerating renal elimination and
X-Ray Contrast Media
reducing the passage through the blood-brain (RCM)
In iodinated RCM, the hydrophilicity depends on the barrier. Accordingly, a high hydrophilicity reduces
Magnetic Resonance
number of hydrophilic groups such as OH and N neurotoxicity, immunogenicity and nephrotox- Contrast Agents
groups that are present in the substituent chains of icity and lowers the risk of allergic reactions.
Ultrasound Contrast
the inherently hydrophobic triiodobenzene core. Agents

Take-Home Messages

References

Test Your Knowledge

22
<•> CORE KNOWLEDGE

/ Pharmacokinetics of Iodinated RCM / Contrast

Agents
CHAPTER OUTLINE:

Two-Compartment Model Contrast Agents

X-Ray Contrast Media

The pharmacokinetics of iodinated cellular com- (RCM)
RCM are best described using partment. Magnetic Resonance
a two-compartment model: However, it Contrast Agents
can cross Ultrasound Contrast
Following intravascular admin- the placen- Agents
istration, the iodinated RCM is tal barrier Take-Home Messages
rapidly distributed throughout in small
References
the intravascular space, reaching amounts and
a peak plasma concentration is excreted Test Your Knowledge
within 2 minutes, followed by in very small F igure 12

a passage into the interstitial amounts in Two-compartment model with renal elimination.

liquid, which is accessible through breast milk.

pores in the capillary walls.
Elimination of iodinated RCM 90 minutes, and almost the
The iodinated RCM thus intro- occurs almost exclusively by entire applied dose is excreted
duced into the extracellular space passive glomerular filtration. within 24 hours. In case of renal
cannot pass an intact blood brain With normal kidney function, the impairment, the elimination half-
barrier and is not distributed in the elimination half-life is approximately life is considerably prolonged. 23
<•> CORE KNOWLEDGE

Pharmacokinetics and Imaging

With regard to imaging with iodinated RCM,

/ Contrast
Agents
there are three post-injection phases: CHAPTER OUTLINE:

Contrast Agents
/ vascular phase, which is of very
X-Ray Contrast Media
short duration of less than 1 min- (RCM)
ute, for imaging of arteries
Magnetic Resonance
Contrast Agents
/ interstitial phase, which is of short duration
of 1.5-10 minutes, for imaging of organs Ultrasound Contrast
Agents
/ elimination phase, which is delayed Take-Home Messages
post injection (5 minutes) but then
References
of longer duration up to 30 minutes,
for imaging of the urinary tract Test Your Knowledge

<!> AT T E N T I O N

F igure 1 3
In general, the distribution from the intravascular compartment to
Post injection phase with
highly perfused organs, such as brain, liver, and kidney, is rapid, iodinated RCM. Note the
whereas distribution to less perfused organs and tissues, such as temporal contrast differences
bone and fat, is much slower. between the various spaces. 24
<•> CORE KNOWLEDGE

Opacification Modes of RCM

RCM are extensively used to visualise certain structures in the F igure 14

/ Contrast
Agents
organism and to obtain information on organ function, which Barium X-ray CHAPTER OUTLINE:

is achieved by applying four different modes of opacification: * (upper gastro-

intestinal tract) in a
patient with hiatal
Contrast Agents

hernia (asterisk). X-Ray Contrast Media

Note normal (RCM)
Direct Luminal Filling opacification
of small bowel
Magnetic Resonance
loops. Courtesy:
Contrast Agents
The identification of morphological structures is the main objec- Georgy Varnay,
MD, University
tive of direct luminal filling, which can occur through a natural Hospitals Geneva. Ultrasound Contrast
Agents
access (Fig. 14) or through an iatrogenically created access.
This mode of opacification permits the differentiation of superfi- Take-Home Messages
cial or mural changes, and it can provide functional information, References
e.g., about changes in tone or peristalsis in hollow passages.
Test Your Knowledge

Functional Organ Imaging

Functional opacification, which is applied in urography

(Fig. 15) and cholegraphy, exploits the fact that the contrast F igure 1 5

density depends significantly on the functionality of the Normal

urography. Case
kidneys and urinary tract or the hepatobiliary system. Con- courtesy of Dr.
MT. Niknejad,
sequently, the radiographic assessment of these organs
Radiopedia.org,
reveals both morphological and functional changes. rID: 85286. 25
<•> CORE KNOWLEDGE

Parenchymal Enhancement

In parenchymal staining, enhancement of

F igure 16

Contrast
enhanced CT
/ Contrast
Agents
(parenchymal
contrasts between tissues results from the staining) showing CHAPTER OUTLINE:
a small tumour
passage and selective accumulation of arising from the Contrast Agents
RCM in different organs or tissues, thereby hypopharynx
(green arrow) X-Ray Contrast Media
improving the differentiation of morphological and a right lymph (RCM)
node metastasis
structures, especially between normal and
(red arrow).
Magnetic Resonance
pathological tissues. This allows, or at least Case courtesy:
Contrast Agents
Minerva Becker,
facilitates, the demonstration of pathological MD, University
Ultrasound Contrast
processes and of their etiology as well (Fig. 16). Hospitals Geneva.
Agents

Take-Home Messages

Angiography References

Test Your Knowledge

In angiography (Fig. 17), selective opacifica-
tion can be achieved by direct RCM injection
into the vessel of interest, followed by evalu-
ation of RCM distribution and filling patterns
including gaps in opacification of the target
anatomy. This evaluation yields detailed F igure 17

diagnostic information regarding normal Normal

angiography
and abnormal morphology and function. of the carotid
arteries.
Lateral view. 26
<•> CORE KNOWLEDGE

/ Indications of RCM Application / Contrast

Agents
CHAPTER OUTLINE:

Intravenous RCM Injection Contrast Agents

X-Ray Contrast Media

Intravenous RCM administration for the purpose of CT Applications of intravenous RCM administration: (RCM)
scanning is the most common use of iodinated RCM / Computed tomography Magnetic Resonance
and has a wide variety of indications. Intravenous admin- / Digital subtraction angiography Contrast Agents
istration first leads to an arterial opacification, which is / Intravenous urography Ultrasound Contrast
followed by a parenchymal contrast enhancement. / Venography (phlebography) Agents

/ Inferior vena cava and its tributaries Take-Home Messages

For arterial opacification, the rate of / Superior vena cava and its tributaries References
iodine delivery plays a key role. / Extremities
Test Your Knowledge
/ Other venous sites
For the evaluation of a solid organ, such as the liver / Epidural venography
or pancreas, parenchymal organ enhancement
depends primarily on the total amount of iodine
administered, because lesion conspicuity may require
a larger volume of contrast medium to be injected.

27
<•> CORE KNOWLEDGE

The timing of image acquisition, relative to the time of injection of the contrast agent, has an impact on which anatomic
structures have accumulated the greatest concentration of the administered RCM and thus can be optimally visualised. / Contrast
Agents
Five phases of contrast enhancement for CT imaging: CHAPTER OUTLINE:

Contrast Agents
Non-enhanced phase: imaging prior to RCM Portal venous phase: later phase of image acquisi-
X-Ray Contrast Media
injection: determination of the baseline status tion, when the RCM is maximally concentrated in the (RCM)
of the anatomy and detection of calcified struc- mesenteric venous structures: assessing liver perfusion,
Magnetic Resonance
tures (e.g., calculi, vascular calcifications, and examining cirrhotic patients for portal hypertension. Contrast Agents
dystrophic calcification in some tumours).
Ultrasound Contrast
Delayed phase or wash out phase or the equi- Agents
Early arterial phase: image acquisition a few seconds librium phase: visualisation of lesions that pres-
Take-Home Messages
after bolus administration of intravenous RCM: detec- ent a slower RCM uptake, or in order to charac-
tion of arterial abnormalities (e.g., arterial dissections). terize slow wash-out kinetics (e.g. tumours). References

Test Your Knowledge

Late arterial phase: image acquisition 15 to 20
seconds after the early arterial phase: examina-
tion of highly vascularised anatomic structures
(e.g., liver, spleen, kidneys), especially for the
identification of well-vascularized masses.

28
<•> CORE KNOWLEDGE

A B

/ Contrast
Agents
CHAPTER OUTLINE:

Contrast Agents

X-Ray Contrast Media

(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast
Agents
C D

Take-Home Messages

References

Test Your Knowledge

F igure 18

Example of a CT of the abdomen with different phases of contrast enhancement. A. Non-enhanced phase. B. Arterial
phase. C. Venous phase. D. Late phase. Case courtesy: Thomas de Perrot, MD, University Hospitals Geneva. 29
<•> CORE KNOWLEDGE

Intraarterial RCM Injection

Intraarterial injection is the primary method of iodinated Applications of intraarterial RCM administration:
/ Contrast
Agents
RCM delivery used in diagnostic catheter angiogra- / Angiocardiography
CHAPTER OUTLINE:

phy and catheter-directed arterial intervention, such / Computed tomography angiography Contrast Agents
as percutaneous angioplasty and stent placement. / Coronary angiography X-Ray Contrast Media
/ Pulmonary angiography (RCM)
High rates of RCM administration combined with / Aortography Magnetic Resonance
a selective approach are required to opacify the / Visceral and peripheral arteriography Contrast Agents
target vessels due to the high arterial flow rate. / Digital subtraction angiography Ultrasound Contrast
/ Vascular pathologies of the Agents
central nervous system Take-Home Messages
/ Cerebral, vertebral and spinal angiography
References

Test Your Knowledge

30
<•> CORE KNOWLEDGE

Oral and Rectal RCM Applications

Oral or rectal contrast media are utilised in a variety of ways for imaging of the gastrointestinal tract, which is pre-
/ Contrast
Agents
dominantly done with barium sulfate suspensions and, in selected cases, with iodinated contrast media. CHAPTER OUTLINE:

Contrast Agents

X-Ray Contrast Media

Barium Sulfate (RCM)

For radiographic imaging of the gastrointestinal Barium sulfate is neither absorbed nor metab- Magnetic Resonance
Contrast Agents
tract, barium sulfate suspension is administered olised in subjects with a normal gastrointestinal
orally, rectally or instilled into an enterostomy tube tract and is excreted unchanged in the faeces. Ultrasound Contrast
Agents
or catheter, and is employed to fill the gastrointes-
tinal tract lumen or to coat the mucosal surface. Indications of barium sulfate in radiographic Take-Home Messages
imaging include differentiation of morphologi- References
Improved delineation of the gastrointestinal tract cal structures, especially between normal and
Test Your Knowledge
lumen and mucosa may be achieved by double-con- pathological tissue, as well as functional changes
trast examination with filling of the lumen with gas and through the entire gastrointestinal tract.
coating of the wall with barium sulfate (Fig. 19, see next
page). For this purpose, barium sulfate administration is
followed by a gel, carbon dioxide or a gas-forming agent
or air might get insufflated through the enema tube.

31
<•> CORE KNOWLEDGE

Adverse Reactions

The most common adverse reactions of barium sulfate include

/ Contrast
Agents
nausea, vomiting and abdominal cramping or discomfort CHAPTER OUTLINE:

during and after the examination and mild allergic reactions.

Contrast Agents
The hypoosmolality of the suspension causes water with-
drawal from the GI tract, which can lead to colon obstruction. X-Ray Contrast Media
(RCM)

The most serious complication from the use of barium sulfate Magnetic Resonance
Contrast Agents
in the GI tract is leakage into the mediastinum or peritoneal
cavity, leading to persistent peritonitis or mediastinitis. Ultrasound Contrast
Agents

Take-Home Messages

<!> AT T E N T I O N References

Test Your Knowledge

Contraindications

Contraindications for barium sulfate include suspected

perforation and postoperative insufficiency of suture as
well as previous allergic reactions to barium products.

Barium sulfate should not be used in individuals who are sus-

pected or known to suffer from necrotic colitis, ileus and degluti-
F igure 19
tion difficulties due to the risk of aspiration, and particular caution
Colon with barium sulfate followed by
is required for newborns, elderly and critically ill persons. a gel: double contrast image. 32
<•> CORE KNOWLEDGE

Oral Iodinated RCM

The current applications of oral iodinated RCM

/ Contrast
Agents
(Fig. 20) are primarily limited to visualisation of the CHAPTER OUTLINE:

GI tract when barium sulfate is contraindicated.

Contrast Agents

Diluted water-soluble ionic high-osmolality RCM X-Ray Contrast Media

(RCM)
are preferred for oral use, but diluted non-ionic
contrast agents can also be employed. Magnetic Resonance
Contrast Agents

Water-soluble contrast media are absorbed rap- Ultrasound Contrast

Agents
idly from the interstitial spaces and peritoneal cav-
ity, which makes them uniquely useful in examining Take-Home Messages
patients with a suspected hollow viscus perforation. References
No permanent deleterious effects from the presence
Test Your Knowledge
of water-soluble contrast media in the mediastinum,
pleural cavity or peritoneal cavity have been reported.

Excretion of orally administered iodinated RCM

occurs mainly through the faecal route and is depen-
dent on GI transit time, while only a small volume of
iodinated RCM is absorbed from the GI tract and
subsequently excreted into the urinary tract. F igure 20

CT with oral iodinated RCM. Note the heterogenous contrast in the small
bowel with higher iodine concentration in the distal part (red arrows). 33
<!> AT T E N T I O N

Contraindications

Hyperosmolal RCM may lead to deglutition difficulties and are, therefore, contraindicated for oral administration in
/ Contrast
Agents
patients at risk for aspiration. In such patients, non-ionic low-osmolality or iso-osmolality iodinated RCM should be CHAPTER OUTLINE:

used for oral administration because, even if aspirated, they are associated with only minimal bronchogenic toxicity.
Contrast Agents

Enteric hyperosmolal RCM should also be avoided in patients with fluid and electrolyte imbal- X-Ray Contrast Media
(RCM)
ances, particularly the very young or elderly patients with hypovolemia or dehydration.
Magnetic Resonance
Contrast Agents
Due to a slight systemic uptake of orally administered RCM, a careful use is indi-
cated in case of pregnancy, renal insufficiency and underlying thyroid disorder. Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

34
<•> CORE KNOWLEDGE

/ Adverse Reactions to RCM <!> AT T E N T I O N

/ Contrast
Agents
The incidence of adverse reactions related to the intravascular administration of iodin- CHAPTER OUTLINE:

ated RCM, which has been drastically reduced with the change in usage from ionic high-os-
Contrast Agents
molality RCM to non-ionic low-osmolality or iso-osmolality RCM, is now generally low.
X-Ray Contrast Media
(RCM)
Acute Adverse Reactions Magnetic Resonance
Contrast Agents
Acute adverse reactions to RCM occur within hypotension, bronchospasm and dyspnea, up to Ultrasound Contrast
1 hour after application, and the severity of such hypotensive shock and respiratory or cardiac arrest. Agents
reactions can range from mild to severe and Take-Home Messages
life-threatening. Acute reactions are categorised
References
as either hypersensitivity reactions and aller-
gy-like reactions, or chemotoxic reactions. Test Your Knowledge

Hypersensitivity and allergic-like reactions are

likely independent of dose and concentration
of the RCM and tend to be unpredictable.

F igure 21
Symptoms of hypersensitivity and allergic-like reac-
Illustration of a
tions include urticaria, pruritis, cutaneous edema, hypersensitivity
maculopapular
itching and diffuse erythema. Severe acute reactions
reaction due to
typically manifest as facial and laryngeal edema, contrast media. 35
<•> CORE KNOWLEDGE

<!> AT T E N T I O N / Contrast
Agents
Chemotoxic adverse reactions relate to a specific Serious chemotoxic adverse reactions can manifest CHAPTER OUTLINE:

molecular attribute of the RCM such as its chemical as cardiac arrhythmias, depressed myocardial con- Contrast Agents
structure, osmolality, viscosity and ionicity, and they tractility, cardiogenic pulmonary edema, convulsions
X-Ray Contrast Media
are generally dose and concentration dependent. and seizures. They are more frequent and signifi- (RCM)
cant in patients with underlying cardiac disease.
Magnetic Resonance
Common chemotoxic adverse reactions include Contrast Agents
nausea and vomiting, flushing, warmth, chills, Patient-related risk factors for an acute reaction to
Ultrasound Contrast
headache, dizziness, anxiety, taste alterations RCM are a history of a previous allergic-like reac- Agents
and hypertension. Vasovagal reactions can occur tion to a contrast agent and a history of asthma
Take-Home Messages
and appear as bradycardia with hypotension. and atopy, while contrast medium related risk fac-
tors are high-osmolality ionic contrast media. References

Test Your Knowledge

36
<•> CORE KNOWLEDGE

<!> AT T E N T I O N
/ Contrast
Agents
Delayed Adverse Reactions CHAPTER OUTLINE:

Contrast Agents
Delayed adverse reactions may develop from 60 min- Pregnancy and lactation
X-Ray Contrast Media
utes to up to one week following RCM exposure and are In pregnant women, when radiographic examination is (RCM)
most commonly but not limited to cutaneous reactions. essential, iodine-based contrast media may be given. Magnetic Resonance
Following such administration, the thyroid function Contrast Agents
Typical delayed cutaneous reactions can man- should be checked in the neonate during the first week Ultrasound Contrast
ifest as rashes, pruritus, erythema and swelling, and monitored for the first three years. Agents
while delayed non-cutaneous symptoms include
nausea, vomiting, headache, musculoskeletal Breast feeding may be continued normally when iodine- Take-Home Messages

pain, diarrhea and, occasionally, hypotension. based contrast media is given to the mother. References

Test Your Knowledge

Risk factors for a delayed reaction to RCM are a pre-
vious late contrast medium reaction and a treatment
with interleukin-2, as well as use of non-ionic dimers.

37
<•> CORE KNOWLEDGE

<!> AT T E N T I O N / Contrast
Agents
Thyrotoxicosis CHAPTER OUTLINE:

Contrast Agents
A contributing factor to adverse
X-Ray Contrast Media
reactions is the deiodination process (RCM)
and iodide impurity in the solutions
Magnetic Resonance
thus leading to traces of free iodide in Contrast Agents
the body with concentrations above
Ultrasound Contrast
the recommended daily intake. Agents

Take-Home Messages
In subjects with a normal thyroid func-
tion, the exposure with excess iodide References
can be compensated by a transient Test Your Knowledge
decrease of thyroid hormone synthe-
sis, the so-called Wolff-Chaikoff effect.
F igure 22

This intrinsic regulatory mecha- Light exposure might lead to a deiodination with iodide release.

nism is impaired in subjects with an

underlying thyroid disorder, so that
the application of iodinated contrast
media may lead to a thyrotoxicosis.
38
<•> CORE KNOWLEDGE

<!> AT T E N T I O N
/ Contrast
Agents
Risk factors for development of thyrotoxicosis Following administration of iodine-based contrast CHAPTER OUTLINE:

are Graves’ disease and multinodular goiter with media to a pregnant woman, thyroid function should
Contrast Agents
thyroid autonomy, especially in elderly individu- be checked in the neonate during the first week.
als and/or in areas of dietary iodine deficiency. X-Ray Contrast Media
(RCM)
Premature infants and neonates might be particularly
For individuals suspected of being at risk of thy- susceptible to developing clinically significant hypothy- Magnetic Resonance
Contrast Agents
rotoxicosis, knowledge of thyroid function before roidism because the immature gland may not be able
administration of iodinated RCM is helpful, and to fully reverse the acute Wolff-Chaikoff effect. Thyroid Ultrasound Contrast
Agents
close monitoring after administration is recom- function should be monitored up to the age of three.
mended. Selected high-risk patients may ben- Take-Home Messages
efit from prophylactic thyrostatic therapy. References

Test Your Knowledge

In patients with established hyperthyroidism, adminis-
tration of iodinated contrast media is contraindicated.

39
<•> CORE KNOWLEDGE

<!> AT T E N T I O N
/ Contrast
Agents
Renal Adverse Reactions CHAPTER OUTLINE:

Contrast Agents
Intravascular administration of a contrast medium The estimated glomerular filtration rate (eGFR),
X-Ray Contrast Media
may result in a deterioration of the renal func- calculated from the serum creatinine, is the rec- (RCM)
tion and even in acute kidney failure. ommended parameter to estimate renal function
Magnetic Resonance
before contrast medium administration. The current Contrast Agents
The standard diagnostic criterion for Post-Contrast guidelines of the European Society of Urogenital
Ultrasound Contrast
Acute Kidney Injury (PC-AKI) is defined as an increase in Radiology (ESUR) define the following threshold Agents
serum creatinine by > 0.3 mg/dl (or > 26.5 μmol/l), or to values for patient related risk of developing PC-AKI:
Take-Home Messages
> 1.5 times baseline within 48-72 hours of intravascular
administration of a contrast medium. eGFR < 45 ml/min/1.73 m2 References

Test Your Knowledge

before intraarterial contrast medium administra-
A preexisting renal dysfunction is the greatest risk tion with first pass renal exposure or in intensive
factor for developing PC-AKI, and the risk becomes care unit patients.
larger with increasing baseline renal impairment.
eGFR < 30 ml/min/1.73 m2
before intravenous contrast medium or intra-arte-
rial contrast medium administration with second
pass renal exposure.

40
>•< FURTHER KNOWLEDGE

In their Manual on Contrast Media 2024, the ACR Com-

<•> CORE KNOWLEDGE
/ Contrast
Agents
Further risk factors for developing PC-AKI
mittee on Drugs and Contrast Media of the American include diabetes mellitus, cardiovascular
CHAPTER OUTLINE:

College of Radiology, mention the following threshold disease, hypertension, hyperuricemia, protein- Contrast Agents
value for patient related risk of developing PC-AKI: uria, diuretic use, dehydration, advanced age X-Ray Contrast Media
and multiple iodinated contrast medium doses (RCM)
eGFR < 30 ml/min/1.73 m2 administered in a short time interval. Magnetic Resonance
Contrast Agents
Preventive strategies comprise 1-12 hours of
prehydration with intravenous saline or sodium Ultrasound Contrast
Agents
bicarbonate followed by 4-12 hours of posthy-
dration and the use of low- or iso-osmolal RCM Take-Home Messages
with the minimum dose. References

Test Your Knowledge

41
<•> CORE KNOWLEDGE

Extravasation
/ Contrast
Agents
An unintended extravascular injection of iodinated Extravasations involving larger volumes of RCM, espe-
CHAPTER OUTLINE:
RCM occurs in very rare cases only and typi- cially high-osmolality and high-viscosity agents, or the
cally causes self-limiting symptoms such as pain, use of a power injector, and those occurring at problem- Contrast Agents
erythema and swelling, but in severe cases, skin atic injection sites such as the dorsum of the hand, foot X-Ray Contrast Media
ulceration and necrosis may occur. The most com- or ankle, are more likely to result in severe tissue injury. (RCM)
monly reported severe injury after extravasation is Magnetic Resonance
the development of the compartment syndrome. Continuous monitoring and accurate conservative Contrast Agents
management help to avoid sequelae. The treat- Ultrasound Contrast
A severe extravasation injury is more likely to result ment consists in elevation of the affected extremity, Agents
in patients with arterial insufficiency or compromised ice cooling, topical application of silver sulfadia- Take-Home Messages
venous or lymphatic drainage in the affected extremity. zine and, in extreme cases, surgical intervention.
References

Test Your Knowledge

42
 / Contrast
Agents

/ Magnetic CHAPTER OUTLINE:

Contrast Agents

Resonance
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast

Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

Agents
43
<•> CORE KNOWLEDGE

/ Magnetic Resonance / Contrast

Agents

Contrast Agents CHAPTER OUTLINE:

Contrast Agents

X-Ray Contrast Media

(RCM)
Magnetic resonance imaging (MRI) contrast agents
Magnetic Resonance
are diagnostic pharmaceutical compounds that Contrast Agents
affect the nuclear magnetic resonance signal of
Ultrasound Contrast
the 1H-hydrogen nuclei (protons) of water mol- Agents
ecules contained in the surrounding tissue.
Take-Home Messages

The contrast of an MR image results from a com- References

plex interplay of various factors such as proton Test Your Knowledge
density, the longitudinal (spin-lattice) relaxation
time T1 and the transverse (spin-spin) relaxation
time T2, and on the applied MRI sequences.

Contrast agents (CAs) used in MRI either consist

of paramagnetic metal ions or of superpara-
F igure 23
magnetic particles, and they act to modify T1
Single spins (here electrons) are magnetised in the MR and
and T2 of water protons present in the tissue. interact with protons thus changing the tissue signal.

44
>•< FURTHER KNOWLEDGE

/ Paramagnetic Contrast Agents / Contrast

Agents
CHAPTER OUTLINE:
Paramagnetic CAs contain metal ions that the effect on T2 becomes increasingly sig-
have unpaired electrons in their outer shell, nificant at higher concentrations. Contrast Agents
which implies a resultant electron spin and X-Ray Contrast Media
a permanent magnetic moment. (RCM)

Magnetic Resonance
The magnetic moment of a tumbling para- Contrast Agents
magnetic CA molecule induces an additional, Ultrasound Contrast
time-variable magnetic field in the hydrogen Agents
nuclei of the surrounding water molecules, Take-Home Messages
which in turn can increase the rate r1 of lon-
References
gitudinal spin-lattice relaxation and the rate
r2 of transverse spin-spin relaxation. Test Your Knowledge

The increase in relaxation rate caused by a

CA leads to a corresponding shortening of
T1 and T2 in the region of interest, producing
hyperintense signals in T1-weighted images and
F igure 24
hypointense signals in T2-weighted images.
Gadolinium interacting with the surrounding water protons at
different levels. Usually 1-2 water protons get closer to the central
atom surrounded by a ligand (inner-sphere interaction). With newer
The effect on T1 is already evident at low con-
agents the number of interacting protons can double allowing direct
centrations of the contrast agent, whereas interaction of 2 water molecules (q-factor of 2 instead of 1). 45
>•< FURTHER KNOWLEDGE

Relaxivity

The efficacy of a MR contrast agent is expressed in

Manganese-Based Contrast Agents

Manganese-based CAs contain bivalent manga-

/ Contrast
Agents
terms of relaxivity R, which refers to the ability of the nese, a transition metal with five unpaired elec- CHAPTER OUTLINE:

CA to enhance the proton relaxation rate. It is generally trons, which is also naturally present in the body. Contrast Agents
measured experimentally in water and is defined as the
X-Ray Contrast Media
increase in relaxation time of the solvent (water) induced Paramagnetic manganese is available either (RCM)
by 1 mmol L−1 of the active ion of the contrast agent: in the form of small molecules or as the more
Magnetic Resonance
recently developed nanometre sized materials. Contrast Agents
R1 = 1 / T1 (1 Mol, 20°C)
Ultrasound Contrast
Mangafodipir trisodium (Mn-DPDP) is a liver spe- Agents
The contrast efficiency is expressed as the r2/ cific CA in which a manganese ion Mn2+ is che-
r1 ratio: the higher the ratio, the greater the rel- lated with a dipyridoxyldiphosphate ligand. Take-Home Messages
ative effect on T2 and vice versa on T1. References

Test Your Knowledge

GADOPICLENOL GADOTERATE GADOBUTROL GADOTERIDOL GADOBENATE GADODIAMIDE GADOPENTETATE

Relaxivity mM-1s-1
12.2/15.0 2.9 / 3.2 3.3 / 3.9 2.9 / 3.2 4.0 / 4.3 3.3 / 3.6 3.3 / 3.9
in water 37°C, 1.5T

Dosing in mmol Gd 0.075 (CNS)

0.05 0.1 0.1 0.1 0.1 0.1
per kg BW and 0.1

Table 2

Doses: The higher relaxivities of certain agents allow to adapt the dosing in mmols per kg body-weight in
clinical routine. This permits to reduce the gadolinium exposition of the patient. Robic C et al. Invest Radiol. 2019 46
<•> CORE KNOWLEDGE

/ Gadolinium-Based Contrast Agents / Contrast

Agents
CHAPTER OUTLINE:

Gadolinium-based CAs, which contain trivalent gad-

Contrast Agents
olinium – a metal from the lanthanide series with
seven unpaired electrons – are the most clinically X-Ray Contrast Media
(RCM)
used CAs in MRI because of their high magnetic
moment and long electronic spin relaxation time. Magnetic Resonance
Contrast Agents

However, the cytotoxicity of gadolinium in its Ultrasound Contrast

Agents
free ionic form Gd3+ makes it necessary to mask
the gadolinium by providing chelating ligands Take-Home Messages
which form chemically stable complexes. References

Test Your Knowledge

Administering gadolinium as an inert and sta-
ble coordination complex prevents the cellular
uptake of free Gd3+ and maintains the biodistri-
bution within the extracellular space, thereby
enhancing renal filtration and urinary excretion.

F igure 25

Macrocyclic gadolinium complex with Gd3+ as the central atom

bound tightly to a ligand presenting a ring-like structure. 47
>•< FURTHER KNOWLEDGE

Structure of the Gadolinium Complexes

/ Contrast
Agents
The currently available gadolinium-based contrast The molecular characteristics of the four classes of
CHAPTER OUTLINE:
agents can be classified into four main categories gadolinium complexes have a significant impact on
according to their structure, particularly the nature some key properties such as osmolality and viscos- Contrast Agents
of the chelating moiety, and to their ionicity. ity, but also on their relaxivity and biodistribution. X-Ray Contrast Media
(RCM)
In linear complexes, the gadolinium ion is only The molecular characteristics are also responsi- Magnetic Resonance
partially surrounded by a chain-like structure ble for the differences between the various gado- Contrast Agents
of the ligand, whereas in macrocyclic com- linium complexes regarding their thermodynamic Ultrasound Contrast
plexes, the gadolinium ion is enclosed within a stability constants and kinetic rate constants. Agents
cage-like structure formed by the ligand. Take-Home Messages

References
Both, the linear and the macrocyclic gadolinium com-
plexes can either be non-ionic or ionic. In the ionic Test Your Knowledge
gadolinium complexes, the remaining anionic groups
are salified with meglumine or sodium cations.

48
>•< FURTHER KNOWLEDGE

Stability of Gadolinium Complexes

/ Contrast
Agents
In solutions of gadolinium-containing CAs, there is
CHAPTER OUTLINE:
always an equilibrium between complexed gadolin-
ium (Gd-Ligand) and free gadolinium ions (Gd3+): Contrast Agents

X-Ray Contrast Media

(RCM)
Gd3+ + Ligand ⟷ Gd-Ligand
Magnetic Resonance
Contrast Agents

The equilibrium state can be characterised Ultrasound Contrast

Agents
by the thermodynamic stability constant:
Take-Home Messages

[Gd-Ligand] References
KTD =
[Gd3+] ∙ [Ligand] Test Your Knowledge

which is often expressed in logarithmic form

log KTD. For the gadolinium complexes used
as contrast agents, this equilibrium strongly
favors the side of the complexed gadolinium,
with log KTD ranging from 16.9 to 25.6.

49
>•< FURTHER KNOWLEDGE

/ Contrast
COMPLEXES ST R U CT U R E T H E R M O DY N A M I C K I N ET I C STA B I L I T Y D I S S O C I AT I O N H A L F-
STA B I L I T Y - LO G K AT P H 7. 4 L I F E AT 2 5° C, P H 1.0

Agents
Gadopiclenol macrocyclic, non-ionic 18.7 high 20 days+/-3d
CHAPTER OUTLINE:

Gd-DOTA macrocyclic, ionic 25.6 high 338 hours

Contrast Agents

Gd-HP-DO3A macrocyclic, non-ionic 23.8 high 3.9 hours X-Ray Contrast Media
(RCM)

Gd-BT-DO3A macrocyclic, non-ionic 21.8 high 43 hours Magnetic Resonance

Contrast Agents

Gd-BOPTA inear-ionic 22.6 medium < 5 sec Ultrasound Contrast

Agents

Gd-DTPA linear-ionic 22.1 low < 5 sec Take-Home Messages

References
Gd-DTPA-BMA linear-non-ionic 16.9 low < 5 sec
Test Your Knowledge

Table 3

Stability of gadolinium complexes Robic C et al. Invest Radiol. 2019

The thermodynamic stability of gadolin- Macrocyclic complexes generally have a higher ther-
ium complexes decreases with decreasing modynamic and kinetic stability than linear complexes.
pH, so that in acidic environment the com-
plexes are more prone to decomplexation. Ionic compounds tend to have a slightly higher thermo-
dynamic and kinetic stability than non-ionic compounds. 50
>•< FURTHER KNOWLEDGE

Transmetallation
/ Contrast
Agents
Decomplexation of the gadolinium complexes A further factor contributing to the toxicity of Gd3+
CHAPTER OUTLINE:
may result from reactions with other metal ions ions is their tendency to bind to endogenous anions,
that are present in human body fluids. particularly phosphates and carbonates, creating Contrast Agents
insoluble salts which are taken up by the reticuloen- X-Ray Contrast Media
In particular, the Gd3+ ion in a chelate complex may be dothelial system (RES) through phagocytosis and (RCM)
replaced by Zn2+, which leads to release of toxic Gd3+ accumulating in human tissues (style). This process is Magnetic Resonance
ions and to formation of zinc complexes resulting in accompanied by a stimulation of local macrophages Contrast Agents
an undesirable zinc washout via renal elimination. to initiate an inflammatory response with the release of Ultrasound Contrast
cytokines and cytokine triggered transcription factors. Agents
An important reason for the toxicity of free Gd3+ Take-Home Messages
ions is the size similarity and resulting competi-
References
tion with Ca2+ ions in cellular and biochemical pro-
cesses, leading to an inhibition of calcium channels Test Your Knowledge
and a blockage of Ca2+ dependent enzymes.

51
<•> CORE KNOWLEDGE

Pharmacokinetics
/ Contrast
Agents
After intravenous administration, gadolin-
CHAPTER OUTLINE:
ium complexes are rapidly distributed into
the intravascular space and then passed, Contrast Agents
through the capillaries, into the interstitial X-Ray Contrast Media
space, with the intravascular half-life time (RCM)
being dependent on the molecular weight Magnetic Resonance
and on the extent of plasma protein binding. Contrast Agents

Ultrasound Contrast
Depending on its structure, a gado- Agents
linium complex may also be partially Take-Home Messages
distributed in the liver through passive
References
diffusion or through a selective uptake
by hepatocytes via carrier-mediated Test Your Knowledge
transport across the cell membranes.

Gadolinium contrast agents do not pen-

etrate the intact blood-brain barrier.

Low molecular weight gadolinium com-

plexes are generally not metabolised.
F igure 26

Early vascular distribution of the iv injected gadolinium contrast agent. 52

<•> CORE KNOWLEDGE

/ Contrast
Agents
The gadolinium complexes CHAPTER OUTLINE:
Extracellular compartiment
are excreted either almost Intracellular
Contrast Agents
exclusively via the kidneys, or compartiment
Intravascular Interstitial
X-Ray Contrast Media
they have a dual elimination (RCM)
pathway via the kidneys and
Magnetic Resonance
via the hepatobiliary system in Contrast Agents
case of liver-specific agents
Kidneys Liver Ultrasound Contrast
(Gadobenate, Gadoxetate). Agents
Renal Hepatobiliary
Take-Home Messages
Patients with normal renal ecxretion ecxretion
function eliminate more References
than 90% of low molecu- Urine Bile
Test Your Knowledge
lar weight gadolinium CAs
(non-specific) within the first
12 hours after injection. Gallbladder and
Intestinum

F igure 27

Distribution sites and elimination pathways for intravenously administered gadolinium complexes. 53
>•< FURTHER KNOWLEDGE

/ Superparamagnetic Contrast Agents / Contrast

Agents
Superparamagnetic contrast agents consist of which predominantly leads to a shortened T2 and CHAPTER OUTLINE:

iron oxide nanoparticle cores coated with a pro- concomitant negative contrast enhancement in
Contrast Agents
tective layer of a biocompatible material like poly- pathologically relevant T2-weighted images. With
ethylene glycol, dextran, heparin or albumin. decreasing size of the superparamagnetic particles, X-Ray Contrast Media
(RCM)
shortening of T1 becomes more pronounced, so that
The magnetic moment of the superparamagnetic small superparamagnetic particles with core diam- Magnetic Resonance
Contrast Agents
cores tends to align with the external magnetic field, eters of less than 10 nm can produce positive con-
inducing local magnetic field gradients that dephase trast in anatomically relevant T1-weighted images. Ultrasound Contrast
Agents
the transverse magnetisation of water protons,
Take-Home Messages

A B
References

Test Your Knowledge

* *
*
F igure 28

Liver MRI pre (A) and post

(B) iv administration of

*
iron oxide nanoparticles
with no uptake in the
hepatocellular carcinoma
(red asterisk) and uptake
in normal liver tissue
(green asterisks). 54
<•> CORE KNOWLEDGE

/ Indications / Contrast
Agents
CHAPTER OUTLINE:

MR contrast agents can be classified according to their biodistribution pattern and the con- Contrast Agents
sequent applications in the morphological and functional diagnostic practice.
X-Ray Contrast Media
(RCM)

Non-Specific Extracellular Contrast Agents Magnetic Resonance

Contrast Agents

Ultrasound Contrast
Extracellular MR contrast agents are low molec- The extracellular MR contrast agents are mainly Agents
ular weight gadolinium complexes which, after applied for CNS examinations aimed at the detection
Take-Home Messages
injection, rapidly diffuse from the intravascular of various neoplasms, the assessment of demyelinat-
space into the extracellular space, from where they ing diseases, infectious and inflammatory processes, References
are then gradually eliminated by the kidneys. the characterisation of vascular anomalies and the Test Your Knowledge
diagnosis of cerebral ischemia and infarction. These
These contrast agents circulate freely in the extra- agents are also extensively used in body imaging to
cellular space but do not penetrate into tissues with asses certain pathologic processes, such as hepato-
specialised vascular barriers. Accordingly, they tend cellular carcinoma or renal cell carcinoma and also for
to accumulate in tissues with abnormal perfusion certain muskuloskeletal applications (see next page).
or capillary permeability and in regions where
the blood-brain barrier permeability is altered.

55
<•> CORE KNOWLEDGE

/ Contrast
<!> AT T E N T I O N
Some extracellular MR contrast agents can also be
employed in MR angiography but due to their short Indications for Non-Specific
Agents
residence time in the intravascular space, the imag- Extracellular CAs
CHAPTER OUTLINE:
ing acquisition time window is very limited.
Central Nervous System Contrast Agents
For the use as extracellular nonspecific contrast agents, most Detection of primary neoplasms and brain
metastases, assessment of demyelinating X-Ray Contrast Media
gadolinium complexes are equally effective because of their diseases, detection of infectious and (RCM)
similar relaxivities inflammatory processes, characterisation
of vascular anomalies and diagnosis of Magnetic Resonance
and biodistributions. cerebral ischemia and infarction. Contrast Agents
With the recent intro-
Abdomen and Pelvis Ultrasound Contrast
duction of Gadop- Agents
Detection and characterisation of lesions,
iclenol offering a and determination of the extent of malignant Take-Home Messages
higher molar relaxiv- tumour dissemination.
References
ity per mmol gadolin- MR Angiography
ium the dosing needs Assessment of vascular anatomy and Test Your Knowledge
to get adapted (0.05 disease.
mmol/kg instead of Breast
0.1 mmol/kg bw or Differentiation of malign and benign lesions,
0.075 mmol/kg in detection of multicentric malignancies,
recurrent local breast cancer or benign post
case of gadobutrol therapeutic fibrosis.
CNS exams).
Musculoskeletal System
F igure 29 Detection and characterisation of mass
Gadolinium-enhanced MRI lesions and inflammatory processes and
of the carotid arteries. evaluation of the extent of disease. 56
<•> CORE KNOWLEDGE

Blood Pool Agents / Contrast

Agents
Blood pool agents are high molecular weight gado- Blood pool agents* cause a significant reduction in the CHAPTER OUTLINE:

linium compounds which have a slow diffusion rate T1 relaxation time of circulating blood; thus, these agents
Contrast Agents
from the intravascular into the extracellular space are used for MR angiography, including coronary artery
because of their albumin binding and which require imaging, and for assessing tumour angiogenesis. X-Ray Contrast Media
(RCM)
metabolisation of their macromolecular moiety
before renal excretion, so that their concentration Magnetic Resonance
Contrast Agents
in plasma remains stable for over one hour.
Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

*) These blood pool agents are currently not available anymore. 57

<•> CORE KNOWLEDGE

Organ-Specific Gadolinium-Based Contrast Agents

/ Contrast
Agents
The two linear ionic complexes Gd-BOPTA
CHAPTER OUTLINE:
and Gd-EOB-DTPA exhibit liver specificity
because of their selective uptake by hepato- Contrast Agents
cytes and their partial hepatobiliary excretion.
* X-Ray Contrast Media
(RCM)
After intravenous administration, these CAs have an
Magnetic Resonance
initial extracellular phase, which allows imaging of Contrast Agents
hepatic vasculature, followed by a delayed hepatocytic
Ultrasound Contrast
uptake and biliary elimination phase, which permits the Agents
evaluation of hepatic tissue with altered functionality.
Take-Home Messages

References
<!> AT T E N T I O N

*
Test Your Knowledge

*
The uptake by hepatocytes selectively F igure 30
increases the signal intensity of normal Liver MRI pre
liver parenchyma, while focal lesions and 20 min post

*
containing mutated cells or altered iv administration
structure do not uptake the CA and will of Gd-EOB-
appear hypointense, enhancing the DTPA with no
uptake in an
visualisation of the lesion and helping to adenoma (red
characterise its nature. asterisk) and
contrast agent
They can also be useful to improve uptake in normal
detection of metastases and liver tissue
hepatocellular carcinoma. (green asterisk). 58
<•> CORE KNOWLEDGE

Tissue Specific Reticuloendothelial and Lymph Node Agents

/ Contrast
Agents
Superparamagnetic iron oxide particles (SPIO) are selectively taken up by the reticuloendothelial sys-
CHAPTER OUTLINE:
tem (RES) through phagocytosis, with the size of the particles determining the tissue specificity.
Contrast Agents
Large SPIO are rapidly metabolised by phagocytic Small SPIO with a core size under 10 nm enter the X-Ray Contrast Media
cells like Kupffer cells in the liver and spleen, producing lymphatic system and are metabolised by phagocytes in (RCM)
negative contrast in T2 weighted images. Since most normal lymph nodes, whereas metastatic lymph nodes Magnetic Resonance
liver lesions, including metastases and the vast major- retain a certain quantity of the CA, allowing to differ- Contrast Agents
ity of hepatocellular carcinomas, do not have an intact entiate between normal tissue, which has a negative Ultrasound Contrast
RES, their signal intensity is unchanged by adminis- contrast enhancement in T2 weighted images, and met- Agents
tration of SPIO, so that the contrast between normal astatic tissue, which maintaining high signal intensity. Take-Home Messages
and abnormal liver tissue is increased as the lesion
References
appears hyperintense relative to the normal tissue. Small SPIO particles are utilised in the study of lymph
nodes and bone marrow (limited availability). Test Your Knowledge
Large SPIO particles can be used
in liver and spleen imaging.

59
<•> CORE KNOWLEDGE

Direct MR Arthrography
/ Contrast
Agents
Direct MR arthrography involves
CHAPTER OUTLINE:
the injection of a contrast agent into
a joint region under fluoroscopic Contrast Agents
or ultrasound guidance, followed X-Ray Contrast Media
by magnetic resonance imaging. (RCM)
MR arthrography provides clearer Magnetic Resonance
images of the tendons, ligaments Contrast Agents
and cartilage in the affected region. Ultrasound Contrast
Agents
The low concentrated solutions Take-Home Messages
correspond to 1:200-250 fold dilu-

*
References
tions (2-2.5 mM) of the iv approved
products (500-1000 mM). Test Your Knowledge

F igure 31

Direct MR arthrography of the shoulder using a 2.5 mM GBCA (Artirem®).

GBCA in the joint space is indicated by an asterisk. 60
<•> CORE KNOWLEDGE

/ Contrast
Agents
CHAPTER OUTLINE:
Dosage of Gadolinium Contrast Agents
Contrast Agents
For clinical use, the recommended dose of extra- Liver-specific contrast agents are effec-
X-Ray Contrast Media
cellular MR contrast agents is 0.1 mmol/kg of body tive in lower doses of 0.05 to 0.1 mmol/kg for (RCM)
weight for most of body imaging examinations. Gadobenate (Gd-BOPTA) and 0.025 mmol/
Magnetic Resonance
With the recent introduction of Gadopiclenol this kg for Gadoxetate (Gd-EOB-DTPA). Contrast Agents
agent can be used with 0.05 mmol/kg body-weight
Ultrasound Contrast
due to its higher molar relaxivity. When used in MR Agents
angiography and CNS imaging, some of the extra-
Take-Home Messages
cellular MR contrast agents may be utilised with
a higher dose up to 0.3 mmol/kg body-weight References
(please refer to the SmPCs in your country). Test Your Knowledge

61
<•> CORE KNOWLEDGE

/ Adverse Reactions
<!> AT T E N T I O N

/ Contrast
Agents
CHAPTER OUTLINE:

The most frequently reported adverse events of gad- Pregnancy and lactation
Contrast Agents
olinium contrast agents are rated as mild and include In pregnant women, only when there is a very strong
coldness, warmth or pain at the injection site, nausea, indication for an enhanced MRI, a macrocyclic gadolin- X-Ray Contrast Media
(RCM)
vomiting and headache, paresthesias and dizziness. ium contrast agent may be administered using the small-
Magnetic Resonance
est possible dose. Contrast Agents
Allergic-like reactions with gadolinium complexes,
which occur only very rarely, consist of sweat- Breast feeding may be continued normally when mac- Ultrasound Contrast
ing, rash, urticaria, itching and facial swelling. rocyclic gadolinium-based contrast agents are given to Agents
the mother. Take-Home Messages
Risk factors for developing an allergic-like reac- References
tion are a previous moderate or severe acute reac-
Test Your Knowledge
tion to a gadolinium-based or iodinated contrast
agent, asthma, and various other allergies.

Hypersensitivity is
the major risk!

62
<•> CORE KNOWLEDGE

<!> AT T E N T I O N

/ Contrast
Agents
/ Nephrogenic Systemic CHAPTER OUTLINE:

Fibrosis (NSF) Contrast Agents

X-Ray Contrast Media

F igure 32 (RCM)
Nephrogenic systemic fibrosis (NSF) is a rare Manifestations
Magnetic Resonance
of nephrogenic
but highly disabling disorder, which can occur systemic fibrosis.
Contrast Agents
in patients with highly impaired renal function A: Tightness and
Ultrasound Contrast
hardness of the
exposed to less stable gadolinium-based CAs. hands combined Agents
with joint
contractures. Take-Home Messages
Clinical manifestations of NSF are extensive thickening B: Firm nodules
establishing a References
and hardening of the skin and subcutaneous tissues cobblestone
associated with erythematous papules, as well as configuration. Test Your Knowledge
C: Tight and firm
muscle weakness, bone pain and joint contractures. skin on lower legs.
Reproduced from:
Elmholdt TR et
Progressed NSF may also involve other organs, such as
al., Nephrogenic
the liver, lungs, esophagus, heart and skeletal muscle. Systemic Fibrosis
in Denmark– A
Nationwide
Symptoms develop and progress rapidly, are Investigation.
PLOS ONE 2013;
irreversible and can lead to extreme disabil- 8(12): e82037.
doi:10.1371/
ity and death because of scarring alterations of
iournal.pon
the organs with consequent loss of function. e.0082037.0001 63
<•> CORE KNOWLEDGE

<!> AT T E N T I O N
/ Contrast
Agents
As a pathophysiological mechanism it is assumed that Risk Factors for the Development of NSF CHAPTER OUTLINE:

a reduced renal function, which is associated with a The greatest risk factors for the development of Contrast Agents
considerably prolonged tissue exposure to the gado- NSF are a reduced renal function, particularly
linium complex, increases the probability for precipita- with a glomerular filtration rate of eGFR < 15 ml/ X-Ray Contrast Media
(RCM)
tion of insoluble toxic gadolinium salts. This process is min/1.73 m2, and patients on dialysis.
supposed to stimulate a subsequent proinflammatory Magnetic Resonance
cascade of events leading to the fibrosing process. The risk for developing NSF is substantially more Contrast Agents
pronounced after the administration of non-ionic Ultrasound Contrast
and ionic linear gadolinium complexes, and it Agents
increases with contrast agent dose and multiple Take-Home Messages
exposure.
References
Further risk factors include metabolic acido-
Test Your Knowledge
sis, elevated blood levels of iron, calcium or
phosphate, a high-dose erythropoietin therapy,
immunosuppression, vasculopathy and infection
or other acute proinflammatory events.

64
<•> CORE KNOWLEDGE

/ Gadolinium Retention in the Brain

<!> AT T E N T I O N

/ Contrast
Agents
CHAPTER OUTLINE:

Repeated administration of gadolinium-based contrast To date, no neurological symptoms associated with

Contrast Agents
agents is associated with gadolinium accumulation in gadolinium retention in the brain have been reported.
the brain regions of the dentate nucleus and globus X-Ray Contrast Media
(RCM)
pallidus even in subjects with normal renal function. Gadolinium deposits may also occur in the bone,
liver and skin, independently of renal function. Magnetic Resonance
Contrast Agents
While such deposits have been reported for all gad-
olinium-based agents, the highest levels found after Bone and liver retention do not produce any Ultrasound Contrast
Agents
the administration of linear agents were substantially clinical symptoms, whereas skin depos-
higher than after the use of macrocyclic agents. its manifest as red skin plaques. Take-Home Messages

References
A significant positive correlation exists between
Test Your Knowledge
the amount of gadolinium accumulated and
the cumulative dose of previous administra-
tions of gadolinium-based contrast agents.

65
>•< FURTHER KNOWLEDGE

/ Safety Recommendation / Contrast

Agents
CHAPTER OUTLINE:

The European Medicines Agency (EMA) has classi- maintained by EMA as non-specific gadolinium con-
Contrast Agents
fied the linear complexes Gd-DTPA-BMA, Gd-DTPA trast agents. However, they should be used with
and Gd-DTPA-BMEA as high risk agents and sus- caution in patients with GFR < 30 ml/min, observing X-Ray Contrast Media
(RCM)
pended their intravenous usage, with the exception a period of at least 7 days between two injections.
that Gd-DTPA may still be employed Magnetic Resonance
Contrast Agents
for direct MR arthrography.
Ultrasound Contrast
Agents
The linear complexes Gd-BOPTA
and Gd-EOB-DTPA, which are Take-Home Messages
rated as intermediate risk agents, References
remain approved by EMA for
Test Your Knowledge
hepato-biliary imaging only.

The macrocyclic agents are

considered as low-risk and are

F igure 33

Image from Wikimedia Commons.

https://commons.wikimedia.org/wikiFile:Primum_Non_Nocere.
jpg#filelinks 66
>•< FURTHER KNOWLEDGE

TYPE IONICITY P R O D U CT COMPLEX E M A R EC O M M E N DAT I O N

/ Contrast
Agents
Gd-DTPA gadopentetate dimeglumine restricted use for direct MR arthrography
CHAPTER OUTLINE:

ionic Gd-BOPTA gadobenate dimeglumine restricted use as for hepato-biliary imaging Contrast Agents

X-Ray Contrast Media

Linear Gd-EOB-DTPA gadoxetate restricted use as for hepato-biliary imaging (RCM)

Magnetic Resonance
Gd-DTPA-BMA gadodiamide suspended Contrast Agents
non-ionic
Ultrasound Contrast
Gd-DTPA-BMEA gadoversetamide suspended
Agents

ionic Gd-DOTA gadoterate meglimine maintained as non-specific GdCA Take-Home Messages

References
Gd-HP-DO3A gadoteridol maintained as non-specific GdCA
Macrocyclic Test Your Knowledge
non-ionic
Gd-HP-DO3A gadoteridol maintained as non-specific GdCA

Gadopiclenol Gadopiclenol approved 2023, non-specific

Table 4

Recommendation of the use of gadolinium-based CAs according to the European Medicines Agency (EMA). Since 2023
Gadopiclenol has been approved by EMA with the following characteristics: macrocyclic, non-ionic, non-specific GdCA 67
 / Contrast
Agents
CHAPTER OUTLINE:

/ Ultrasound
Contrast Agents

X-Ray Contrast Media

(RCM)

Magnetic Resonance

Contrast
Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages

Agents
References

Test Your Knowledge

68
<•> CORE KNOWLEDGE

/ Ultrasound Contrast Agents / Contrast

Agents
CHAPTER OUTLINE:

Contrast Agents
Ultrasound contrast agents are used in order to increase the reflection of ultrasound
X-Ray Contrast Media
waves from blood, thus resulting in an enhancement of the contrast between blood (RCM)

and surrounding tissue. Magnetic Resonance

Contrast Agents

Ultrasound Contrast
Agents

/ Microbubbles Take-Home Messages

References

Ultrasound contrast agents consist of suspensions con- shell and maintains an elevated vapour concentration Test Your Knowledge
taining microscopically small gas bubbles encapsulated within the microbubble. The stabilising shell is made
in thin stabilising shells. The gas core of the microbub- of a biodegradable material, such as phospholipids or
bles is generally composed of an inert high molecular albumin, which reduces the likelihood of coalescence
weight and low solubility gas such as a perfluorocarbon and allows the microbubbles to persist in the vasculature
or sulfur hexafluoride which does not diffuse across the and permit diagnostic evaluation for several minutes.

69
<•> CORE KNOWLEDGE

Commercially available ultrasound contrast agents con-

tain a mixture of microbubbles of various sizes in the range
of 1-10 μm, which is approximately the same size range
>•< FURTHER KNOWLEDGE
/ Contrast
Agents
Composition of Currently Used
as erythrocytes. After intravenous injection the micro- ­Ultrasound ­Contrast Agents:
CHAPTER OUTLINE:

bubbles move passively with the blood flow and act as Contrast Agents
tracers providing an enhanced ultrasound signal. / Air microbubbles encapsulated in a
shell of galactose stabilised with palmitic X-Ray Contrast Media
(RCM)
acid.
Magnetic Resonance
/ Sulfur hexafluoride (SF6) microbubbles Contrast Agents
encapsulated in a shell of phospholipids
Ultrasound Contrast
and palmitic acid. Agents
/ Perfluoropropane (perflutren, C3F8) Take-Home Messages
microbubbles encapsulated in an albu-
References
min shell.
Test Your Knowledge
/ Perfluoropropane (perflutren, C3F8)
microbubbles encapsulated in a shell of
phospholipids.

F igure 34

Structure of microbubble composed

of a core of sulfur hexafluoride gas and
a monolayer phospholipid shell. 70
>•< FURTHER KNOWLEDGE

/ Ultrasound Echo Enhancement by Microbubbles / Contrast

Agents
CHAPTER OUTLINE:

The contrast enhancement achieved with microbubbles / at low acoustic powers, the microbubbles act
Contrast Agents
is due to a substantial difference in acoustic impedance as simple reflectors, so that only a backscat-
at the interface between the microbubble structure and tered linear signal can be received. X-Ray Contrast Media
(RCM)
the surrounding blood plasma, which leads to backscat-
tering of the sound wave at the microbubble surface. / at intermediate acoustic powers, the microbubbles Magnetic Resonance
are induced to oscillate and thereby to emit an Contrast Agents

This acoustic response of an ultrasound contrast agent intensive non-linear resonance signal, which con- Ultrasound Contrast
is specific for the microbubbles used and also depends tains, in addition to the fundamental vibration fre- Agents

on the acoustic power of the irradiated ultrasound wave. quency, also harmonic upper frequencies. Take-Home Messages

/ at even higher acoustic powers, the microbub- References

ble vibration is so violent that the microbubbles Test Your Knowledge
are destroyed by tearing of the membranes.
This process is accompanied by emission of
a detectable ultrasound pulse.

71
>•< FURTHER KNOWLEDGE

/ Contrast
Agents
CHAPTER OUTLINE:

Contrast Agents

X-Ray Contrast Media

(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

* The mechanical index (MI) is a unitless metric for the bioeffects of an ultrasound beam. It is proportional to the peak rarefaction pressure and inversely
proportional to the frequency of the ultrasound wave.

F igure 3 5

Influence of irradiated ultrasound power on the acoustic behavior of microbubbles. 72

>•< FURTHER KNOWLEDGE

/ Contrast
Agents
Implementation of contrast-specific ultrasound tech- The improved contrast effect permits real time scan- CHAPTER OUTLINE:

niques such as harmonic and coded imaging and, ning with the possibility of prolonged organ insona- Contrast Agents
particularly, phase and amplitude modulation, allows tion, thus enabling dynamic imaging of blood flow and
X-Ray Contrast Media
discrimination of the specific signal generated by the measuring organ perfusion with high sensitivity. (RCM)
contrast agent microbubbles from other acoustic signals
Magnetic Resonance
such as from specular reflection and tissue scattering. Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

73
<•> CORE KNOWLEDGE

/ Biodistribution and Elimination / Contrast

Agents
CHAPTER OUTLINE:

The intravascularly administered microbubbles are After spontaneous dissolution of the microbubbles, the
Contrast Agents
small enough to pass through the pulmonary capil- inert gas content is released and is mostly eliminated
laries and reach the systemic capillary network, but within 10 to 20 minutes by lung ventilation, whereas the X-Ray Contrast Media
(RCM)
they generally remain confined to the blood pool shell material is metabolised and eliminated by the liver.
and do not extravasate into the interstitial space. Magnetic Resonance
Contrast Agents
Ultrasound contrast agents are not excreted through
However, some ultrasound contrast agents exhibit a the kidneys, and thus have no known nephrotoxicity. Ultrasound Contrast
Agents
postvascular hepato- and/or spleno-specific phase from
2 to 5 minutes after intravenous injection. This phenome- No evidence of biological effects resulting from inertial Take-Home Messages
non is probably due to an adherence of the microbubbles cavitation – the rapid formation, growth and collapse References
to the hepatic sinusoids or to a selective uptake by the of a gas cavity in a fluid as a result of intense ultra-
Test Your Knowledge
phagocytic Kupffer cells of the reticuloendothelial system. sound exposure – has been reported in humans.

74
<•> CORE KNOWLEDGE

/ Administration of Ultrasound Contrast Agents / Contrast

Agents
CHAPTER OUTLINE:

Ultrasound contrast agents are administered Continuous infusion leads to a plateau-like enhancement
Contrast Agents
intravenously as a bolus injection or as a con- and thus to a prolongation of the diagnostic time win-
tinuous infusion, or they are instilled into hol- dow that is important for quantifying tissue perfusion. X-Ray Contrast Media
(RCM)
low structures, such as the urinary bladder.
Magnetic Resonance
Contrast Agents
Bolus injection produces a rapid rise in enhance-
ment followed by a slower washout, and it is the Ultrasound Contrast
Agents
most commonly used administration form for imag-
ing with low and intermediate acoustic power. Take-Home Messages

References

Test Your Knowledge

75
<•> CORE KNOWLEDGE

/ Indications / Contrast
Agents
CHAPTER OUTLINE:

Ultrasound contrast agents are primarily used for cardiovascular imaging, including echocardiography,
Contrast Agents
and for ultrasound diagnostics of the liver and, less frequently, of other parenchymatous organs.
X-Ray Contrast Media
(RCM)

Cardiovascular Imaging Vascular Imaging Magnetic Resonance

Contrast Agents

In echocardiography, contrast agents are used for The clinical vascular applications using ultrasound Ultrasound Contrast
Agents
direct visualisation of the left ventricular chamber and contrast agents include contrast enhancement of
endocardial surfaces, which permits clinical assess- the aorta, carotid arteries and the peripheral venous Take-Home Messages
ment of the left ventricular systolic function, structure system. Specifically, ultrasound contrast agents are References
and filling status. Ultrasound contrast agents are also applied for examination of the carotid artery lumen
Test Your Knowledge
applied for the examination of left ventricular structural and of atherosclerotic plaque neovascularisation, but
abnormalities such as intracavitary thrombi, left ventric- also for the assessment of the intima-media-thickness
ular aneurysms and pseudo aneurysms, the study of as surrogate marker of systemic atherosclerosis.
Takotsubo cardiomyopathy and myocardial perfusion.

76
<•> CORE KNOWLEDGE

Liver Lesions
/ Contrast
Agents
The main application area of contrast-enhanced ultrasound imaging is the detection and characterisa-
CHAPTER OUTLINE:
tion of focal liver lesions, particularly the distinction between benign and malignant nodules.
Contrast Agents
The differential diagnosis of hepatic tumours is facilitated by the highly sensitive visualisation of the X-Ray Contrast Media
capillary network achieved with ultrasound contrast media and the reliable information about tis- (RCM)
sue perfusion, which can be deduced from the influx and washout of the contrast agent. Magnetic Resonance
Contrast Agents
After intravenous administration of the ultra- The characteristic features in these three phases Ultrasound Contrast
sound contrast agent, three phases of enhance- allow detection of a hepatocellular carcinoma with Agents
ment in the liver can be distinguished: high sensitivity and specificity, and they enable Take-Home Messages
a differentiation of metastases in the liver.
/ the arterial phase, in which the con- References
trast agent reaches the liver first via the Test Your Knowledge
hepatic artery (up to 25s after injection)

/ the portal phase, where the contrast

agent has passed circulation and spreads
through the liver in the portal branches
(between 25 and 45s after injection)

/ the late or parenchymal phase, in which the

agent slowly distributes within the entire liver
parenchyma (> 2 minutes after injection) 77
<•> CORE KNOWLEDGE

Further Indications
/ Contrast
Agents
Other applications of ultrasound contrast agents include are also used for the assessment of fallopian tube
CHAPTER OUTLINE:
the detection and characterisation of breast, pancreatic, patency and of the vesico-ureteric reflux, but also for
renal and endocrine tumours. Moreover, these agents the identification of solid organ traumatic injury (Fig. 38). Contrast Agents

X-Ray Contrast Media

(RCM)
A B
Magnetic Resonance
Contrast Agents

Ultrasound Contrast
Agents

Take-Home Messages

References

Test Your Knowledge

F igure 36

US images of the right kidney in a trauma patient before (A) and after (B) intravenous injection of a sonographic CA. On the image before CA
administration (A), a heterogeneous peri-renal hematoma (white arrows) is seen, however, no kidney injury. The image after CA administration (B)
shows in addition to the perirenal hematoma (white arrows) also a parenchymal laceration (red arrow). Note that following CA administration, the
normal kidney parenchyma is strongly hyperechoic (asterisks). Images courtesy: Alexandra Platon, MD, University Hospitals Geneva. 78
<•> CORE KNOWLEDGE

/ Adverse Reactions / Contrast

Agents
CHAPTER OUTLINE:

Adverse reactions associated with ultrasound of warmth or flushing, cutaneous eruptions and
Contrast Agents
contrast administration are rare and usu- asymptomatic premature ventricular contractions.
ally of transient nature and mild intensity. X-Ray Contrast Media
(RCM)
Hypersensitivity events are due to anaphylactoid
A B
The most common adverse events include tissue reactions to the gas or shell and include hypo- Magnetic Resonance
Contrast Agents
irritation at the site of injection, headache, nau- tension, bronchospasm, urticaria and pruritus.
sea and vomiting, taste alterations, dyspnea, chest Ultrasound Contrast
Agents
pain, hypo- or hypertension, vertigo, a sensation
Take-Home Messages

References

Test Your Knowledge

79
<•> CORE KNOWLEDGE

Contraindications
/ Contrast
Agents
Contraindications to intravenously administered micro- Microbubble contrast agents should be avoided in the
CHAPTER OUTLINE:
bubble contrast agents are a history of hypersensitivity 24 hours before extracorporeal shock wave treatment.
reaction to the constituent gas or shell of the agents. Contrast Agents
Microbubble contrast agents should be used X-Ray Contrast Media
Due to the possible risk for a serious cardiopulmonary in pregnancy only if the benefit outweighs (RCM)
reaction,
A intravenous microbubble contrast agents Bthe risk. Breast feeding women may con-
Magnetic Resonance
should not be used in individuals with an unstable sider pumping and discarding of milk. Contrast Agents
cardiopulmonary condition such as severe pulmo- Ultrasound Contrast
nary hypertension, acute coronary syndrome, unstable Agents
angina, recent myocardial infarction, clinically unstable Take-Home Messages
congestive heart failure and cardiac rhythm disorder.
References

Test Your Knowledge

80
<•> CORE KNOWLEDGE

/ Take-Home Messages / Contrast

Agents
CHAPTER OUTLINE:

/ Contrast agents developed for radiographic / The incidence of adverse reactions related to
Contrast Agents
examinations, magnetic resonance imaging and the intravascular administration of iodinated
sonography have revolutionised the application RCM, which has been drastically reduced X-Ray Contrast Media
(RCM)
field of diagnostic imaging in clinical practice. with the change in usage from ionic high-
osmolality RCM to nonionic low-osmolality or Magnetic Resonance
/ Today's contrast agents are remarkably well iso-osmolality RCM, is now generally low. Contrast Agents
tolerated and safe, but it remains the physician’s Ultrasound Contrast
responsibility to understand the potential adverse / In patients with established hyperthyroidism, Agents
effects, and the specific situations, in which a administration of iodinated RCM is contraindicated Take-Home Messages
particular patient might be at increased risk. due to the risk for development of thyrotoxicosis.
References
/ Radiographic contrast media (RCM) mainly comprise / Preexisting renal dysfunction is a significant Test Your Knowledge
iodinated compounds that enhance image contrast risk factor for developing a contrast
by locally inducing a change in X-ray absorptivity. media-induced nephropathy.

/ Radiographic examinations using contrast / MR contrast agents primarily comprise

media, which provide reliable diagnostic paramagnetic gadolinium complexes, which affect
information regarding normal and abnormal the relaxation times of water protons present
morphology and function, are applied routinely in the surrounding tissue and thereby cause
in clinical practice for a plurality of indications. an increase or decrease in signal intensity.

81
<•> CORE KNOWLEDGE

/ Non-specific extracellular MR contrast agents are

used for CNS and body imaging to asses pathologic
processes and functional abnormalities, whereas
/ Ultrasound contrast agents consist of
microbubbles composed of a high molecular
weight and low solubility gas encapsulated
/ Contrast
Agents
organ and tissue specific contrast agents are used in a stabilising shell, which backscatter the CHAPTER OUTLINE:

for detection and characterisation of tumours in impinging ultrasound waves at their membrane Contrast Agents
liver, spleen, lymph nodes and bone marrow. due to a local change in acoustic impedance.
X-Ray Contrast Media
(RCM)
/ Gadolinium-based MR contrast agents are / Indications for ultrasound contrast agents primarily
well tolerated by the vast majority of patients, comprise cardiovascular imaging, including Magnetic Resonance
Contrast Agents
but the rate of adverse events tends to be echocardiography, and the detection and
higher with liver specific contrast agents than charactersation of focal liver lesions, particularly the Ultrasound Contrast
Agents
with extracellular gadolinium agents. distinction between benign and malignant lesions.
Take-Home Messages
/ Patients with impaired renal function may / Ultrasound contrast agents benefit from an excellent
References
develop a nephrogenic systemic fibrosis after the safety profile, with the only, very rarely occurring
administration of linear gadolinium complexes, which adverse event being a hypersensitivity reaction. Test Your Knowledge
is why the European Medicines Agency (EMA) has
suspended or restricted intravenous use of all high
risk linear gadolinium-based contrast agents.

/ Repeated administration of linear gadolinium-

based contrast agents is associated with a dose-
dependent accumulation of gadolinium in brain
regions even in subjects with normal renal function.
82
<∞> REFERENCES

/ References / Contrast
Agents
CHAPTER OUTLINE:

/ ACR Manual On Contrast Media. 2024, ACR Committee on / Shao-Pow Lin, Jeffrey J. Brown. MR Contrast Agents: Physical Contrast Agents
Drugs and Contrast Media. American College of Radiology. and Pharmacologic Basics. Journal of Magnetic Resonance
ISBN: 978-1-55903-012-0. Imaging. 2007; 25: 884-899. X-Ray Contrast Media
(RCM)
/ ESUR Guidelines on Contrast Agents. The Contrast Media Safety / Marie-France Bellin. MR contrast agents, the old and the new.
Committee of the European Society of Urogenital Radiology. European Journal of Radiology. 2006; 60: 314-323. Magnetic Resonance
2018; 10.0. Contrast Agents
/ Igor V. Kuriashkin, John M . Losonsky. Contrast Enhancement iIn
/ Luca Caschera, Angelo Lazzara, Lorenzo Piergallini, Domenico Magnetic Resonance Imaging Using Intravenous Paramagnetic Ultrasound Contrast
Ricci, Bruno Tuscano, Angelo Vanzulli. Contrast agents in diag- Contrast Media: A Review. Veterinary Rudiology & Ultrasound. Agents
nostic imaging: Present and future. Pharmacological Research. 2000; 41(1): 4-7.
2016; 110: 65-75. Take-Home Messages
/ M. F. Bellin, M. Vasile, S. Morel-Precetti. Currently used non-spe-
/ Jeffrey J. Pasternak, Eric E. Williamson. Clinical Pharmacology, cific extracellular MR contrast media. Eur Radiol. 2003; 13: References
Uses, and Adverse Reactions of Iodinated Contrast Agents: A 2688-2698.
Primer for the Non-radiologist. Mayo Clin Proc. 2012; 87(4): 390- Test Your Knowledge
402. / Jean-Marc Idée, Marc Port, Caroline Robic, Christelle Medina,
Monique Sabatou, Claire Corot. Role of Thermodynamic and
/ Ulrich Speck. X-Ray Contrast Media – Overview, Use and Phar- Kinetic Parameters in Gadolinium Chelate Stability. Journal of
maceutical Aspects. 5. Auflage, Springer, Magnetic Resonance Imaging. 2009; 30: 1249-1258.
https://doi.org/10.1007/978-3-662-56465-3.
/ Marc Port, Jean-Marc Idee, Christelle Medina, Caroline Robic,
/ Cathrine Christiansen. X-ray contrast media – an overview. Toxi- Monique Sabatou and Claire Corot. Efficiency, thermodynamic
cology. 2005; 209: 85–187. and kinetic stability of marketed gadolinium chelates and their
possible clinical consequences: a critical review. Biometals.
/ H.S. Thomsen, S.K. Morcos. Radiographic contrast media. BJU 2008 21: 469-490Wui K. Chong, Virginie Papadopoulou, Paul A.
International. 2000; 86(Suppl. 1): 1-10. Dayton. Imaging with ultrasound contrast agents: current status
and future. Abdom Radiol. 2018; 43: 762-772.
/ Robic C et al., Invest. Radiology 2019
83
<∞> REFERENCES

/ Yu-Dong Xiao, Ramchandra Paudel, Jun Liu, Cong Ma, Zi-Shu

Zhang And Shun-Ke Zhou. MRI contrast agents: Classification
and application (Review). International Journal of Molecular Medi-
cine 2016; 38: 1319-1326.
/ Contrast
Agents
CHAPTER OUTLINE:
/ Carlos F. G. C. Geraldesa and Sophie Laurent. Classification
and basic properties of contrast agents for magnetic resonance
Contrast Agents
imaging. Contrast Media Mol. Imaging 2009; 4: 1-23.
X-Ray Contrast Media
/ Adrian Săftoiu, Peter Vilmann, Michiel Postema, Odd Helge Gilja.
(RCM)
Contrast-enhanced and targeted ultrasound. World J Gastroen-
terol. 2011; 17(1): 28-41.
Magnetic Resonance
Contrast Agents
/ Steven B. Feinstein, Blai Coll, Daniel Staub, Dan Adam, Arend F. L.
Schinkel, Folkert J. ten Cate, Kai Thomenius. Contrast enhanced
Ultrasound Contrast
ultrasound imaging. J Nucl Cardiol. 2010; 17: 106-115.
Agents
/ Reshani H. Perera, Christopher Hernandez, Haoyan Zhou, Pavan
Take-Home Messages
Kota, Alan Burke, Agata A. Exner. Ultrasound Imaging Beyond the
Vasculature with New Generation Contrast Agents. Wiley Inter-
References
discip Rev Nanomed Nanobiotechnol. 2015; 7(4): 593-608.
Test Your Knowledge
/ Emilio Quaia. Microbubble ultrasound contrast agents: an update.
Eur Radiol. 2007; 17: 1995-2008.

84
 / Contrast
Agents
CHAPTER OUTLINE:

Contrast Agents

/ Test Your
X-Ray Contrast Media
(RCM)

Magnetic Resonance
Contrast Agents

Ultrasound Contrast

Knowledge
Agents

Take-Home Messages

References

Test Your Knowledge

85
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

1 Which elements are incorporated

<?> QUESTION Contrast Agents

in routinely used RCM? X-Ray Contrast Media

(RCM)

Magnetic Resonance
□ Manganese in form of superparamagnetic particles Contrast Agents

Ultrasound Contrast
□ Iodine in form of organic molecules Agents

□ Barium as barium sulfate suspension Take-Home Messages

References
□ Gadolinium in form of chelating complexes
Test Your Knowledge
□ Xenon as gas

86
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

1 Which elements are incorporated

<?> ANSWER Contrast Agents

in routinely used RCM? X-Ray Contrast Media

(RCM)

Magnetic Resonance
□ Manganese in form of superparamagnetic particles Contrast Agents

Ultrasound Contrast
█ Iodine in form of organic molecules Agents

█ Barium as barium sulfate suspension Take-Home Messages

References
□ Gadolinium in form of chelating complexes
Test Your Knowledge
□ Xenon as gas

87
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

2 Which of the following statements

<?> QUESTION Contrast Agents

regarding iodinated RCM are correct? X-Ray Contrast Media

(RCM)

Magnetic Resonance
□ RCM with a carboxylate substituent dissociate Contrast Agents

in solution forming ionic compounds Ultrasound Contrast

Agents
□ Highly hydrophilic RCM have an Take-Home Messages
enhanced plasma protein binding
References
□ Iodinated RCM in solution undergo a Test Your Knowledge
deiodination process releasing free iodide
□ A cholegraphic RCM has an accelerated
glomerular filtration rate
□ Osmolality is higher in ionic RCM than in
non-ionic RCM, each with the monomeric
agents having a higher osmolality

88
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

2 Which of the following statements

<?> ANSWER Contrast Agents

regarding iodinated RCM are correct? X-Ray Contrast Media

(RCM)

Magnetic Resonance
█ RCM with a carboxylate substituent dissociate Contrast Agents

in solution forming ionic compounds Ultrasound Contrast

Agents
□ Highly hydrophilic RCM have an Take-Home Messages
enhanced plasma protein binding
References
█ Iodinated RCM in solution undergo a Test Your Knowledge
deiodination process releasing free iodide
□ A cholegraphic RCM has an accelerated
glomerular filtration rate
█ Osmolality is higher in ionic RCM than in
non-ionic RCM, each with the monomeric
agents having a higher osmolality

89
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

3 Which factors are associated

<?> QUESTION Contrast Agents

with an increased risk for X-Ray Contrast Media

(RCM)
adverse effects using RCM? Magnetic Resonance
Contrast Agents

□ Radiographic imaging of the gastrointestinal Ultrasound Contrast

Agents
tract using barium sulfate suspension
Take-Home Messages
□ Intravenous administration of high osmolality RCM References

□ Intravenous cholangiographic contrast media to Test Your Knowledge

patients with an undelaying thyroid disorder
□ Intravenous administration of high viscosity RCM
□ Visualisation of the gastrointestinal
tract with oral iodinated RCM

90
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

3 Which factors are associated

<?> ANSWER Contrast Agents

with an increased risk for X-Ray Contrast Media

(RCM)
adverse effects using RCM? Magnetic Resonance
Contrast Agents

□ Radiographic imaging of the gastrointestinal Ultrasound Contrast

Agents
tract using barium sulfate suspension
Take-Home Messages
█ Intravenous administration of high osmolality RCM References

█ Intravenous cholangiographic contrast media to Test Your Knowledge

patients with an undelaying thyroid disorder
█ Intravenous administration of high viscosity RCM
□ Visualisation of the gastrointestinal
tract with oral iodinated RCM

91
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

4 Which patients are at risk for developing

<?> QUESTION Contrast Agents

post-contrast acute kidney injury after X-Ray Contrast Media

(RCM)
administration of iodinated RCM? Magnetic Resonance
Contrast Agents

□ Patients with impaired renal function Ultrasound Contrast

Agents
with eGFR < 45 ml/min/1.73 m2
Take-Home Messages
□ Patients suffering from multiple myeloma References

□ Patients suffering from diabetes mellitus Test Your Knowledge

□ Patients suffering from cardiovascular disease

92
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

4 Which patients are at risk for developing

<?> ANSWER Contrast Agents

post-contrast acute kidney injury after X-Ray Contrast Media

(RCM)
administration of iodinated RCM? Magnetic Resonance
Contrast Agents

█ Patients with impaired renal function Ultrasound Contrast

Agents
with eGFR < 45 ml/min/1.73 m2
Take-Home Messages
□ Patients suffering from multiple myeloma References

█ Patients suffering from diabetes mellitus Test Your Knowledge

█ Patients suffering from cardiovascular disease

93
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

5 Which compounds are routinely

<?> QUESTION Contrast Agents

used as MR contrast agents? X-Ray Contrast Media

(RCM)

Magnetic Resonance
□ Gd in form of complexes with chelating ligands
3+ Contrast Agents

Ultrasound Contrast
□ Perfluorocarbon nanoparticles for 19F imaging Agents

□ Fe2O3 nanoparticles Take-Home Messages

References
□ Mn2+ in form of complexes with chelating ligands
Test Your Knowledge

94
<•> CORE KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

5 Which compounds are routinely

<?> ANSWER Contrast Agents

used as MR contrast agents? X-Ray Contrast Media

(RCM)

Magnetic Resonance
█ Gd in form of complexes with chelating ligands
3+ Contrast Agents

Ultrasound Contrast
□ Perfluorocarbon nanoparticles for 19F imaging Agents

█ Fe2O3 nanoparticles Take-Home Messages

References
█ Mn2+ in form of complexes with chelating ligands
Test Your Knowledge

95
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

6 Which statements about non-specific

<?> QUESTION Contrast Agents

extracellular contrast agents are correct? X-Ray Contrast Media

(RCM)

Magnetic Resonance
□ They circulate freely in the extracellular space but Contrast Agents

do not penetrate the intact blood-brain barrier Ultrasound Contrast

Agents
□ They require metabolisation of their Take-Home Messages
macromolecular moiety before renal excretion
References
□ They are applied for CNS examinations Test Your Knowledge

□ The various extracellular gadolinium

contrast agents show widely varying
efficiencies with respect to their relaxivity

96
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

6 Which statements about non-specific

<?> ANSWER Contrast Agents

extracellular contrast agents are correct? X-Ray Contrast Media

(RCM)

Magnetic Resonance
█ They circulate freely in the extracellular space but Contrast Agents

do not penetrate the intact blood-brain barrier Ultrasound Contrast

Agents
□ They require metabolisation of their Take-Home Messages
macromolecular moiety before renal excretion
References
█ They are applied for CNS examinations Test Your Knowledge

□ The various extracellular gadolinium

contrast agents show widely varying
efficiencies with respect to their relaxivity

97
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

7 Which MR contrast agents are

<?> QUESTION Contrast Agents

recommended for detection and X-Ray Contrast Media

(RCM)
characterisation of liver tumours? Magnetic Resonance
Contrast Agents

□ Linear ionic Gd3+ complexes Ultrasound Contrast

Agents

□ Linear non-ionic Gd3+ complexes Take-Home Messages

□ Macrocyclic Gd3+ complexes References

Test Your Knowledge

□ Large superparamagnetic iron oxide particles
□ Small superparamagnetic iron oxide particles

98
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

7 Which MR contrast agents are

<?> ANSWER Contrast Agents

recommended for detection and X-Ray Contrast Media

(RCM)
characterisation of liver tumours? Magnetic Resonance
Contrast Agents

█ Linear ionic Gd3+ complexes Ultrasound Contrast

Agents

□ Linear non-ionic Gd3+ complexes Take-Home Messages

□ Macrocyclic Gd3+ complexes References

Test Your Knowledge

█ Large superparamagnetic iron oxide particles
□ Small superparamagnetic iron oxide particles

99
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

8 Which of the following are risk factors

<?> QUESTION Contrast Agents

for developing a nephrogenic systemic X-Ray Contrast Media

(RCM)
fibrosis after administration of a Magnetic Resonance
gadolinium-based contrast agent? Contrast Agents

Ultrasound Contrast
Agents
□ Impaired renal function with a glomerular Take-Home Messages
filtration rate of eGFR < 15 ml/min/1.73 m2
References
□ Patients suffering from a hepatic disease Test Your Knowledge

□ Administration of a linear gadolinium contrast agent

□ Patients with elevated blood levels of iron
□ Application of superparamagnetic
iron oxide particles

100
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

8 Which of the following are risk factors

<?> ANSWER Contrast Agents

for developing a nephrogenic systemic X-Ray Contrast Media

(RCM)
fibrosis after administration of a Magnetic Resonance
gadolinium-based contrast agent? Contrast Agents

Ultrasound Contrast
Agents
█ Impaired renal function with a glomerular Take-Home Messages
filtration rate of eGFR < 15 ml/min/1.73 m2
References
□ Patients suffering from a hepatic disease Test Your Knowledge

█ Administration of a linear gadolinium contrast agent

█ Patients with elevated blood levels of iron
□ Application of superparamagnetic
iron oxide particles

101
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

9 What are the recommendations of the

<?> QUESTION Contrast Agents

European Medicines Agency (EMA) X-Ray Contrast Media

(RCM)
about the use of gadolinium-based Magnetic Resonance
CAs regarding the risk of developing Contrast Agents

nephrogenic systemic fibrosis? Ultrasound Contrast

Agents

□ The use of all linear gadolinium- Take-Home Messages

based complexes is suspended References

□ The use of macrocyclic ionic gadolinium-based Test Your Knowledge

complexes is restricted to hepato-biliary imaging

□ The use of linear non-ionic gadolinium-
based complexes is suspended
□ The use of linear ionic gadolinium-based
complexes is restricted to hepato-biliary
imaging and arthrography, respectively
102
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

9 What are the recommendations of the

<?> ANSWER Contrast Agents

European Medicines Agency (EMA) X-Ray Contrast Media

(RCM)
about the use of gadolinium-based Magnetic Resonance
CAs regarding the risk of developing Contrast Agents

nephrogenic systemic fibrosis? Ultrasound Contrast

Agents

□ The use of all linear gadolinium- Take-Home Messages

based complexes is suspended References

□ The use of macrocyclic ionic gadolinium-based Test Your Knowledge

complexes is restricted to hepato-biliary imaging

█ The use of linear non-ionic gadolinium-
based complexes is suspended
█ The use of linear ionic gadolinium-based
complexes is restricted to hepato-biliary
imaging and arthrography, respectively
103
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

10 Which statements regarding the

<?> QUESTION Contrast Agents

use of microbubbles as ultrasound X-Ray Contrast Media

(RCM)
contrast agents are correct? Magnetic Resonance
Contrast Agents

□ They are excreted through the kidneys Ultrasound Contrast

Agents
□ They are mostly eliminated through the lung Take-Home Messages

□ They cannot be used for measuring References

the tissue perfusion of the liver Test Your Knowledge

□ They can rapidly pass an intact blood-brain barrier

□ They generally remain confined to the blood pool

104
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

10 Which statements regarding the

<?> ANSWER Contrast Agents

use of microbubbles as ultrasound X-Ray Contrast Media

(RCM)
contrast agents are correct? Magnetic Resonance
Contrast Agents

□ They are excreted through the kidneys Ultrasound Contrast

Agents
█ They are mostly eliminated through the lung Take-Home Messages

□ They cannot be used for measuring References

the tissue perfusion of the liver Test Your Knowledge

□ They can rapidly pass an intact blood-brain barrier

█ They generally remain confined to the blood pool

105
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

11 What are the advantages of

<?> QUESTION Contrast Agents

ultrasound imaging using X-Ray Contrast Media

(RCM)
microbubble contrast agents? Magnetic Resonance
Contrast Agents

□ They allow real time imaging of blood flow Ultrasound Contrast

and organ perfusion with high sensitivity Agents

Take-Home Messages
□ The microbubbles can also be therapeutically
used for targeted drug delivery References

Test Your Knowledge

□ They have an excellent safety profile
□ The new generation microbubbles with
improved stability can persist under
insonation with high acoustic power

106
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

11 What are the advantages of

<?> ANSWER Contrast Agents

ultrasound imaging using X-Ray Contrast Media

(RCM)
microbubble contrast agents? Magnetic Resonance
Contrast Agents

█ They allow real time imaging of blood flow Ultrasound Contrast

and organ perfusion with high sensitivity Agents

Take-Home Messages
□ The microbubbles can also be therapeutically
used for targeted drug delivery References

Test Your Knowledge

█ They have an excellent safety profile
□ The new generation microbubbles with
improved stability can persist under
insonation with high acoustic power

107
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

12 Which imaging method is indicated for the

<?> QUESTION Contrast Agents

detection of a hepatocellular carcinoma X-Ray Contrast Media

(RCM)
in a patient with renal insufficiency? Magnetic Resonance
Contrast Agents

□ Radiographic imaging using iodinated RCM Ultrasound Contrast

Agents
□ Ultrasound imaging using Take-Home Messages
microbubbles contrast agents
References
□ MR imaging using the liver-specific Test Your Knowledge
linear gadolinium complexes

108
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

12 Which imaging method is indicated for the

<?> ANSWER Contrast Agents

detection of a hepatocellular carcinoma X-Ray Contrast Media

(RCM)
in a patient with renal insufficiency? Magnetic Resonance
Contrast Agents

□ Radiographic imaging using iodinated RCM Ultrasound Contrast

Agents
█ Ultrasound imaging using Take-Home Messages
microbubbles contrast agents
References
□ MR imaging using the liver-specific Test Your Knowledge
linear gadolinium complexes

109
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

13 Which functional principles

<?> QUESTION Contrast Agents

determine liver specificity in the X-Ray Contrast Media

(RCM)
different imaging methods? Magnetic Resonance
Contrast Agents

□ Partial distribution of contrast agent Ultrasound Contrast

in the liver through passive diffusion, Agents

used in radiographic examinations Take-Home Messages

□ Selective uptake of contrast agent by phagocytic References

cells in the liver, used in MR imaging Test Your Knowledge

□ Partial hepatobiliary excretion and uptake of

contrast agent by hepatocytes, used in MR imaging
□ Accumulation of contrast media depending
on the functionality of the hepatobiliary
system, used in ultrasound imaging

110
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

13 Which functional principles

<?> ANSWER Contrast Agents

determine liver specificity in the X-Ray Contrast Media

(RCM)
different imaging methods? Magnetic Resonance
Contrast Agents

□ Partial distribution of contrast agent Ultrasound Contrast

in the liver through passive diffusion, Agents

used in radiographic examinations Take-Home Messages

█ Selective uptake of contrast agent by phagocytic References

cells in the liver, used in MR imaging Test Your Knowledge

█ Partial hepatobiliary excretion and uptake of

contrast agent by hepatocytes, used in MR imaging
□ Accumulation of contrast media depending
on the functionality of the hepatobiliary
system, used in ultrasound imaging

111
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

14 Which statements concerning adverse

<?> QUESTION Contrast Agents

reactions in respect of the various X-Ray Contrast Media

(RCM)
imaging methods are correct? Magnetic Resonance
Contrast Agents
□ The incidence of adverse reactions related to iodinated Ultrasound Contrast
RCM has been reduced in routine clinical practice due Agents
to the restricted use of ionic high-osmolality RCM Take-Home Messages
□ Orally administered iodinated contrast media for References
radiographic imaging of the gastrointestinal tract are
Test Your Knowledge
contraindicated in patients with suspected perforation
□ Repeated administration of linear gadolinium-based contrast agents
is associated with a dose-dependent accumulation of gadolinium
in brain regions even in subjects with normal renal function.
□ Microbubble ultrasound contrast agents increase
the risk for pulmonary embolism
□ In patients with established hyperthyroidism, administration
of iodinated contrast media is contraindicated
112
>•< FURTHER KNOWLEDGE

/ Test Your Knowledge / Contrast

Agents
CHAPTER OUTLINE:

14 Which statements concerning adverse

<?> ANSWER Contrast Agents

reactions in respect of the various X-Ray Contrast Media

(RCM)
imaging methods are correct? Magnetic Resonance
Contrast Agents
█ The incidence of adverse reactions related to iodinated Ultrasound Contrast
RCM has been reduced in routine clinical practice due Agents
to the restricted use of ionic high-osmolality RCM Take-Home Messages
□ Orally administered iodinated contrast media for References
radiographic imaging of the gastrointestinal tract are
Test Your Knowledge
contraindicated in patients with suspected perforation
█ Repeated administration of linear gadolinium-based contrast agents
is associated with a dose-dependent accumulation of gadolinium
in brain regions even in subjects with normal renal function.
□ Microbubble ultrasound contrast agents increase
the risk for pulmonary embolism
█ In patients with established hyperthyroidism, administration
of iodinated contrast media is contraindicated
113
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