The Well-Balanced Contrast Medium

Monograph

Bayer Schering Pharma AGBusiness Unit Diagnostic Imaging13342 Berlin, Germany

www.diagnostic-imaging.bayerscheringpharma.dewww.bayerscheringpharma.dewww.ultravist.de

Enhancing Diagnosis. Empowering Care.G

BU.D

I.09-

2009

.000

8

All rights reserved.

This publication or parts thereof may not betranslated into other languages or reproduced inany form mechanical or electronic (includingphotocopying, tape recording, microcopying) orstored in a data carrier or computer system withoutwritten consent of Bayer Schering Pharma AG.

© Bayer Schering Pharma AG 2009

ULTRAVIST® 150/240/300/370 Composition: Ultravist® 150, 240, 300, 370: 1 ml contains 0.312 g, 0.499 g, 0.623 g, 0.769 g iopromide in aqueous solution. For diagnostic use! Indications: Ultravist® 240/300/370: For intravascular use and use in body cavities. Contrast enhancement in computerised tomography (CT), arteriography and venography, intravenous/intraarterial digital subtraction angiography (DSA); intravenous urography, use for ERCP, arthrography and examination of other body cavities. Ultravist® 150: for intraarterial digital subtraction angiography (DSA), checking the patency of a dialysis shunt. Ultravist® 240: also for intrathecal use. Ultravist® 370: especially for angiocardiography Ultravist® 150/300/370: not for intrathecal use. Contraindications: There are no absolute contraindications to the use of Ultravist®. Undesirable effects: Intravascular use. • Immunological Anaphylactoid reactions/hypersensitivity. (uncommon) Anaphylactoid shock (including fatal cases) (rare). • Endocrine. Alteration in thyroid function, thyrotoxic crisis. • Nervous, Psychiatric: dizziness, restlessness, paraesthesia / hypoaesthesia, confusion, anxiety, agitation, amnesia, speech disorders, somnolence, unconciousness, coma, tremor, convulsion, paresis / paralysis, cerebral ischaemia/infarction, stroke, transient cortical blindness • Eye. Blurred/disturbed vision (uncommon), conjunctivitis, lacrimation (rare) • Ear. Hearing disorders. • Cardiac. Arrhythmia Palpitations, chest pain / tightness, bradycardia, tachycardia, cardiac arrest, heart failure, myocardial ischemia/infarction cyanosis. • Vascular. Vasodilatation (uncommon), Hypotension, hypertension, shock Vasospasm, thromboembolic events (rare) • Respiratory. Sneezing, coughing (uncommon), rhinitis, dyspnea, mucosal swelling, asthma, hoarse-ness, laryngeal / pharyngeal / tongue / face edema, bronchospasm, laryngeal/pharyngeal spasm, pulmonary edema, respiratory insufficiency, respiratory arrest (rare). • Gastrointestinal. nausea (common), vomiting, taste disturbance (uncommon), throat irritation, dysphagia, swelling of salivary glands, abdominal pain, diarrhea (rare) • Skin and subcutaneous tissue. Urticaria, pruritus, rash, erythema (uncommon), angioedema, mucocutaneous syndrome (e.g. Stevens-Johnson’s or Lyell syndrome) (rare) • Renal and urinary. Renal impairment (uncommon), Acute renal failure (rare) • General disorders and administration site conditions. heat or pain, sensations, headache (common), malaise, chills, sweating, vasovagal reactions (uncommon), pallor, body temperature alterations, edema, local pain, mild warmth and edema, inflammation and tissue injury in case of extravasation (rare). Intrathecal use. Based on experience with other non-ionic contrast media, the following undesirable effects may occur with intrathecal use in addition to the undesirable effects listed above: • Nervous, Psychiatric. Neuralgia, meningism (common). Paraplegia, psychosis, aseptic meningitis, EEG-changes (rare). • General disorders and administration site conditions: Micturition difficulties uncommon. back pain, pain in extremities, injection site pain. Headache, including severe prolonged cases, nausea and vomiting occur commonly. The majority of the reactions after myelography or use in body cavities occur some hours after the administration. ERCP: In addition to the undesirable effects listed above, the following undesirable effects may occur with use for ERCP: Elevation of pancreatic enzyme levels (common), pancreatitis (rare). Use in other body cavities. The possibility of pregnancy must be excluded before performing hysterosalpingography. Inflammation of the bile ducts or salpinx may increase the risk of reactions following ERCP or hysterosalpingography procedures. Low osmolar water-soluble contrast media should be routinely used in gastrointestinal studies in newborns, infants and children because these patients are at particular risk for aspiration, intestinal occlusion or extraluminal leakage into the peritoneal cavity. Special warnings and special precautions: Caution is advised in patients with: hypersensitivity or a previous reaction, bronchial asthma, latent hyperthyroidism or goiter, severe cardiac or cardiovascular diseases; very poor general state of health, severe renal insufficiency, severe liver dysfunction in case of severe renal insufficiency, metformin therapy, symptomatic cerebrovascular diseases, cerebral convulsive disease, myeloma or paraproteinemia, pheochromocytoma, autoimmune disorders, myasthenia gravis, alcoholism, homocystinuria, pregnancy. Instructions for Use/Handling: Ultravist® should be warmed to body temperature prior to use. Contrast media should be visually inspected prior to use and must not be used, if discolored, nor in the presence of particulate matter (including crystals) or defective containers. Date of revision of the text: October 2006. Please note! Not all concentrations / volumes mentioned may be available in your country. For current prescribing information and listing of available presentations / concentrations please refer to the package insert and /or contact your local Bayer Schering Pharma organisation. Bayer Schering Pharma AG, 13342 Berlin, Germany

Ultravist® M

onograph

Ultravist_Umschlag.indd U1Ultravist_Umschlag.indd U1 18.09.2009 14:38:2618.09.2009 14:38:26

3 Introduction

4 Product Profile

5 Product Characteristics5 Fields of Application

5 Properties of the Molecule

5 Limited Interaction with Biomolecules

5 Iodine Concentration

5 Low Osmolality

6 Low Viscosity

6 Physiologic pH

6 Pharmacokinetics

7 Contrast Application 7 Introduction

7 General Principles of Opacification in

Computed Tomography

8 General Principles of Contrast Media

Opacification in CT

9 Patient-related Inter-individual Variability

9 Procedure-related Inter-individual Variability

9 Scan Timing

10 Saline Flush

11 Clinical Use11 Computed Tomography

11 CT of the Head

13 CT of the Chest

14 CT of the Heart

17 CT of the Abdomen

19 CT of the Liver

20 CT Angiography (CTA)

24 Conventional Angiography

25 Cerebral Arteriography

25 Cardioangiography and

Coronary Angio graphy

25 Peripheral Angiography

26 Venography

26 Conventional Radiography

26 Intravenous Urography (IVU)

27 Contrast Radiography of Duct Systems

and Body Cavities

28 Arthrography

28 Pediatric Radiology

29 Pediatric CT

30 Tips for Handling30 General Recommendation

30 Optical Inspection

30 Warming

30 Extravasation

30 Thromboembolic Events

31 Safety Profile31 Types of Reaction – Overview

31 Ultravist® General Safety Data

31 The Mortele Study

32 The Ultravist® PMS Study

33 Delayed Skin Reactions

33 Undesirable Effects – Information Given

in the Ultravist® Package Insert*

35 Contrast Nephropathy – a Concern in

Renally Impaired Patients

35 Pathogenesis of Contrast Nephropathy

36 The Choice of Modern Contrast Agents –

the Case for Non-ionic Monomers

37 Clinical Evidence – Severely Hampered by

the Chosen Surrogate Marker

39 Prophylaxis of Contrast Nephropathy

39 Other Adverse Effects*

Table of Contents

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Ultravist.indd 1 16.09.2009 14:04:06

40 Chemistry and Pharmaceutics40 Physicochemistry

40 Electrical Charge

40 Osmolality

42 Viscosity

42 Chemotoxicity

43 Ecochemistry

44 Pharmacology and Toxicology44 Pharmacokinetics

44 Experiments in Animals

44 Human Studies

44 Interactions

45 Biochemical Data

45 Protein Binding

45 Lysozyme Inhibition

45 Acetylcholinesterase Inhibition

46 Urokinase Inhibition

46 Interaction with the Complement System

46 Histamine Release

47 Toxicology

47 Systemic Tolerance on

Single Administration

47 Systemic Tolerance on

Repeated Administration

47 Reproductive Toxicity

48 Genotoxic Potential

49 Abbreviations Used in the Text

50 References59 Head-to-Head Comparisons on Renal

Tolerance LOCM vs. IOCM in Risk Patients

61 Index

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Ultravist® (iopromide, CAS 73334-07-3) has been

successfully used in Europe since 1985 and in Asia/

Pacific since 1987. It was approved by the FDA and

introduced in the United States in 1995. One year

later, iopromide was registered by the Japanese

drug authority (KOSEISHO) and is marketed in Japan

under the brand name Proscope®. Today, Ultravist®

is approved in more than 100 countries and mar-

keted on all continents in more than 70 countries.

In conclusion, it is truly a global brand in the XR/CT

market.

As a result of years of research and development,

Ultravist® is backed up by the experience of a

company which is a world leader in in-vivo diag-

nostics, serving specialists in over 100 countries of

the world. Bayer Schering Pharma is continuing its

research activities to provide excellent scientific sup-

port and further improvements in the application

and use of its products in clinical radiology.

Ultravist® is a non-ionic, monomeric, low-osmolar

extracellular X-ray contrast medium (LOCM). It is

highly suitable for all modern X-ray techniques re-

quiring contrast enhancement. Ultravist® is known

as the well-balanced contrast medium with the

right mix of osmolality, viscosity and iodine concen-

tration.

Ultravist® has shown an outstanding safety profile

and excellent imaging qualities in over 130 million

procedures. (PSUR 2009) Currently, Ultravist® is

being applied more than 10 million times a year.

In 2008, a large post marketing surveillance (PMS)

study with 74,717 patients has been published,

highlighting its extremely well documented safety

record. (Kopp et al. 2008)

Ultravist® is available as a stable, ready-to-use

aqueous solution of iopromide in a wide range of

concentrations and volumes.

Introduction

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Ultravist.indd 3 16.09.2009 14:04:24

Product Profile

Ultravist® is an iodine-containing X-ray contrast

agent, approved for all modern X-ray techniques

(conventional radiography, angiography, computed

tomography) requiring water-soluble contrast me-

dia. For the details regarding approved indications,

please refer to your local package inserts.

The substance combines high contrast quality with

excellent local and systemic tolerance.

Ultravist® is

Q non-ionic

Q monomeric

Q extracellular

Q low-osmolar

Q low-viscous

Q highly hydrophilic

Developed and manufactured by Bayer Schering

Pharma, Ultravist® has been proven, and is backed

by more than two decades of extensive positive clini-

cal experience and a large number of publications.

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Ultravist.indd 4 16.09.2009 14:04:25

Product Characteristics

Ultravist® is a stable and well-balanced aqueous

solution of iopromide, a triiodinated monomeric

low-osmolar non-ionic X-ray contrast agent, which

can be injected into veins, arteries and body cavities.

Figure 1: Structural formula of iopromide, Ultravist®

Fields of ApplicationUltravist® is indicated for a wide range of contrast-

enhanced conventional radiographic methods,

angiographic procedures and contrast-enhanced

computed tomography including all of its various

applications, even the most modern developments

such as Dual-Source CT. Furthermore, Ultravist®

is highly suitable for use in interventional tech-

niques such as percutaneous transluminal

(coronary) angioplasty (PTA, PTCA) or embolization

procedures. Ultravist® also performs well in the

depiction of small ducts and body cavities, e.g. in

endoscopic retrograde cholangiopancreatography

(ERCP), arthrography, hysterosalpingography and

fistulography. For the details regarding approved

indications, please refer to your local package

inserts.

Properties of the MoleculeIopromide is a non-dissociable derivative of triiodi-

nated benzoic acid and carries three iodine atoms

per molecule. The resulting iodine ratio (3:1) per

osmotically active particle provides excellent radio-

graphic contrast at low osmolality. (Krause 1994a)

Limited Interaction with BiomoleculesHydrophilicity combined with a reduced tendency

to form hydrogen bonds results in low binding

of iopromide to plasma proteins, enzymes and

cell membranes. Thus, the risk of adverse effects

caused by interferences with a variety of biologic

processes is negligible. The low protein binding of

Ultravist® compares favorably with the correspond-

ing characteristics of other X-ray contrast agents.

(Krause 1994b, 1996)

Iodine ConcentrationUltravist® is available in four different iodine

concentrations in most countries: 150 mg I/mL,

240 mg I/mL, 300 mg I/mL and 370 mg I/mL, thus

providing a variety of options to the user for differ-

ent clinical questions and applications.

Low OsmolalityEven at high iodine concentrations Ultravist® has

a favorably low osmolality. Apart from the concen-

tration of 370 mg I/mL, all Ultravist® preparations

feature osmolalities around or below the empiric

pain threshold of 600 mOsmol/kg H2O, thus ensur-

ing high overall tolerance of the substance. (Speck

1980, Hagen 1983a, b)

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Low ViscosityAs to viscosity, Ultravist® is superior to most other

low or iso-osmolar X-ray agents which results in

low-pressure high delivery rates during injection,

and in addition might provide benefits in the context

of contrast-induced nephropathy. (Persson 2005)

Consequently, the rapid administration of large vol-

umes (as is necessary in angiography and computed

tomography) and the injection through thin-bore

cannulas and catheters is greatly facilitated. When

prewarmed to body temperature, the viscosity of

Ultravist® further significantly decreases. (Krause

1994a)

Physiologic pHThe Ultravist® preparations are adjusted to a pH of

7.4 (6.5–8.0) at 25±2ºC. To be very close to the physi-

ologic pH is mandatory for contrast media which are

often administered in large volumes and with high

injection rates.

PharmacokineticsFollowing systemic administration (e.g. intravenous

or intra-arterial), Ultravist® is rapidly eliminated via

the kidneys. (Krause 1994c)

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Contrast Application (adapted from Seidensticker 2007)

IntroductionWith the advent of highly advanced scanner genera-

tions that offer a heretofore unmatched procedural

robustness, contrast medium (CM) administration

has become one of the most crucial and sophisti-

cated aspects of today’s multidetector CT (MDCT)

procedure. MDCT has substantially improved over

the past years with faster gantry rotation, more

powerful X-ray tubes, dedicated interpolation algo-

rithms, the introduction of Dual-Source CT (DSCT) in

2006 and today’s CT scanners with up to 320 detec-

tor rows.

As one of the consequences of this technical evolu-

tion, CT angiography (CTA) has become an estab-

lished technique for minimally invasive imaging

and has together with MR angiography replaced a

high percentage of diagnostic catheter angiogra-

phies. Fundamental advantages of the newest MDCT

scanners are defined by three cornerstones, i.e.

shorter scan time, larger scan range, and improved

spatial resolution.

Faster image acquisitions can obviously be of ad-

vantage. With 64-slice MDCT scanners, imaging of

the entire aorta can easily be performed in a single

breath-hold, and scan ranges the size of the whole

body using true submillimeter resolution are also

feasible today. However, modern CTA procedures are

less forgiving in terms of contrast applications as

one may inject a larger bolus than necessary or miss

it completely if injection regimens are not adapted

to the scanner capabilities.

General Principles of Opacification in Computed TomographyThe CT image consists of a matrix of pixels ( usually

512 512). Because pixels represent a given slice

thickness of typically between 0.5 mm and 5.0 mm,

they are referred to as voxels because they actually

represent a volume of tissue rather than just a two-

dimensional surface image. The mean opacifica-

tion value of a single voxel is expressed on a scale

of Hounsfield units (HU). By definition, water was

selected as the fixed midpoint of this opacification

scale and was assigned a value of zero HU. The

lower and upper limits of the scale correspond to the

range of typical opacification values produced by X-

rays passing through the human body and therefore

the opacification of air was defined as –1000 HU and

the opacification of highly dense bones was defined

as +1000 HU. The physical opacification behavior of

certain tissues or structures in CT depends on their

density and the atomic number of dominating at-

oms in the region of interest. In the context of intra-

vascular contrast media iodine, with its high atomic

number and low toxicity, has until today shown to

be the only feasible element providing high con-

trast and an acceptable low rate of adverse events.

However, the k-edge of iodine, i.e. the optimal X-ray

energy level at which the element produces a maxi-

mal opacification, lies far beneath the energies used

in the CT sector leading to a theoretical sub-optimal

dose-opacification relationship. The excellent safety

profile of these compounds allows for a “relative

overdosing” in this respect but there is room for

further development of better suited elements as a

core for new CT contrast media.

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Ultravist.indd 7 16.09.2009 14:04:25

General Principles of Contrast Media Opacification in CTFor CT, the general opacification behavior of contrast

media and their X-ray attenuating core iodine can be

described by a very simple and linear relationship .

1 mg I /mL = ∆ 25 HU @120 kV

2 mg I /mL = ∆ 50 HU @120 kV

In order to achieve a certain iodine concentration in

a region of interest, different physiological and phar-

macokinetic models are to be taken into account.

After intravenous injection, contrast media are rap-

idly distributed between the vascular and interstitial

compartments of the extracellular space. The differ-

ent phases of contrast media distribution in humans

are classified in CT as follows:

Arterial Phase: Opacification of the arterial vascu-

lar tree.

Late Arterial Phase: Opacification of arterial vas-

cular tree and hypervascular tissue (hemangiomas,

spleen).

Portal-venous Phase: Opacification of the portal

vascular tree. Homogenous enhancement of paren-

chymal organs (liver).

Venous Phase: Opacification of venous vessels. Ho-

mogenous opacification of parenchymal organs.

Late Phase: Equilibrium of arterial and venous ves-

sels.

The overall iodine load in grams of iodine is the

main determinant for organ studies (e.g. of the liver

or kidney) in which relatively slow accumulation of

the contrast medium into the extracellular space is

the underlying mechanism of “contrast enhance-

ment”. However, the overall amount of contrast

material applied to the patient is of minor impor-

tance for a CTA study, where vessels are in focus that

show a constant blood flow. The iodine delivery rate

(IDR), given in g I /mL/s, is the determining factor for

the quality of the bolus in these examinations and

can easily be calculated by multiplying the iodine

concentration of the contrast material (mg I/mL)

with the flow rate of the injector (mL/s) (and convert-

ing from mg to g).

IDR (g I/s) = CMCon. (mg I/mL) * CMFlow (mL/s)/1 000

Usually the IDR will be in the range of 1.5–2.0 g I /

mL/s for CTA applications. This can be realized by a

high-concentrated contrast medium (e.g. Ultravist®

370) in combination with moderate flow rates. On

the other hand, the same IDR can also be achieved

by increasing the flow rates for contrast material

with 300 mg of iodine per mL. Normalizing the IDR

is a straightforward approach to make different

injection protocols comparable. It seems obvious

that the choice of a highly concentrated agent

could keep the flow rates lower and may help to

avoid local complications such as extravasation.

However, in this context it should be kept in mind

that the relation between iodine concentration and

its viscosity is exponential. This means that pres-

sures that are built up by the power injector and the

resulting pressures in the patients’ veins might be

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Ultravist.indd 8 16.09.2009 14:04:25

even higher with highly concentrated agents despite

the fact that they are injected with relatively slower

flow rates. The clinical effect of different flow rates

and contrast medium viscosities on the incidence

of extravasations is not fully understood and would

require large population studies. However, the

benefit of large access lines (e.g. 18G cannulas) and

preheating the contrast material to mean body

temperature of 37° Celsius in order to bring down

the viscosity is intuitively obvious.

Iodine Delivery Rate 300 mg I/mL 370 mg I/mL

1.0 g I/s 3.3 mL/s 2.7 mL/s

1.25 g I/s 4.2 mL/s 3.4 mL/s

1.5 g I/s 5.0 mL/s 4.1 mL/s

1.75 g I/s 5.8 mL/s 4.7 mL/s

2.0 g I/s 6.6 mL/s 5.4 mL/s

Table 1: Injection rates for Ultravist® 300 and 370 for vari-

ous routine iodine delivery rates.

Patient-related Inter-individual Variability There is a strong variation between individuals

regarding the degree and time course of vascular

opacification. On the one hand, the CM transit times

from the injection site to the aorta can vary between

8 and 30 seconds, primarily depending on the car-

diac function and also on the central blood volume.

The cardiac output is theoretically inversely related

to the degree of arterial attenuation, especially dur-

ing first pass dynamics. When more blood is ejected

by the heart per time, the CM injected per time unit

will be more diluted. The central blood volume is

also inversely related to arterial enhancement but

affects recirculation and tissue enhancement rather

than first pass effects. Central blood volume also

correlates with body weight giving the physician an

opportunity to adjust the flow rate at least in very

small (< 60 kg) and very large (> 100 kg) patients.

However, despite the theoretical inverse relation-

ships of arterial opacification with cardiac output,

in clinical practice there often appears to be a

counterintuitive direct relationship between the two

whereby the first pass bolus appears to remain more

compact and more highly concentrated in normal

patients with a higher cardiac output than it does in

patients with low cardiac output such as in patients

with CHF.

Procedure-related Inter-individual Variability As discussed above, the Iodine Delivery Rate (IDR)

is the determining factor for the opacification of

arterial vessels in CT. Comparing different contrast

media in CTA should therefore always be performed

on the basis of a normalized IDR to avoid misleading

results. In the context of parenchymal studies on the

other hand, normalization needs to be done on the

basis of the overall iodine load as this is the major

factor for the opacification of organs. Additionally,

the IV cannula size, exact position of the arm, leading

to a potential collapse of the vena axillaris, and the

quality of the chosen access vein are factors that can

cause strong inter-individual differences.

Scan Timing In any case, empiric scan delays can no longer be

recommended with MDCT. Using 16-slice or greater

MDCT technique, the start delay of a CTA has to

be chosen individually. In the clinical setting, two

methods are currently available for an optimal

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Ultravist.indd 9 16.09.2009 14:04:25

enhancement after intravenous contrast delivery:

(1) Automated bolus tracking and (2) test bolus.

In automated strategies, dedicated vascular beds

and contrast phases (e.g. CTA of the A. hepatica or

the late arterial hepatic phase for the detection of

hypervascularized liver lesions) can individually

be determined by the acquisition of single-level

dynamic CT series (automated bolus tracking). A

pre-monitoring scan is performed within the target

volume to localize the target vessel for contrast tim-

ing. Usually low-dose scanning technique (120 kVp;

20 mAseff.) is used for this purpose. A region-of-

interest is placed in the target vessel and opacifica-

tion values (in Hounsfield units; HU) are continu-

ously measured during the contrast injection. If the

trigger threshold level (e.g. 140 HU) is reached, an

automated start of the spiral scan is initialized.

Alternatively, test-bolus methodology can be

applied: A small additional volume of contrast

material (usually 15–20 mL) will be injected at the

same flow rates as used for the contrast-enhanced

scan protocol. By repeat acquisition of serial scans

(monitoring scans every 2 s from approximately

10–40 s; usually at the level of the heart), individual

flow dynamics can be assessed more precisely:

From the enhancement over time within the target

vessel lumen, the time-to-peak enhancement can

be calculated accordingly. The latter will be cho-

sen as start delay. The test-bolus data also allows

for estimation of the bolus geometry with a given

amount of contrast material at a selected flow-rate.

Moreover, this technique allows for determination

of cardiac output from the contrast enhancement

curve and therefore constitutes a more individual-

ized approach to the injection regimen as compared

to automated bolus tracking.

Saline FlushAfter injection of the contrast medium into a

peripheral vein, about 30 mL of contrast remain in

the “dead space” between the brachial vein and the

superior vena cava and do not contribute to im-

age quality. As CM volumes needed per CT scan are

constantly declining, these 30 mL can account for

up to 50% of the overall injected bolus. Automated

saline-flushing at the injection site using dual-head

power injectors has therefore been advocated, espe-

cially for CTA examinations. Performing saline flush

improves vascular and parenchymal enhancement

and reduces the amount of contrast needed for a

diagnostic examination. This has positive impacts

on patient safety and costs.

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Clinical Use

Computed TomographyCT of the HeadWith the advent of multidetector CT (MDCT), a multi-

modal stroke assessment, including non-enhanced CT,

perfusion CT, and CT angiography of the head and the

neck, is becoming clinical routine for stroke imaging.

Thus, comprehensive information regarding the extent

of ischemic damage to the brain can be rapidly obtained.

(Nabavi 2002, Hacke 2000, Barber 2001, König 1998)

While unenhanced MDCT scans rule out major bleed-

ing, perfusion scans provide information about the

regional blood flow, blood volume, mean transit

time, and time to peak of the contrast agent. These

parameters permit a safe differentiation between

irreversibly damaged parenchyma and reversibly im-

paired tissue at risk and allow decisions for an appro-

priate therapy. As whole brain perfusion MDCT is not

in wide clinical use yet, the central brain region most

likely to be correlated with the clinical symptoms is

selected for the perfusion scan. When occlusion of the

middle cerebral artery is suspected on a native im-

age, the level of the basal ganglia is selected for the

perfusion study. A 40 mL bolus of Ultravist® is then

applied at an injection rate between 4 and 8 mL/s.

The subsequent changes in brain tissue attenuation

are monitored during the contrast transit time of ap-

proximately 5 seconds with high temporal resolution.

(Tomandl 2003, Eastwood 2001)

For the display of both extra- and intracranial arteries,

contrast-enhanced MDCT angiography must cover the

anatomical region between the fifth cervical vertebra

and the vertex during the passage of the contrast

agent. An optimal display of the intracranial arterial

vasculature can be achieved with 100 mL of Ultravist®

injected through an antecubital vein at a flow rate

of 4 mL/s. (Tomandl 2003) MDCT angiography now

offers high diagnostic accuracy in the detection of

intracranial vascular malformations, e.g. aneurysms.

(Papke 2007) Furthermore, automated postprocessing

techniques permit a fully segmented display of intra-

cranial cerebral arteries. (Manniesing 2008)

For optimal timing of the bolus, the bolus tracking

method is often used. If bolus tracking is not avail-

able, the test bolus method should be applied for the

timing of data acquisition. In all patients studied by

Klingebiel et al., the arteries and veins of the brain

were comprehensively depicted from the bifurcation

of the common carotid arteries up to the third seg-

ment of the major cerebral arteries. In addition, the

dural sinuses, the great vein of Galen, and the inter-

nal cerebral veins could be studied. (Klingebiel 2001)

4 slices 16 slices 64 slices

Collimation 4 × 2/4 × 3 mm 16 × 1/16 × 1.5 mm 64 × 1/64 × 1.5 mm

Slice width/spatial resolution 3/3 mm 3/2 mm 3/1 mm

Rotation time/temporal resolution 0.5 s/250 ms 0.375–0.5 s/200–220 ms 0.375 s/200 ms

Scan time 30–40 s 15–25 s 10–20 s

Contrast protocol 100 @ 2 mL/s 100 @ 2 mL/s 100 @ 2 mL/s

Iodine concentration 300 mg I/mL (Ultravist®)

100 mL @ 2 mL/s, delay: 35 s

Table 2: Protocol suggestions for contrast-enhanced CT examinations of the head. Protocol according to Groell 1999

11

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2a 2b

2c 2d

Figure 2: Occlusion of the right MCA at the level of the trifurcation. While hardly any changes can be depicted on the native

scan (2a), the Ultravist®-enhanced MDCT angiography nicely shows the occlusion (2b). 3D perfusion scans (2c, 2d) display the

extent of the infarct of the right hemisphere. Figure 2b, c reproduced with permission of Springer. (Seifarth 2008)

12

Ultravist.indd 12 16.09.2009 14:04:26

CT of the ChestContrast media administration is essential for chest

MDCT and MDCT angiography of the thoracic ves-

sels. Ultravist® has been successfully employed for

many indications and a wide variety of pathologies.

With the growing use of dual-head injector systems,

which permit a saline flush of the contrast bolus,

some changes of the administration regime have to

be made.

Contrast-enhanced MDCT of the chest with multipla-

nar reformatted images provides an excellent ana-

tomic display of pathological findings. Grandy et al.

studied patients with stage IIIa bronchial carcinoma

before and after chemotherapy and prior to surgery.

After administration of 100 mL Ultravist® 300 with a

flow rate of 2.5 mL/s and a delay of 25 seconds, the en-

tire thorax was scanned with MDCT with a collimation

of 1 mm. The coronal reformatted images provided

excellent depiction of the tumor extent. In particular,

important details for surgical planning were depicted

such as tracheobronchial tumor growth and involve-

ment of infracarinal lymph nodes. (Grandy 2001)

The diagnostic performance of contrast-enhanced

MDCT is sometimes hampered by streak artifacts origi-

nating from highly concentrated contrast media in the

superior vena cava. In order to reduce these artifacts,

Vogel et al. used a saline flush after administration

of the contrast medium. Injection of Ultravist® 300

(120 mL) was immediately followed by a saline injec-

tion (60 mL). The incidence of artifacts was less than

50% of that of controls without saline flush. The sug-

gested protocol reduces artifacts mainly by a vigorous

washout of the agent in the central veins. However, this

injection regime maintains the mandatory contrast

agent volume for a diagnostic ally proper examination.

(Vogel 2001) The duration of the injection also mat-

ters: Lee et al. used Ultravist® 370 for pulmonary artery

imaging with MDCT and achieved best contrast en-

hancement when injecting the agent over 30 seconds

followed by a 10 second saline flush. (Lee 2007)

4 slices 16 slices 64 slices

Collimation 4 × 2/4 × 2.5 mm 16 × 1/16 × 1.5 64 × 1/64 × 1.5 mm

Slice width/spatial resolution 3/2 mm 2/1 mm 2/1 mm

Rotation time/temporal resolution 0.5 s/250 ms 0.375–0.5 s/200–220 ms 0.375 s/200 ms

Scan time 20–30 s 15–25 s 10–20 s

Contrast protocol 60 @ 4 mL/s 60 @ 4 mL/s 40–50 @ 4 mL/s

Iodine concentration 300 mg I/mL

Table 3: Protocol suggestions for contrast-enhanced CT perfusion studies of the brain. Protocol according to Wintermark 2004

4 slices 16 slices 64 slices

Collimation 4 × 2.5/4 × 5 mm 16 × 1.25/16 × 2/16 × 2.5 mm 64 × 1.25/64 × 2.5/64 × 5 mm

Slice width/spatial resolution 5/3 mm 3/1.3 mm 2/1 mm

Rotation time/temporal resolution 0.5 s/250 ms 0.375–0.5 s/200–220 ms 0.375 s/200 ms

Scan time 30–40s 20–30s 15–25s

Contrast protocol 100 @ 2.5 mL/s 100 @ 2.5 mL/s 100 @ 2 mL/s

Iodine concentration 300 mg I/mL

Saline flush 20 mL @ 2.5 mL/s, delay: 70 s

Table 4: Recommended protocol for contrast-enhanced CT examinations of the chest (excl. cardiac investigations). Protocol

according to Schoellnast 2004 and O’Malley 2000

13

Ultravist.indd 13 16.09.2009 14:04:30

CT of the HeartContrast-enhanced MDCT of the heart has become a

standard procedure. CT-based coronary angio graphy

permits a safe and reliable assessment of the coro-

nary artery tree and of coronary artery bypass grafts.

In addition to coronary artery imaging, retrospectively

ECG-gated CT of the heart enables quantification of

the left ventricular function from the same data set.

(Ropers 2001, Wintersperger 2006, Mahnken 2008a)

Recent technical developments regarding the num-

ber of detector rows markedly reduce radiation dose

and deliver outstanding image quality even at high

heart rates. Diagnostic performance can be further

improved by using data from the diastolic phase

of the cardiac cycle at heart rates below 70 beats/

minute. Employing dedicated cardiac software,

coronary segments 1 mm in diameter can usually be

assessed. (Nieman 2002, Johnson 2006)

Contrast-enhanced MDCT permits the safe detection

of coronary artery stenoses > 50% with sensitivities

and specificities over 90%. (Becker 2002)

Coronary vascular enhancement can be achieved by

intravenous bolus injection of Ultravist® in a wide

range of doses. The contrast effect is optimized by

prior determination of the veno-arterial transit time

of a test bolus or by a semi-automated bolus-track-

ing technique.

Most simply, arterial enhancement is determined by

two user-controllable factors: the iodine administra-

tion rate (injection flow rate, “iodine flux”) and the

3a 3b

Figure 3: Bronchial carcinoma of the right lung with liver metastases. The coronal image shows the tumor in the right up-

per lobe (3a, curved arrow) and the partially necrotic metastasis in the liver (3a, straight arrows), as well as the left adrenal

metastasis (arrowhead). With postprocessing techniques, the tumor can be displayed in color (3b). (Laghi 2006)

14

Ultravist.indd 14 16.09.2009 14:04:30

injection duration. Iodine flux is directly proportional

to arterial enhancement, and is determined by (1)

the injection flow rate and (2) the iodine concentra-

tion of the contrast media. Therefore, an increase in

the injection flow rate (mL/s) or utilization of higher

concentrations of iodine, or both, will result in in-

creased vascular enhancement if other factors remain

constant. (Mollet 2005a, b, Pugliese 2006) For more

details, please refer to the chapter Contrast Applica-

tion on p. 9.

Excellent spatial resolution at best sub-millimeter

is a fundamental prerequisite for proper visualiza-

tion of the heart’s anatomical structures, such as the

coronary arteries. Scan data acquisition has to be

controlled by the patient’s electrocardiogram (ECG) to

provide consistent images in the same relative phase

of the patient’s cardiac cycle. Furthermore, the com-

plete heart volume should be covered within the time

of one breath-hold. Since 2000, shorter examination

times for coronary CTA have been realized with MDCT

systems offering 8 1.25 mm collimation. 16-slice

CT systems with sub-millimeter collimation (16 0.5,

16 0.625, 16 0.75 mm) and gantry rotation times

down to 0.375 s, have provided improved spatial

and temporal resolution compared with 4-slice and

8-slice scanners, while examination times were

considerably reduced to about 15–18 s. 64-slice CT

systems available since 2004 are a further leap in

integrating coronary CTA into routine clinical algo-

rithms. 64-slice CT systems provide further improved

temporal resolution (165 ms and less with multiseg-

ment reconstruction) due to gantry rotation times

down to 0.33 s. The wider coverage with thinner

slices has shortened the scan time to 6–12 s, which

is an adequate breath-hold time even for dyspneic

patients and helps to establish cardiac MDCT in

clinical practice. Table 5 lists typical acquisition

parameters for 4-slice, 16-slice and 64-slice cardiac

CT examinations for coronary angiography. (Mollet

2005a, b, Meijboom 2007, McCollough 2007)

The recent introduction of dual-source MDCT imag-

ing now offers a functional evaluation of valves,

myocardium and the coronary arteries with very

robust image quality using Ultravist® 370.

( Johnson 2006)

4 slices 16 slices 64 slices

Collimation 4 1/4 1.25 mm 16 0.5/16 0.625/16 0.75 mm 64 0.5/64 0.625/2 32 0.6 mm

Slice width/spatial resolution 1.3/1 mm 0.8–1/0.6 mm 0.6–0.8/0.4–0.6 mm

Rotation time/temporal resolution 0.5 s/250 ms 0.375–0.42 s/188–210 ms 0.33–0.4 s/165–200 ms

Scan time to cover the heart volume 40 s 15–20 s 6–12 s

Contrast protocol (typical) ~150 mL @ 3.5 mL/s ~110 mL @ 4 mL/s ~80 mL @ 5 mL/s

Table 5: Protocol suggestions for contrast-enhanced cardiac CT (Concentration: 370 mg I/mL). (Mollet 2005a, b,

Meijboom 2007, McCollough 2007)

15

Ultravist.indd 15 16.09.2009 14:04:31

4a

4b

4c

4d

Figure 4: Occlusion of the LAD as confirmed in catheter angiogram (arrows in 4a) and with various multiplanar reformats

(4b, 4c) and a MIP-image (4d) after the injection of Ultravist® 370. Figure 4a–d reproduced with permission of Springer. (Achen-

bach 2008)

16

Ultravist.indd 16 16.09.2009 14:04:31

CT of the Abdomen MDCT has rapidly advanced to become the reference

standard for imaging of the abdominal viscera. This

new modality has helped refine the diagnostic work-

up of abdominal masses by allowing faster image

acquisition in various phases of enhancement after

intravenous administration of a single bolus of

contrast material. The scanning protocol should

comprise an unenhanced scan followed by series

of the arterial and parenchymal phases of contrast

distribution. The early arterial parenchymal phase

is most sensitive for tumor detection, while later

phases are essential for depiction of the veins and

potential tumor extension. 3D reconstructions pro-

vide the surgeon with a road map of the anatomical

relationship between lesion and major vessels as

well as adjacent organs.

Active hemorrhage after abdominal blunt trauma

can be reliably identified as a jet of extravasated

contrast agent following the intravenous injection

of 120–150 mL Ultravist®. (Willmann 2002a)

The impact of different concentrations of iodi-

nated contrast medium on organ enhancement in

MDCT was recently studied by various groups using

Ultravist® with different iodine concentrations. The

total iodine load of 37 g I/patient and a uniform

flow rate of 4 mL/s was kept constant, while the

injected volume differed depending on the iodine

concentration (240–370 mg/mL).

Comparison of all patient groups showed that

enhancement is a result of iodine delivery rate and

the overall iodine load irrespective of the concentra-

tion of a particular agent. (Engeroff 2001, Sandstede

2006, Behrendt 2008a, b)

A very intelligent approach towards a combined

thoracic and abdominal MDCT protocol using a

single bolus of iodinated contrast material has been

described recently. (Behrendt 2008b)

Multiplanar MDCT of the stomach and the small

intestine (including 3D reconstructions) is an important

supplement to conventional X-ray imaging. Instructing

the patient to drink 1.5–2.0 L of water for stomach dis-

tension, or even distending the small intestine through

a duodenal tube with up to 2.5 L of methyl cellulose,

can dramatically increase image quality. (Rust 1999)

Multidetector computed tomography angiography

(MDCTA) of the abdominal vessels is often useful

for the identification of gastric fundal varices and

may help distinguishing between submucosal and

perigastric convolutions. (Willmann 2002b)

With the colon properly cleaned and distended by wa-

ter or air, virtual colonoscopy with MDCT can reliably

detect polyps and cancer of the large bowel. A prereq-

uisite for proper imaging intestinal wall changes is

the intravenous administration of iodinated contrast

agent. To this end, both Ultravist® 300 or Ultravist®

370 can be given at a dose of 120 mL with a flow rate

of 3 mL/s. A scan delay of 60 seconds is optimal for

large bowel imaging. (Rust 2000, Mainenti 2006)

MDCT urography provides high-resolution images

of the entire genito-urinary tract. Data acquisition

is started approximately five minutes after intra-

17

Ultravist.indd 17 16.09.2009 14:04:34

venous administration of 100 mL of Ultravist®.

MDCT urography also has been reported to be an

important diagnostic tool for assessing surgical

complications of kidney allografts with diagnostic

accuracies above 90%. (Sciascia 2002)

Virtual cystoscopy has been found to be useful for

the evaluation of the urinary bladder in patients

with gross hematuria. CT data of the contrast-

material-filled bladder are obtained using a multi-

detector scanner and transferred to a workstation

for postprocessing. The sensitivity and specificity

for identifying bladder lesions with virtual cysto-

scopy are 95% and 87%, respectively, and 95% and

93%, respectively, for detecting abnormal bladders.

(Kim 2002)

5a 5b

Figure 5: Gastric wall carcinoma as displayed by enhanced MDCT scan in transverse (5a) and multiplanar coronal reformats

(5b), water as oral contrast used in axial CT (5a). (Laghi 2006)

4 slices 16 slices 64 slices

Collimation 4 × 2.5/4 × 5 mm 16 × 1.25/16 × 2/16 × 2.5 mm 64 × 1.25/64 × 2.5/64 × 5 mm

Slice width/spatial resolution 5/3 mm 3/1.3 mm 2/1 mm

Rotation time/temporal resolution 0.5 s/250 ms 0.375–0.5 s/200–220 ms 0.375 s/200 ms

Scan time 30–40 s 20–30 s 15–25 s

Contrast protocol 100 @ 2.5 mL/s 100 @ 2.5 mL/s 100 @ 2 mL/s

Iodine concentration 300 mg I/mL

Saline flush 20 mL @ 2.5 mL/s, delay: 70 s

Table 6: Protocol suggestion for contrast-enhanced CT examinations of the abdomen (incl. dynamic liver examinationsa)

Protocol according to Schoellnast 2004 and O’Malley 2000

a Contrast-enhanced CT examinations of the liver are dynamic: first, a native scan of the liver is acquired. Approximately 20 seconds after intravenous contrast administration

the scan is repeated in the arterial phase. The portal-venous phase and late phase are acquired 40 and 90 seconds, respectively, after contrast injection. These four phases

permit a safe characterization of focal liver lesions based on the perfusion of the respective lesion.

18

Ultravist.indd 18 16.09.2009 14:04:34

6a

6d

6b

6e

6c

6f

Figure 6: Polyps and malignant masses are easily detected with contrast-enhanced MDCT. Figure 6a–f reproduced with

permission of Springer. (Laghi 2006)

CT of the Liver MDCT allows fast and reliable imaging of the liver

during multiple phases of contrast enhancement.

A double- or triple-phase technique, highlighting

the arterial, portal-venous and parenchymal phases

of enhancement, is recommended as standard of

reference. Arterial phase and portal-venous phase

images are acquired approximately 20 seconds and

60 seconds, respectively, after intravenous contrast

material injection. (Kopp 2002)

The effect of iodine concentration on the detection

of focal liver lesions has been widely evaluated.

(Hanninen 2000)

Multiphase MDCT of the liver also has a major impact

on patient selection and surgical planning for liver

transplantation. Arterial, portal-venous, and hepatic-

venous anatomy are clearly depicted as are vascular

variants. The technique provides a comprehensive

analysis of potential donors who are being evaluated

for right-lobe liver transplantation. Additionally, liver

parenchyma can be assessed for fatty infiltration by

precontrast imaging or by a dual-energy technique,

and total and lobar liver volumes can be determined.

(Kamel 2001) 3D-CT cholangiography with minimum

intensity projection has the potential to compete with

MRCP due to its excellent spatial resolution with regard

to the biliary duct system. MDCT data are obtained

roughly 65 seconds after the IV injection of Ultravist®

(volume: 150 mL, flow rate: 3 mL/s). (Park 2001)

19

Ultravist.indd 19 16.09.2009 14:04:34

7

Figure 7: Multiple liver metastases as clearly depicted in the

portal-venous phase of contrast distribution on MDCT. Figure 7

reproduced with permission of Springer. (Laghi 2006)

CT Angiography (CTA)For almost all vascular disorders, MDCT angiography

(MDCTA) is a fast and non-invasive alternative to

diagnostic catheter angiography. Ultravist® has been

successfully used for the display of a variety of con-

genital and acquired vessel lesions with MDCTA. The

introduction of MDCT has substantially improved

the quality as well as the simplicity of performing CT

angiography. MDCTA has become a reliable method

of vascular imaging and is now an established exam-

ination in many radiology departments.

A dense and homogeneous enhancement of the

entire aorta can be achieved by using a biphasic

injection protocol with a total volume of 120 mL

Ultravist®. The first 40 mL are given at a flow rate of

5 mL/s, the remaining 80 mL follow at 2.5 mL/s.

8

Figure 8: The colored Maximum Intensity Projection of the

Ultravist®-enhanced CTA shows an infrarenal abdominal aortic

aneurysm (AAA). The diameter can easily be measured and the

origin of all visceral and renal branches can be appreciated. Figure

8 reproduced with permission of Springer. (Mahnken 2008b)

This injection scheme provides optimal vascular

contrast. (Engeroff 2002)

MDCTA is also a highly accurate tool for the detection

of hemodynamically relevant renal artery stenoses. In

addition, volume-rendered MDCT angiograms enable

high-quality 3D evaluation of renal artery stents and as-

sessment of their position and patency. (Mallouhi 2003)

Ultravist®-enhanced MDCTA offers valuable preopera-

tive information about the celiac trunk and the mesen-

teric arteries. In patients who are scheduled for major

liver surgery, normal and variant arterial, portal-venous

and hepatic vein anatomy can be accurately displayed,

and the relationship of neoplasms to neighboring struc-

tures can be delineated convincingly. (Sahani 2002)

20

Ultravist.indd 20 16.09.2009 14:04:36

MDCTA very clearly depicts relevant stenoses of the

iliac arteries and the arteries of the thigh and lower

leg in patients with peripheral arterial occlusive

disease. It can be performed using Ultravist® 300 and

370, respectively, (volume: 100 to 150 mL) at a flow

rate of 3 mL/s taking advantage of the bolus tracking

technique. (Balzer 2001, Rieger 2001a, Puls 2001)

High-resolution MDCTA provides good images of

the lower extremity arteries as small as 1 mm in di-

a meter. Occlusions are recognized with an accuracy

of almost 100%. (Balzer 2001)

With DSA as standard of reference, hemodynami-

cally relevant stenoses (i.e., reduction of diameter

over 50%) can still be detected with a sensitivity of

86%, a specificity of 86% and an accuracy of 72%.

MDCTA of the lower extremities has thus become the

preferred method for planning surgical and X-ray-

guided interventions. (Puls 2001)

Ultravist®-enhanced MDCTA also provides rapid

minimal-invasive imaging of the arteries of the

hands. Due to the high resolution of 2D-images and

3D-reconstructions, even arteries ≤1 mm in dia meter

can be well identified. Moreover, the technique also

performs well for vascular lesions in traumatized

patients and is therefore considered to be an integral

part of total body examination in patients who have

been seriously injured. (Rieger 2001b)

CTA Upper Extremity Runoff at 64-MDCT

Collimation 64×0.6 mm

Coverage Aortic arch to finger tips

Pitch Variable = function of volume coverage

Rotation time 0.5 s

Scan time Fixed: 30 s

CM injection

Injection duration Fixed: 30 s

Scan timing Bolus trigger: aortic arch, trigger level 100 HU

Scanning delay t(CMT) + 2–3 s

Biphasic CM injection profile:

Kg Volume 1 Flow rate 1 Volume 2 Flow rate 2

≤55 kg 20 mL 4.0 mL/s 80 mL 3.2 mL/s

56–65 kg 23 mL 4.5 mL/s 90 mL 3.6 mL/s

66–85 kg 25 mL 5.0 mL/s 100 mL 4.0 mL/s

86–95 kg 28 mL 5.5 mL/s 110 mL 4.4 mL/s

>95 kg 30 mL 6.0 mL/s 120 mL 4.8 mL/s

Saline flush: 40 mL at corresponding slower flow rate.

Table 7: Protocol CTA Upper Extremity. Protocol according

to Hallett 2006

CTA Abdomen/Pelvis at 64-MDCT

Collimation 64×0.6 mm

Coverage Above celiac trunk to lesser trochanter

Pitch Variable = function of volume coverage

Rotation time 0.5 s

Scan time: Fixed: 10 s

CM injection

Injection duration Fixed: 18 s

Scan timing: Bolus trigger: supra-celiac aorta, 100 HU trigger

Scanning delay t(CMT) + 8 s (scan starts 8 s after contrast

arrives in aorta)

Body weight adjusted single phase CM injection profile

Kg CM flow rate CM volume

≤55 kg 4.0 mL/s 72 mL

56–65 kg 4.5 mL/s 81 mL

66–85 kg 5.0 mL/s 90 mL

86–95 kg 5.5 mL/s 99 mL

>95 kg 6.0 mL/s 108 mL

Table 8: Protocol CTA Abdomen/Pelvis. Protocol according

to Hallett 2006

21

Ultravist.indd 21 16.09.2009 14:04:38

9a 9b 9c

Figure 9: Stanford B dissection in multiplanar reformats (9a: sagittal and 9b: coronal) as well as a sagittal MIP image (9c)

which all clearly show the origin and the extent of the intimal tear. Figure 9a–c reproduced with permission of Springer.

(McDonald 2008)

CTA Lower Extremity Runoff at 64-MDCT

Collimation 64×0.6 mm

Coverage Above celiac trunk to toes

Pitch Variable = function of volume coverage

Rotation time 0.5 s

Scan time Fixed: 40 s

CM Injection

Injection duration Fixed: 35 s

SCAN TIMING Bolus trigger: supra-celiac aorta, 100 HU trigger

Scanning delay t(CMT) + 2–3 s

Body weight adjusted single phase CM injection profile

Kg Volume 1 Flow rate 1 Volume 2 Flow rate 2

≤55 kg 20 mL 4.0 mL/s 96 mL 3.2 mL/s

56–65 kg 23 mL 4.5 mL/s 108 mL 3.6 mL/s

66–85 kg 25 mL 5.0 mL/s 120 mL 4.0 mL/s

86–95 kg 28 mL 5.5 mL/s 132 mL 4.4 mL/s

>95 kg 30 mL 6.0 mL/s 144 mL 4.8 mL/s

Saline flush: 40 mL @ corresponding slower flow rate.

Bolus trigger: in aorta at level of level SMA, 100 HU trigger.

Table 9: Protocol CTA Lower Extremity Runoff. Protocol

according to Hallett 2006

22

Ultravist.indd 22 16.09.2009 14:04:38

10a 10b 10c

11

Figure 11: Infrarenal aneurysm of the aorta and a partially

thrombosed left iliac artery aneurysm can be detected on

this MDCT scan after the injection of Ultravist® 370. Figure 11

reproduced with permission of Springer. (Wintersperger 2007)

Figure 10: Postprocessed data sets of a contrast-enhanced peripheral MDCTA of a 66-year-old patient with bilateral occlusions and

multiple stenoses of the superficial femoral artery (SFA). Figure 10a–c reproduced with permission of Springer. (Misselt 2008)

23

Ultravist.indd 23 16.09.2009 14:04:40

Conventional AngiographyConventional angiography through an intra-arterial

access is most often performed by DSA-technique

(Digital Subtraction Angiography). Today, because

of its invasiveness and inherent risks, diagnostic

DSA is more and more frequently being replaced by

non-invasive examinations, e.g. CTA and MRA. Nev-

ertheless, conventional angiography with Ultravist®

will remain indispensable, especially in the field of

interventional procedures.

12

Figure 12: Catheter-DSA of the abdominal aorta with Ultra-

vist® gives an optimal overview of the anatomic site for proce-

dure planning. Figure 12 shows the proximal placement of the

main body of the bifurcated stent graft of an elective endovas-

cular aneurysm repair (EVAR) procedure. (Mahnken 2008b)

13a 13b

Figure 13: These two DSA angiographies with Ultravist® accu-

rately display stenoses and occlusions of the SFA and runoff-arter-

ies in these two examples of peripheral arterial occlusive disease.

(Mahnken 2008c)

24

Ultravist.indd 24 16.09.2009 14:04:46

14

Figure 14: The selective injection of Ultravist® into the right

carotid artery adequately shows a normal intracranial arte-

rial vascular system. (Mahnken 2008c)

Cerebral ArteriographyIn cerebral angiography, iopromide ranks favorably

among the other non-ionic monomeric contrast

agents. The performance of Ultravist® 300 was

evaluated in a double-blind randomized multi-center

study with 173 patients. Iopromide was compared

to iopamidol and iohexol. Ultravist® exhibited the

lowest rate of adverse effects. The proportion of

patients reporting drug-related adverse events

was 21% for iopromide and 44% for the reference

substances. Severe sensations of pain were seen

considerably less with Ultravist®. (Haughton 1994)

Cardioangiography and Coronary Angio graphyCardiologists often prefer Ultravist® 370 for di-

agnostic as well as for interventional purposes,

because the higher iodine delivery rates that are

possible with Ultravist® 370 provide excellent con-

trast quality.

Its high performance is reflected by the results of

double-blind trials, which compared iopromide to

iopamidol and iohexol in coronary arteriography

and left ventriculography (n = 161 patients). The

incidence of side-effects was equally low and the

diagnostic efficacy similar for the three compounds

studied, with Ultravist® providing good-to-excellent

images in 99% of the cases. (Bergelson 1994)

Peripheral AngiographyGood local tolerance is especially important when

small arteries like those of the hands are studied by

angiography. Only when necessary multiple contrast

injections are well tolerated, the procedure will be

finished rapidly and with reliable imaging results. For

better endothelial tolerance, Ultravist® 150 is used

with a superselective position of the catheter.

Unlike most angiographic procedures performed for

diagnostic purposes, PTA and stenting often require

numerous injections of contrast agents into the same

or neighboring vessels. Excellent local tolerance is

needed in order to avoid additional endothelial dam-

age and to keep the risk of thrombosis as low as pos-

sible. Ultravist® fulfills these requirements by its high

standards of general, local and vascular tolerance.

In laser angioplasty, possibly harmful interaction

of the laser light and the contrast agent may occur

due to the high concentration of the contrast-giving

substance proximal to the stenosis or occlusion.

25

Ultravist.indd 25 16.09.2009 14:04:46

As an in-vitro study demonstrated, excimer laser

irradiation induced iodine liberation of up to 3.3 mg

iodine/mL. Up to 19% of the contrast agent changed

its original molecular structure. In order to reduce

the level of free iodine and the amount of cytotoxic

photoproducts, it is recommended that the diseased

vessel be flushed with physiologic saline solution

before applying a pulsed excimer laser in arterial

obstructions. (Gronewaller 1998)

VenographyGiven the delicacy of the venous endothelium and

the fact that the slower blood flow in veins length-

ens the contact time of the contrast medium with

the vessel wall, the choice of the contrast agent for

venography is of great importance in order to avoid

subsequent thrombophlebitis, which can result in or

aggravate deep venous thrombosis.

Ultravist® possesses an outstanding endothelial tol-

erance and should therefore be highly suitable for

use in peripheral venography as well as in imaging

of the pelvic, abdominal and thoracic veins. (Krause

1994b)

Conventional RadiographyUltravist® provides excellent contrast and optimal

visualization of normal and pathologic anatomi-

cal structures in all radiographic procedures. Duct

systems and body cavities, natural or artificial, can

be clearly delineated after careful instillation of the

contrast agent. Its superior quality is substantiated

by experience derived from two decades of clinical

use and has been confirmed in a variety of compara-

tive studies.

Intravenous Urography (IVU)The advance of ultrasound (US), CT and MRI have all

revolutionized the assessment of the parenchyma

of the kidneys. Today, intravenous (excretory) uro g-

raphy (IVU) is preferentially used for the depiction of

the corticomedullary and nephrographic phases of

renal parenchymal enhancement as well as for the

depiction of the pelvocaliceal system, ureters and

urinary bladder. Many patients referred for IVU are

being prepared for major abdominopelvic surgery.

Other relevant indications are chronic pyelonephri-

tis, nephroureterolithiasis and anomalies of the

urinary tract.

Using low-osmolar Ultravist® 300, high iodine con-

centrations are measured in the urine which result

in excellent contrast density. A minimum dosage of

about 1.0 mL/kg body weight is generally recom-

mended. Short-term restriction of fluid intake and

compression of the ureters may be helpful for delin-

eating the urinary collecting system in its entirety.

Ultravist® was found to be equal to other non-ionic

monomeric X-ray agents in intravenous urography

in terms of efficacy and safety. (Newhouse 1994,

De Geeter 1994)

In another large study of 767 patients referred for

excretory urography, the acute side-effects of iopro-

mide were compared with an ionic contrast medium.

The rate of adverse events with Ultravist® (7.9%)

was reduced by a factor of 3, which is often found in

comparative studies with ionic compounds. In only one

case the reactions were classified as severe, requiring

hospitalization. In the patient group receiving the ionic

26

Ultravist.indd 26 16.09.2009 14:04:47

compound, adverse events occurred in 104 patients

(23.1%), two cases were rated as severe. (Sahin 1998)

The influence of different dosages of Ultravist®

on the quality of the urograms was examined in

a double-blinded study. Excellent contrast was

obtained by application of both 1.0 and 1.5 mL/kg

body weight of Ultravist® 300. (Dominik 1989)

Contrast Radiography of Duct Systems and Body CavitiesUltravist® is an effective contrast agent for the radio-

logical exploration of duct systems (ERCP, sialogra-

phy, hysterosalpingography) and body cavities (upper

GI tract radiography). Its low osmolality and non-ion-

ic character render the agent particularly favorable

for the depiction of the duct systems in vulnerable

exocrine glands.

Pancreatitis following ERCP and endoscopic sphinc-

terotomy is a frequent complication with sometimes

serious clinical consequences. Its pathogenesis is

complex and also includes osmotoxic and chemo-

toxic effects on epithelia. Hydroxyl groups are less

chemotoxic than carboxyl groups. Iopromide has

four hydroxyl groups per triiodobenzoic acid mole-

cule and no carboxyl groups. ERCP-induced damage

to the pancreatic parenchyma is therefore rare in

patients receiving Ultravist®. The diagnosis of pan-

creatitis was deduced from blood samples analyzed

for pancreatic enzymes and acute-phase proteins as

well as from the clinical pain score. (Goebel 2000)

Acute cholangitis is another serious complication

of ERCP that might be attributed to the cytotoxicity

of the contrast agent. Korean gastroenterologists

compared iopromide with a high-osmolar contrast

agent regarding the effect on cultures of gallbladder

epithelial cells. Low-osmolar non-ionic iopromide

inhibited cell growth to a smaller extent than its

counterpart. Likewise, the chromosomal damage

was less. ( Ju 2002)

Conventional hysterosalpingography (HSG) is per-

formed in modern gynecologic practice, especially

those with greater numbers of reproductive endo-

crinologists trying to improve the fertility of women

trying to conceive despite a prior history of infertil-

ity. Furthermore, due to the advent of newer steri-

lizing procedures that sclerose the fallopian tubes

and require HSG as a follow-up procedure, HSGs are

common. Experience shows that Ultravist® 300 is a

safe and effective contrast medium for depicting the

cavity of the uterus and the patency of the tubes.

(Herbe 1989)

Hyperosmolar contrast media may cause acute in-

flammation and even pulmonary edema, especially

in children, when inadvertently aspirated. Therefore,

low-osmolar and non-ionic agents like Ultravist®

are preferred for oral administration, when patients

at risk of aspiration have to be examined. Ultravist®

240 was used as the contrast medium in dynamic

radiography of the pharynx to study swallowing

disorders. In all 19 patients tested, the mechanism

leading to aspiration could be determined. No major

adverse events were reported. (Koehler 1993)

The results of using Ultravist® 300 and Ultravist®

370 to examine the GI tract in 21 patients with acute

27

Ultravist.indd 27 16.09.2009 14:04:47

abdominal symptoms were presented by a Rus-

sian group. The authors emphasize that Ultravist®

permitted differential diagnosis to be made between

partial and complete small bowel obstruction and

contributed substantially to medical treatment of

the abdominal emergencies. (Beresneva 1997)

ArthrographyCurrently, the use of conventional arthrography is

confined to a few indications (e.g. free intraarticular

bodies) and joints (e.g. the wrist joint). MRI has become

the imaging modality of choice for the evaluation of

the joints. Also the combination of arthrography and

computed tomography, formerly very popular with

shoulder surgeons, has been replaced by direct and in-

direct MR arthrography. For the remaining indications,

good results are usually achieved with Ultravist® 240.

Pediatric RadiologyThe use of contrast media in neonates and infants

requires careful consideration. Extravasation during

intravenous injection is a major concern in pediatric

radiology. Due to their superior local tolerance, non-

ionic compounds are preferred. Apart from the reduced

discomfort for young patients, the concomitant

decrease in unintentional motion and motion artifacts

permit better quality radiographs. (Kaufmann 1994)

Allergic reactions to X-ray contrast media are ob-

served less frequently in infants than in adults (prob-

ably due to the immature immune system). With non-

ionic compounds, the rate is well below 1%.

Very-low-birthweight infants are commonly nour-

ished via non-radioopaque central silastic catheters.

Reliable imaging of these tools can often only be

achieved by using iodinated contrast medium.

Thyroid function was analyzed in 20 premature

babies after injection of Ultravist® 300 (0.3–1.0 mL/

kg bw). The pediatricians did not detect hyperthy-

roidism or hyperthyrotropinemia 4–45 days after

injection. Thus, Ultravist® may be superior to other

contrast agents with regard to thyroid function in

very-low-birthweight infants within the small dose

range. (Dembinski 2000)

Ultravist® 150 proved useful for tracheobronchogra-

phy even of neonates suffering from severe pulmonary

disorders. No adverse reactions were observed during

or after these demanding examinations. (Riebel 1990)

To determine the safety and usefulness of iopromide

in cardiovascular angiography, 78 children were

examined. Although heart rate and left-ventricular

end-diastolic pressure before and after contrast

medium injection were significantly different, iopro-

mide did not result in severe hemodynamic changes

or marked inhibitory action on myocardial contrac-

tility. The overall rate of acute adverse reactions was

5%. No late sequelae were detected. (Misawa 2000)

In another study, kidney function was monitored

in children submitted to cine-angiography using

iopromide. 19 patients were included. The changes

in renal function parameters as well as in urinary

enzymes were insignificant. The authors concluded

that iopromide at a maximum dose of 5 mL/kg body

weight does not result in injury to the tubular epi-

thelium of infantile kidneys. (Kavukcu 1995)

28

Ultravist.indd 28 16.09.2009 14:04:47

Pediatric CTIn pediatrics, CT is a straight-forward and very fast

imaging modality for examining virtually all parts

of the body. Modern CT scanners permit almost

isotropic 3D data acquisition and multiplanar recon-

structions. However, the inherent ionizing radiation

of the technique is a major disadvantage in the

pediatric population. Hence, not only the technique

but also the particular need for a contrast material

has to be weighed carefully for every indication. For

neuroimaging in patients with infectious diseases or

tumors, contrast material should be administered to

evaluate for lesions which disrupt the blood-brain

barrier. CT is often used for chest imaging when con-

ventional radiography does not provide sufficient

information for an appropriate diagnosis or thera-

peutic treatment planning. While lung parenchyma

can readily be assessed without the use of contrast

material, the latter becomes important for mediasti-

nal lymph node detection or complex cardiovascular

malformations. In the abdomen, contrast-enhanced

CT is particularly helpful for the detection and char-

acterization of focal lesions and proper assessment

of parenchymal disease. Also the display of the

vascular system is feasible with contrast-enhanced

CTA in children.

Recently, a study on thoracic and coronary DSCT

in 110 infants (<1 year) with Ultravist® 300 has

been reported. (Ben Saad 2009) In 110 patients,

a total of 142 contrast-enhanced examinations

were performed; 78 babies had a thoracic angio-CT

acquisition alone, 32 others had a thoracic angio-

CT acquisition followed by an ECG-gated cardiac

acquisition for detailed coronary evaluation. The

average volume of contrast medium injected was

11 ± 4 ml (range 4–19 ml). The mean flow rate was

0.8 ± 0.2 ml/s (range 0.5–1.3 ml/s).

Using a weight-based low-dose protocol, it was pos-

sible to achieve an overall diagnostic image qual-

ity in 89% of examinations. In addition, the study

showed that ECG-gated cardiac DSCT improved the

visualization of the coronary arteries significantly,

providing satisfactory delineation in most cases (LCA

91%, RCA 84%). Using a weight-based protocol, ra-

diation exposure parameters were very low. In non-

ECG-gated thoracic acquisitions, the effective dose

amounted 0.5 ± 0.2 mSv (range 0.2–0.9 mSv). These

very-low-dose parameters were achieved through

systematic use of an 80 kVp setting and adaptation

of the tube current to the infant’s weight. Even the

cumulative radiation dose of a non-gated followed

by a gated acquisition led to an effective dose of 1.8

± 0.7 mSv (range 0.9–3.5 mSv). with under 2.5 mSv in

a large majority of cases, which seems reasonable in

terms of the clinical information provided. Regard-

ing contrast safety in infants, no serious adverse ef-

fects related to the contrast medium injection were

observed. No vomiting, no renal deterioration, and

no allergic reactions were observed. There were two

contrast extravasations, which were treated imme-

diately by simple arm and hand massage without

further complications.

29

Ultravist.indd 29 16.09.2009 14:04:47

Tips for Handling

General RecommendationAs with all contrast agents, because of the potential

for chemical incompatibility, Ultravist® should not be

mixed with or injected in intravenous administration

lines containing other drugs, solutions or total nutri-

tional admixtures. Sterile technique must be used in all

vascular injections involving contrast agents. Intravas-

cularly administered iodinated contrast agents should

be at or close to body temperature when injected. If

non-disposable equipment is used, meticulous care

should be taken to prevent residual contamination

with traces of cleansing agents. Withdrawal of contrast

agents from their containers should be accomplished

under strict aseptic condition. Parenteral drug products

should be inspected visually for particulate matter and

discoloration prior to administration and should not

be used if particulates (including crystals) or defective

containers are observed or discoloration has occurred.

Optical InspectionUltravist® is available as a ready-for-use, clear and

colorless to slightly yellowish solution. Contrast

agents should be visually checked before use and

must not be used in the case of discoloration, pres-

ence of particles (including crystals) or damage

to the container. Since Ultravist® is a highly con-

centrated solution, very rarely crystallization can

occur (milky-turbid appearance and/or sediments or

suspended crystals).

WarmingWarming the preparation to body temperature re-

duces the viscosity of the solution and thus adds to

the patient’s comfort. Moreover, it increases the ease

of handling for the user, especially when repeated

manual injections are required.

The low viscosity of warmed Ultravist® solutions is

particularly beneficial in children, when manual in-

jections through thin-bore catheters are necessary.

ExtravasationThe risk of inadequate catheter positioning and

consequent extravasation can be reduced by using

plastic cannulas and large-bore venous access. Due

to their elasticity, plastic cannulas are unlikely to

penetrate vessel walls accidentally, even when the

patient moves. Avoid the use of rigid metal needles.

The vast majority of injuries due to extravasa-

tion are minor, nevertheless there are severe cases

including skin ulcerations, soft tissue necrosis, and

even compartment syndrome. The current ESUR

(European Society of Urogenital Radiology) guide-

lines recommend conservative management such

as limb elevation, applying ice packs and careful

monitoring which are adequate in most cases. In

severe cases, a surgeon should be contacted. (Bellin

2002)

Thromboembolic EventsThe combination of Ultravist® with a soluble antico-

agulant and careful catheter technique minimizes

the risk of blood clotting during diagnostic and

therapeutic angiography.

Frequent and thorough flushing of the catheter with

heparinized saline is mandatory. By using closed

systems with continuous catheter flushing, throm-

boembolic complications can be virtually elimi-

nated. Aspiration of blood into the syringe should

be kept to a minimum. Plastic syringes are generally

preferred to glass syringes. Resterilized angiograph-

ic catheters should not be used.

30

Ultravist.indd 30 16.09.2009 14:04:47

Safety Profile

Types of Reaction – OverviewAdverse drug reactions (ADRs) of contrast media (CM)

are usually classified according to their cause in:

(1) anaphylactoid dose-independet reactions (also

called allergy-like or hypersensitivity reactions),

(2) dose-dependent effects on various organs or or-

gan systems. (Thomsen 2006b) These two types of re-

actions can appear concurrently and cannot always

be clearly distinguished from one another. Amongst

the typical allergy-like adverse reactions are the

skin and mucous membrane reactions; organ-toxic

effects are primarily seen in the kidneys, the central

nervous system (CNS) and the cardiovascular sys-

tem. Delay ed (late) reactions are also known to oc-

cur after CM administration; the majority of the late

reactions occur between 3 and 72 hours after the ap-

plication of contrast media. Subsequently occurring

reactions are rare. As with other pharmaceuticals,

the clinical manifestation is primarily characterized

by allergy-like skin and mucous membrane reac-

tions. Many exogenic and endogenic factors impact

on the severity and frequency of adverse reactions.

Essentially, these consist of:

Q the XRCM used

Q the examination method and mode of application

Q the dosage

Q patient-related risk factors such as medical his-

tory of contrast media, allergies, asthma, renal

insufficiency, certain medicines and many others

The majority of ADRs associated with iodinated

contrast agents are of mild intensity and non-life-

threat ening. Severe ADRs may start as a mild or

moderate reaction, and intensify; nearly all life-

threatening reactions occur immediately or within

the time frame of 20 minutes after CM injection. The

effects of parameters like administered dose, route

of administration and injection rate are not entirely

clear. Also, prediction of a contrast media reaction

is not reliably possible, although some patient

populations are known to have an increased risk for

hypersensitivity (anaphy lactoid) reactions. Among

those are:

Q patients with previous reactions to contrast media

Q patients with bronchial asthma or other allergic

disorders

Ultravist® General Safety DataSince the market introduction in 1985, the good

safety profile of Ultravist® has been proven in a

number of large-scale studies. The most important

of these studies are the Mortele study (Mortele 2005)

and the Ultravist® post-marketing surveillance (PMS)

study that started in Germany in June 1999 and was

concluded in 2003 including almost 75,000 patients

(Kopp 2008).

The Mortele Study (Mortele 2005)The Mortele study describes the evaluation of the

general safety of the universal use of the non-ionic

iodinated contrast agent iopromide in patients un-

dergoing CT in a large urban teaching hospital in the

USA. Over a period of two years, all adverse drug reac-

tions (ADRs) were prospectively recorded which were

temporally associated with the administration of

iopromide (Ultravist®) in 29,508 consecutive patients.

The types, intensities, treatments, and outcomes of

the ADRs were recorded along with relevant patient

history, including risk factors. Descriptive analyses

of the variables, comparisons of means, and pro-

portions using Student’s and Chi-square tests, and

logistic regressions were conducted.

31

Ultravist.indd 31 16.09.2009 14:04:48

The investigation found a generally low ADR rate

listed in Table 10. The most common ADR was urti-

caria (0.55%), followed by nausea and severe vomit-

ing (0.03%). The authors concluded from the data:

“The universal use of iopromide as an IV CT contrast

agent has a favorable safety profile.” (Mortele 2005)

Mortele Study

Patients 29,508

Total ADRs 0.71%

Mild 0.64%

Moderate 0.06%

Severe 0.02%

Table 10: Overall results of the Mortele study. (Mortele 2005)

The Ultravist® PMS Study (Kopp 2008)The large-scale Ultravist® post-marketing surveil-

lance (Ultravist® PMS) project was started in 1999

and monitored adverse reactions following the

administration of Ultravist® in a variety of radio-

logic routine examinations over 4 years. From 27

participating countries globally, overall 74,717

patients were included in the study. ADRs as well

as tolerance indicators (like heat sensation at the

injection site and taste perversions) were recorded.

The overall results are listed in Table 11, while the

individual incidences are listed in Table 12. Consis-

tent with other findings, adverse drug reaction rates

were affected by age, gender and risk factors (espe-

cially previous CM reactions or allergies), but not

by premedication. The overall ADR rates of Ultra-

vist® were similar to the findings reported for other

non-ionic contrast agents. The occurrence of serious

ADRs was extremely rare (0.02%) and comparable

with the findings of the meta-analysis by Caro et al.

(0.031%) which included a number of LOCMs and

about 250,000 patients. (Caro 1991) The incidence,

nature, and intensity of ADRs following the admin-

istration of Ultravist® are comparable to the safety

profile of other iodinated non-ionic CMs reported in

the literature.

Ultravist® PMS Study

Patients 74,717

Total ADRs & TIs* 2.00%

Total ADRs w/o TIs* 1.50%

Mild 0.55%

Moderate 0.48%

Severe 0.17%

Serious** 0.02%

Information on serverity was missing for 0.25% of the cases

* TI = Tolerance Indicators

** Cases, which either required further medical treatment, prolonged

hospitalization, or were considered life-threatening

Table 11: Overall results of the Ultravist® PMS study. (Kopp

2008)

Type of ADRs in Ultravist® PMS Study

Heat sensation 1.14%

Nausea/vomiting 0.52%

Metallic taste 0.44%

Erythema/exanthema/urticaria 0.31%

Itching 0.25%

Sneezing/coughing 0.05%

Edema 0.06%

Dyspnea/bronchospasm 0.06%

Increase/decrease blood pressure 0.06%

Pain 0.18%

Other 0.18%

Table 12: Incidence of ADRs. (Kopp 2008)

32

Ultravist.indd 32 16.09.2009 14:04:48

Summary of results of the Ultravist® PMS study

The Ultravist® PMS study data show:

Q low rate of overall ADRs (1.5%)*

Q low rate of serious ADRs (0.02%)

Q no unexpected ADRs

Q similar severity patterns as known from other

iodinated CMs

* Excluding TIs

The authors conclude on the basis of the obtained

data: “This broad database proves the safe use of

iopromide in different patient groups across a variety

of indications.” (Kopp 2008)

Delayed Skin ReactionsDelayed skin reactions following the administra-

tion of CM occur later than 1 h post injection and

usually manifest in the skin. In a number of head-

to-head comparisons (compare Table 13) it has been

demonstrated that LOCM, such as Ultravist®, have

significantly lower rates of delayed skin reactions

than IOCMs.

Sutton 2003 *(2,108 patients, IA appl.)

Schild 2006 *

(772 patients, IV appl.)

Skin rash Itching Skin rash Itching

LOCM** 2.7% 6.5% – –

Ultravist® – – 5.8% 7.0%

Dimers*** 10.4% 10.4% 8.4% 12.6%

Control**** – – 3.2% 2.8%

* All results are significantly higher for dimers compared to LOCM, except ‘skin rash’ in Schild 2006, for which, however, the dimer result (as opposed to the Ultravist® result) was still significantly higher than contol.

** Sutton 2003 contained two LOCMs. Displayed is the LOCM group with the larger patient number (Iopamidol) (n=738).

*** Investigated non-ionic dimer: Iodixanol (Sutton 2003), Iotrolan (Schild 2006).

**** Without contrast media.

Table 13: Summary of two head-to-head comparisons on

the incidence of delayed skin reactions.

Undesirable Effects – Information Given in the Ultravist® Package Insert** May vary locally – please refer to your local PI for

details.

Undesirable effects in association with the use of

iodinated contrast media are usually mild to moder-

ate and transient in nature. However, severe and

life-threatening reactions as well as deaths have

been reported. Nausea, vomiting, a sensation of

pain and a general feeling of warmth are the most

frequently recorded reactions.

33

Ultravist.indd 33 16.09.2009 14:04:48

Intravascular use:

System organ class Common(≥1/100)

Uncommon (≥1/1,000,<1/100)

Rare (<1/1,000)

Immunological Anaphylactoid

reactions/

hypersensitivity

Anaphylactoid shock (including fatal cases)

Endocrine Alteration in thyroid function, thyrotoxic crisis

Nervous, psychiatric Dizziness,

restlessness

Paresthesia / hypoesthesia, confusion, anxiety, agitation, amnesia, speech

disorders, somnolence, unconsciousness, coma, tremor, convulsion, paresis /

paralysis, cerebral, ischemia / infarction, stroke, transient cortical blindnessa

Eye Blurred /

disturbed vision

Conjunctivitis, lacrimation

Ear Hearing disorders

Cardiac Arrhythmia Palpitations, chest pain / tightness, bradycardia, tachycardia, cardiac arrest,

heart failure, myocardial ischemia / infarction, cyanosis

Vascular Vasodilation Hypotension, hypertension, shock, vasospasma, thromboembolic eventsa

Respiratory Sneezing,

coughing

Rhinitis, dyspnea, mucosal swelling, asthma, hoarseness, laryngeal / pha-

ryngeal / tongue / face edema, bronchospasm, laryngeal / pharyngeal spasm,

pulmonary edema, respiratory insufficiency, respiratory arrest

Gastrointestinal Nausea Vomiting, taste

disturbance

Throat irritation, dysphagia, swelling of salivary glands, abdominal pain,

diarrhoea

Skin and subcuta-

neous tissue

Urticaria, pruritus,

rash, erythema

Angioedema, mucocutaneous syndrome (e.g. Stevens-Johnson’s or Lyell

syndrome)

Renal and urinary Renal impairmenta Acute renal failurea

General disorders and

administration site

conditions

Heat or pain

sensations,

headache

Malaise, chills,

sweating, vaso-

vagal reactions

Pallor, body temperature alterations, edema, local pain, mild warmth and

edema, inflammation and tissue injury in case of extravasation

a Intravascular use only

Frequency estimates are based on data obtained in

pre-marketing studies in more than 3,900 patients

and post-marketing studies in more than 74,000 pa-

tients, as well as data from spontaneous reporting

and the literature. (Frequency estimations are based

predominantly on intravascular use.)

Based on experience with other non-ionic contrast

media, the following undesirable effects may occur

with intrathecal use in addition to the undesirable

effects listed above.

34

Ultravist.indd 34 16.09.2009 14:04:48

The majority of the reactions after myelography

or use in body cavities occur some hours after the

administration.

ERCP:

In addition to the undesirable effects listed above,

the following undesirable effects may occur with

use for ERCP: Elevation of pancreatic enzyme levels

(common), pancreatitis (rare).

Contrast Nephropathy – a Concern in Renally Impaired PatientsThe application of iodinated contrast media can lead

to dramatic renal complications, such as acute renal

failure manifest by tripling of serum creatinine or

necessitating dialysis in renally impaired, multimorbid

patients, which was noted in a number of case reports

as early as the 1970s and 1980s. (Adornato 1976,

Cohen 1978, Kaur 1982, Gregory 1984) Since then this

topic has been subject of intense scientific research.

Pathogenesis of Contrast NephropathyThe pathogenesis of contrast nephropathy is not fully

understood although the underlying mechanism is

very simple. Iodinated contrast agents are almost

exclusively eliminated via the kidney. Because contrast

material is usually administered in considerable

doses, the extra workload on the kidney – while being

no problem in a healthy kidney – may cause further

damage in cases of renal impairment and consider-

ably worsen the renal function status of the patient.

Several characteristics of contrast media have been

linked to contrast nephropathy such as the chemotox-

icity of the substance (a key concern in case of the first

generation ionic monomers, high osmolar contrast

media [HOCM]) and the physico-chemical properties of

osmolality and viscosity. (Persson 2005) The osmolality

is unlikely to be of concern for modern contrast media

regarding renal tolerance simply due to the fact that

the osmolality in the kidney, especially in the area at

risk (i.e. the outer stripe of the medulla) is of the same

order of magnitude (i.e. between 400–600 and up to a

maximum of 1,200 mOsm/kg H2O) as the osmolality

of the contrast agents (Ultra vist® 300/370: 610/770

mOsm/kg H2O). (Persson 2005) The viscosity of the

contrast material, on the other hand, is likely to be of

key relevance for renal tolerance. Two mechanisms

have been proposed: The first is a vascular effect in

the renal vessels, where the blood flow is slowed due

to the viscous contrast medium leading to reduced

oxygenation and thus to hypoxia and eventually renal

damage, while the second effect is a tubular effect. The

renal tubuli get congested in the course of the urine

concentration, as it leads to an exponential increase of

viscosity. The resulting pressure rise leads to a slow-

down or stop of glomerular filtration leading to renal

damage. (Persson 2005)

Additional undesirable effects in intravascular use:

System organ class Common(≥1/100)

Uncommon (≥1/1,000,<1/100)

Rare (<1/1,000)

Nervous, psychiatric Neuralgia, meningism Paraplegia, psychosis, aseptic

meningitis, EEG-changes

Gerneral disorders and admin-

istration site conditions

Headache, including severe prolonged

cases, nausea, vomiting

Micturition difficulties Back pain, pain in extremities,

injection site pain

35

Ultravist.indd 35 16.09.2009 14:04:48

The Choice of Modern Contrast Agents – the Case for Non-ionic MonomersNon-ionic monomers such as Ultravist®, also called

low-osmolar contrast media (LOCM)1, possess both a

low osmolality and a low viscosity in contrast to the

first generation ionic monomers, which are character-

ized by a very high osmolality. However, they also differ

from the iso-osmolar non-ionic dimers (IOCMs), such as

iodixanol, which possess a considerably higher viscosity

at similar iodine concentrations compared to the LOCM.

This is depicted in Figure 15 showing the osmolality and

viscosity of all available contrast classes at 37°C for a

concentration of 300 or 320 mg I/mL. Both the HOCM

and the IOCM have an outlier position for either osmo-

lality or viscosity compared to the physiological values.

The gap between the LOCM and the IOCM class is further

1 This argumentation applies in principle also to the ionic dimers (ioxaglate), which

belong to the class of the LOCMs.

widened in-vivo by the osmodiuretic effect. For LOCMs,

the residual hyperosmolality brings down viscosity and

osmolality in-vivo by the osmodiuretic effect, while this

effect is almost negligible in case of iso-osmolar CM as

they possess an osmolality similar to blood osmolality.

The osmodiuretic effect of the LOCM and the lack of this

effect in case of IOCM has been shown both preclini-

cally and clinically. (Nauert 1989, Stacul 2003) Thus the

viscosity of IOCMs will stay high in-vivo, leading to a

pronounced prolonged kidney retention of iodixanol

compared to Ultravist® seen in preclinical studies. ( Jost

2009) As the cytotoxic potential of non-ionic monomers

and dimers is similar at equal iodine concentration

(Heinrich 2005), it is easy to understand that the bulk of

the preclinical evidence points to lower renal tolerance

of IOCM compared to LOCM. In patients at risk this may,

however, be of minor relevance if accepted prophylactic

measures are adhered to.

Figure 15: X-ray CM classes differ in osmolality and viscosity.

36

Ultravist.indd 36 16.09.2009 14:04:49

Clinical Evidence – Severely Hampered by the Chosen Surrogate MarkerSeveral pharmacological strategies have been hypo-

thesized to be of potential value for the prophy-

laxis of contrast nephropathy, such as supplementing

N-Acetylcysteine, using a sodium bicarbonate hydration

instead of saline hydration or the use of IOCM instead of

LOCM. (Barrett 2006) A sound clinical trial to prove the

value of such a strategy would have to employ ad equate

numbers of patients and use hard clinical outcomes

such as clinically evident renal failure or need for

dialysis in order to demonstrate the medical benefit of

switching to that strategy. Fortunately, the incidence of

these patient outcomes for the general population (even

those with mild or moderately impaired renal function)

is rather low. Patients with severe renal impairment (GFR

<30 mL/min) are only a very small subset of the patients

undergoing contrast procedures. This renders enroll-

ment of such patients into clinical trials rather difficult.

To circumvent these challenges, the use of a surrogate

endpoint for renal damage has become widespread in

clinical trials on contrast nephropathy. The most pop-

ular surrogate marker is a change in serum creatinine.

A typical event in such a trial, which is then termed

“CIN” (“contrast-induced nephropathy”) is an increase in

serum creatinine of >25% over baseline within 3 days of

contrast application. (Thomsen 2006b) Unfortunately, it

has neither been shown that such transient creatinine

increases are really specific for contrast nephropathy

nor that such transient increases are a meaningful

marker for adverse clinical consequences. Recently,

this surrogate marker has been severely criticized:

Newhouse et al. have demonstrated that hospitalized

patients who do not receive contrast media experience

similar rates of creatinine rises as measured in typical

“CIN”-trials. (Newhouse 2008) This may be related to the

intake of nephrotoxic drugs, but might simply reflect

other factors not related to glomerular filtration which

influence serum creatinine levels (such as diet, volume

intake, infections, etc.). The unreliability of the surro-

gate markers may serve as an explanation for certain

variations in the results of clinical trials testing the

same hypothesis, especially in the setting of coronary

intervention, where the number of possible confound-

ing factors for creatinine rises are higher than compared

to the pure IV imaging setting. Notwithstanding these

limitations, the emerging data on the hypo thesis gener-

ated by the NEPHRIC study that IOCMs might have a

better renal tolerability than LOCMs, show both in the

coronary intervention setting and in the IV imaging

setting that there are at least no significant differences

in the incidence of creatinine rises for IOCM and LOCM

in patients with moderately impaired renal function for

LOCM compared to IOCM (Tables 14 and 15). Thus, the

NEPHRIC-generated hypothesis is most likely not cor-

rect. Data on hard clinical outcome are not as plentiful,

but give the most consistent picture. There is no data for

a superiority of IOCM over LOCM. On the contrary, the

largest study, the Swedish registry analysis, with over

55,000 patients, found a significantly higher rate of

renal failure after iodixanol-enhanced PCI (percutaneous

coronary intervention) as compared to PCI with a LOCM

(Table 16). (Liss 2006)

37

Ultravist.indd 37 16.09.2009 14:04:50

Outcomes Favoring IOCM Outcomes Neutral or Favoring LOCM

Multi-center randomized controlled study with surrogate endpoints

NEPHRIC (Iohexol) (n=129) (NEJM 03) CARE (Iopamidol) (n=414) (Circ. 07)

Chalmers and Jackson (Iohexol) (n=102) (BJR 99)

CONTRAST (Iomeron) (n=325) (Abstr ACC 08)

ICON (Ioxaglate) (n=145) (JACC O9)

Juergens et al. (Iopromide) (n=191) (InternMedJ 09)

VALOR (Ioversol) (n=259) (AHJ 08)

Single-center randomized controlled study with surrogate endpoints

Nie et al. (Iopromide) (n=208) (CathCardInt 08)

RECOVER (n=275) (Ioxaglate) (JACC 06)

Feldkamp et al. (Iopromide) (n=221) (ClinNephr 06) (low risk)

Other methodology

McCullough et al. Meta-analysis of GEHC trial database (IA/IV, LOCM)

(n=2,727) (JACC 07)

Swedish registry study (Ioxaglate, Iohexol) (n>55,000) (KidInt 06)

Uder meta-analysis (IV/IA, LOCM) (n=1842)(Radiology 08)

Solomon et al. Pooled analysis (IA/IV, LOCM) (n=1,365) (Kidney Int 05)

Table 14: Head-to-head comparisons on renal tolerance LOCM vs. IOCM in risk patients (Coronary Intervention).

Outcomes Favoring IOCM Outcomes Neutral or Favoring LOCM

Multi-center randomized blinded controlled study with surrogate endpoints

PREDICT (Iopamidol) (n=248) (AJR 08)

ACTIVE (Iomeron) (n=148) (InvRad 08)

IMPACT (Iopamidol) (n=135) (InvRad 07)

Single-center randomized blinded controlled study with surrogate endpoints

Nguyen et al. (Iopromide) (n=117) (Radiology 08) Carraro et al. (Iopromide) (n=64) (EurRad 98)

Other methodology

Uder meta-analysis (IA/IV LOCM) (n=1842) (Radiology 08)

From et al. Case matching (Iohexol) (n=794) (Acta Radiol 08)

Table 15: Head-to-head comparisons on renal tolerance LOCM vs. IOCM in risk patients (IV imaging).

Outcomes Favoring IOCM Outcomes Neutral or Favoring LOCM

Multi-center randomized controlled studies

PREDICT (IV, Iopamidol) (n=248) (AJR 08)

CARE (IA, Iopamidol) (n=414) (Circ. 07)

RECOVER (n=275) (IA, Ioxaglate) (JACC 07)

COURT (n=815) (IA, Ioxaglate) (Circulation 00)

Single-center randomized controlled studies

CONTRAST (IA, Iomeron) (n=325) (Abstr ACC 08)

RECOVER (n=275) (IA, Ixoglate) (JACC 07)

Registry studies

From et al. Case matching (IV, Iohexol) (n=794) (Acta Radiol 08)

Swedish registry study (IA, Ioxaglate, Iohexol) (n>55,000) (KidInt 06)

Table 16: Head-to-head comparisons on renal tolerance LOCM vs. IOCM (hard clinical endpoints).

38

Ultravist.indd 38 16.09.2009 14:04:50

Prophylaxis of Contrast NephropathyThere is a fundamental consensus about key aspects of

CIN prophylaxis. (Thomsen 2006a, Solomon 2006) The

most immediate task is to identify the patients at risk.

The key risk factor is the degree to which the patient’s

renal function is impaired. This is usually done by as-

sessing serum creatinine levels, which are converted

into eGFR values using equations like the MDRD (Modi-

fication of Diet in Renal Disease) formula. However,

it is not certain, what a meaningful GFR cut-off level

is. Recent large scale clinical trials both in coronary

intervention and in IV imaging suggest that the risk of

contrast nephropathy in the patients with moderately

impaired renal function even in the presence of diabe-

tes mellitus (GFR: 30–60 mL/min) is relatively low. The

threshold for defining high risk most probably starts

for patients with a GFR below 30 mL/min. Other risk

factors such as hypertension, heart failure, myeloma

and treatment with nephrotoxic drugs also need to be

considered. In the event of multiple risk factors, a care-

ful risk-benefit analysis must be performed.

If a contrast-enhanced procedure is warranted,

patients should be in an optimal volume status at

the time of exposure to the contrast. Although there

is no consensus as to how “optimal volume sta-

tus” is defined, dehydration is a clear risk factor for

contrast nephropathy, and hydration is thus the key

prophylactic measure. To minimize the risk, patients

should be encouraged to drink water liberally during

the 12 h before receiving the contrast medium. In

hospitalized patient settings, i.v. volume expansion

prior to contrast exposure should be considered,

however, the specific degree of volume expansion

will depend on individual patient characteristics.

Low-osmolality contrast media should be used in

all patients – in other words, high-osmolar, ionic

CM should be avoided. The volume of contrast

media, particularly for high-risk patients, should

be the minimum amount needed for diagnosis and

intervention. Drugs with an adverse affect on renal

function should be withheld prior to and imme-

diately after contrast exposure, provided that this

does not place the patient at an increased risk.

Summarizing the recommendations, it is fair to say

that unfortunately there is no easy recipe to prevent

contrast nephropathy. However, there is a set of meas -

ures which when adapted by the physician according

to the individual patient’s needs will reduce the like-

lihood of the occurrence of contrast nephropathy.

Other Adverse Effects** Please refer to your local PI for details.

Patients receiving iodinated intravascular contrast

agents should be instructed to:

1. Inform their physician if they are pregnant.

2. Inform their physician if they are diabetic or if

they have multiple myeloma, pheochromocy-

toma, homozygous sickle cell disease or known

thyroid disorder.

3. Inform their physician if they are allergic to any

drugs or food, or if they have immune or auto-

immune deficiency disorders. Also inform their

physician if they had any reactions to previous

injections of dyes used for X-ray procedures.

4. Inform their physician about all medications

they are currently taking, including non-pre-

scription (over-the-counter) drugs, before they

have this procedure.

39

Ultravist.indd 39 16.09.2009 14:04:50

Chemistry and Pharmaceutics

Trade Name: Ultravist®

INN Name: Iopromide

IUPAC Name: 5-methoxyacetylamino-2,4,6-

triiodoisophthalic acid-[(2,3-dihydroxy-N-

methylpropyl)-(2,3-di hydroxypropyl)] diamide

Molecular Formula: C18H24I3N3O8

Molecular Weight: 91.12

Iodine Content: 48.1%

Figure 16: Structural formula. (Krause 1994b)

Ultravist® 150 240 300 370

Iopromide 31.2 49.9 62.3 76.9

CaNa2EDTA (stabilizer) 0.01 0.01 0.01 0.01

Tromethamine (buffer) 0.242 0.242 0.242 0.242

Water for injection – ad 100 mL –

Table 17: Composition of Ultravist® formulations (in mg I/mL).

Physicochemistry

Ultravist® 150 240 300 370

Osmolality

(mOsm/kg H2O)

at 37°C 328 483 586 773

Viscosity (mPa*s) at 37°C 1.5 2.8 4.7 10.0

at 20°C 2.3 4.9 8.9 22.0

Hydrophilicity at 20°C 2.3 4.9 8.9 22.0

(partition coefficient butanol/water pH 7.6) 0.149

Density (g/mL) at 37°C 1.158 1.255 1.322 1.399

at 20°C 1.164 1.263 1.328 1.409

pH adjusted to 7.4 (6.5–8.0)

Table 18: Ultravist® physicochemical data. (Krause 1994a)

The ideal contrast medium should be totally inert,

so that it does not interact with the organism at any

level (Krause 1994a), while generating an additional

contrast during the imaging procedure. The iodine

concentration determines the amount of “contrast

generating substance” of the solution, while the fol-

lowing parameters determine the physicochemical

profile of the product: electrical charge, osmolality,

viscosity, lipophilicity, hydrophilicity, and a factor

termed “chemotoxicity”, because it could not be

ascribed to any other physicochemical parameter.

(Krause 1994a) All these characterics are interrelated.

(Krause 1994a) The key parameters will be described

briefly in the following sections.

Electrical ChargeIts non-ionic structure prevents iopromide from

interacting electrically with other molecules, no

matter to natural origin or intravasal drugs. Bind-

ing to electrically charged proteins or membrane

constituents is reduced just as much as interference

with electrolytes. Iopromide does not bind ionic

calcium. (Krause 1994b)

The absence of an electrical charge in the iopromide

molecule gives Ultravist® (just as other non-ionic

iodinated contrast agents) substantial advantages

over ionic contrast agents.

OsmolalityOsmolality has been viewed as a key parameter

during the development of iodinated contrast

media. (Krause 1994a) Figure 17 shows the result of

a comprehensive investigation of the osmolalities

of various contrast media including at least one

representative from each major class. (Krause 1994a)

It should be noted that comparison of osmolality

40

Ultravist.indd 40 16.09.2009 14:04:50

data from different studies should be done with

a degree of caution as the absolute values may

differ somewhat, e. g. the value for Ultravist® 300

obtained by Krause et al. is 586 ± 5 mOsm/kg H2O,

(Krause 1994a) while an earlier study obtained a

value of 607 ± 7 mOsm/kg H2O. (Miklautz 1989)

Both the so-called high-osmolar contrast media

(HOCM), such as diatrizoate, as well as the so-called

low-osmolar contrast media (LOCM), such as Ultra-

vist® are hyperosmolar to blood (blood osmolality:

~ 290 mOsm/kg H2O), however to a significantly

varying degree. The osmolality of the HOCM is 5–7

times higher than the osmolality of blood, while

the LOCM class exhibits an osmolality of about 2–3

times that of blood (compare Figure 15). The class of

the so-called iso-osmolar agents (IOCM) (represented

in Figure 17 by iotrolan) is iso-osmolar to blood.

However, the fact that the LOCM are moderately hy-

perosmolar to blood leads to the effect of osmodilu-

tion in-vivo bringing down osmolality and viscosity

in-vivo, a mechanism which is by definition absent in

IOCM. The osmodilution and eventually the osmo-

diuretic effect can have a variety of consequences

both influencing the imaging properties of LOCM in

comparison to IOCM (Stacul 2003), but being also

potentially of relevance for the renal tolerance of

contrast media (please refer to chapter on renal

tolerance, p. 37).

Osmolality is a key factor for local tolerance, espe-

cially at the injection site. Studies indicate a pain

threshold at 600 mOsm/kg H2O. X-ray contrast agents

with an osmolality of <600 mOsm/kg H2O produce

less frequent and less intense local pain than prepa-

rations with higher osmolality. (Speck 1980, Hagen

1983a, b) There is strong evidence that HOCM are sig-

nificantly inferior to LOCM regarding local tolerance.

(Katayama 1990) There is some evidence that IOCM

have an additional advantage over LOCM regarding

local tolerance. (Verow 1995, Justesen 1997)

X-ray contrast media at concentrations hypertonic

to blood are known to cause a variety of osmolality-

related adverse effects (such as bradycardia, a rise in

pulmonary arterial pressure or dyselectrolytemia).

(Krause 1994b)

Diatrizoate306

Ioversol

Ioxaglate320

Iopamidol

Iotrolan

Ultravist®

Iohexol

Iopentol

1502±16

683±4

667±8

661±3

584±10

640±6

294±3

586±5

0 200 400 600 800 1000 1200 1400 1600

(mOsm/kg H2O)

Osmolality

Figure 17: Comprehensive investigation of osmolalities of key

iodinated contrast media at 37°C. Iodine concentration

300 mg I/mL, except if indicated otherwise. (Krause 1994a)

41

Ultravist.indd 41 16.09.2009 14:04:51

ViscosityThe viscosity of a contrast medium is the other

key physicochemical property. It is, for instance, of

considerable practical importance. When thin-bore

needles, cannulas and catheters are used, solutions

of high viscosity can only be administered with

considerable effort. Similarly, when fast application

is needed, manual injection may become nearly

impossible. On the other hand, power injection is

prone to the risk of catheter damage and tissue

traumatization.

Thus, the low-viscous preparations of Ultravist® are

particularly advantageous for both thin-wall nar-

row gauge catheters and fast intravasal injection.

Worldwide, radiologists prefer small-bore catheters

(F4 and less) not only for selective angiographies,

but also for survey exams, e.g. of the abdomen, the

pelvis and the lower extremities.

Using iopromide for manual injection, a signifi-

cantly higher iodine delivery rate and concomitant

opacification of the vessels can be produced com-

pared to more viscous preparations. (Hughes 1991)

Prewarming contrast agents to 37°C further de-

creases viscosity, facilitates injection, and improves

patient comfort. Figure 17 shows the result of a com-

prehensive investigation of the viscosities of various

contrast media including at least one representative

from each major class. (Krause 1994a) While the

viscosities of LOCM and HOCM are in the same range,

the IOCM have significantly higher viscosities at

similar iodine concentrations compared to the LOCM

(compare Figures 15 and 18).

With increasing iodine concentration the osmolality

and viscosity of Ultravist®, just as any other LOCM,

increases (compare Table 18).

0 2 4 6 8 10 12 14 16mPa*s

18

Ultravist®4.7 ± 0.1

8.9 ± 0.1

Iohexol5.7 ± 0.1

10.9 ± 0.2

Iopamidol4.5 ± 0.0

8.4 ± 0.1

Diatrizioate306

4.9 ± 0.0

9.3 ± 0.1

Iopentol6.5 ± 0.1

12.9 ± 0.2

Ioversol5.2 ± 0.6

10.1 ± 1.2

Iotrolan8.5 ± 0.0

17.5 ± 0.0

Ioxaglate320

7.8 ± 0.4

16.2 ± 1.0

37°C 20°C

Figure 18: Comprehensive investigation of viscosities of key

iodinated contrast media at 37°C and 20°C. Iodine concen-

tration 300 mg I/mL, except if indicated otherwise. (Krause

1994a)

ChemotoxicityGiven the high doses of contrast media necessary

for angiographic or CT procedures, the tolerance of

these agents surpasses that of most other com-

42

Ultravist.indd 42 16.09.2009 14:04:51

pounds used in medicine. However, the frequency

and severity of adverse events is not exclusively

determined by the electric charge, the osmolality

and the lipophilicity. Many side-effects have mecha-

nisms of action that are as yet not fully understood.

The underlying pharmacologic interactions are

summarized under chemotoxicity, a term that is

specifically related to the molecular structure of the

compounds. Chemotoxicity is considered to be at

least partially responsible for many of the substan-

tially different side-effects. (Krause 1994b)

Ecochemistry Iodinated X-ray contrast media are pharmaceu-

ticals which are biologically inert and metaboli-

cally stable during the passage through the body

and excreted almost completely within a day into

waste water. They are not readily biodegradable.

However, in a test system simulating sewage treat-

ment, iopromide was found amenable to primary

degradation. The resulting product (5-amino-N´N´-

bis (2,3-dihydroxypropyl)-2,4,6-triiodo-N-methyl-

isophthalamide) displayed a faster photolysis than

the parent compound and was further degraded

in a test system simulating surface water condi-

tions. Toxicity of the degradation products was low.

(Steger-Hartmann 1999, Steger-Hartmann 2002)

Furthermore, the expected behavior of iopromide

in the environment was tested with systems with

activated sludge, river water and river water plus

sediment. (Kalsch 1999) In activated sludge, approx-

imately 85% of iopromide was transformed into two

metabolites. Like the parent molecule, these were

highly hydrophilic and less than 16% were bound to

sludge solids. In water/sediment systems, disap-

pearance of iopromide started spontaneously with a

first order constant of 0.04 per day. In river water the

shortest half-life was 3.1 days (at a concentration of

16.0 mmol/L) and increased at concentrations above

and below that value. Only traces of iopromide were

identified in surface water after bank filtration.

(Putschew 2000)

The available information on the environmental

fate and effects of iopromide and its degradation

products do not provide evidence of risk for aquatic

life caused by the introduction of the contrast me-

dium into waste water.

43

Ultravist.indd 43 16.09.2009 14:04:51

Pharmacology and Toxicology

The pharmacologic and toxicologic characteristics

of iopromide and its pharmacokinetic properties

were evaluated in numerous preclinical trials. The

investigations included in vitro studies such as the

determination of protein binding, interaction with

other drugs, platelet aggregation and the release

of histamine, as well as in vivo tests in rats, rabbits

and dogs. The animal experiments shed light on the

organ-related tolerance of iopromide and its toxi-

cologic features.

Pharmacokinetics The pharmacokinetics of iopromide are similar

to those of other non-ionic monomeric contrast

agents. Iopromide remains almost completely in the

extracellular space and is excreted in unaltered form

almost exclusively via the kidneys with a half-life of

about two hours in men. (Krause 1994c)

Experiments in Animals The pharmacokinetic properties of iopromide were

studied in rats and dogs. (Mützel 1983a) Using 125-I-

labeled iopromide, it could be shown that more than

90% of the dose was excreted via the kidneys. In rats,

the terminal elimination half-life in blood and urine

was approximately 17 minutes. Recovery of radio-

labeled drugs after 24 hours was 84% in urine, 10%

in feces, and 2% in the carcass. In dogs, the terminal

half-life was 50 minutes. Within 7 days, 94% of the

dose was recovered from urine and 2% from feces.

Metabolization of iopromide could be demonstrated

neither for rats nor for dogs. Biodistribution was

studied by autoradiography of pregnant rats.

Iopromide was quickly distributed in the body, with

the kidneys exhibiting the highest concentrations

of the drug. Passage of radioactivity across the

blood-brain barrier or placental barriers could not

be demonstrated clearly. Any specific or long-lasting

retention of radioactivity could be excluded, except

for the thyroid gland. (Mützel 1983a–d, Mützel 1987)

After oral or intraduodenal administration only 2%

of the dose is absorbed, as shown by experiments in

rats receiving 125I-labeled iopromide. (Mützel 1987)

Enterohepatic circulation is negligibly small. (Krause

1994e)

Human Studies A single-blinded, randomized, placebo-controlled

crossover study demonstrated clearly that iopromide

is distributed in the human body exclusively in the

intravascular space and interstitium. The PK param-

eter obtained in this study for the lower tested dose

of 15 g iodine were an AUC of 2.26 mg h/ml (SD=2.3),

a total clearance of 110 ml/min, and a recovery of

97.7%. In all tested concentrations, the compound

did not significantly penetrate into cells. Iopromide

is almost completely excreted via glomerular filtra-

tion. Only a negligible amount of the compound

is eliminated with the feces. The total clearance of

iopromide equals its renal clearance. (Krause 1994c)

InteractionsMany ionic and some non-ionic contrast media are

known to interact with various intravascular phar-

macologic agents and to form transient or persis-

tent precipitates. Thus, an at least theoretical risk of

vessel occlusion arises.

44

Ultravist.indd 44 16.09.2009 14:04:51

For iopromide, less interactions were observed in a

comparative study in comparison to ionic contrast

media, presumably due to its non-ionic nature. Table

19 summarizes the data. (Krause 1996)

Pharmaceutical Diatrizoate Ioxaglate Iopromide

Cimetidine-HCI – + –

Diazepam + – –

Diphenhydramine-HCI + + –

Gentamycin sulfate – + –

Meperidine-HCI + – +

Papaverine-HCI + + –

Phentolaminemesylate + + –

Protamine sulfate + + –

Tolazoline-HCI – – –

Table 19: Interactions of frequently used intravascular

drugs with contrast media. (Adapted from Krause 1996)

Biochemical DataA number of biochemical reactions are considered to

be more or less closely related to the general toler-

ance of an X-ray contrast agent.

Protein BindingProtein binding points to the ability of a substance

to interact with biologic components. Generally, a

rate of protein binding below 5% is considered a pre-

requisite for modern X-ray contrast media. (Krause

1994b)

In a large comparative study, iopromide was found

to exhibit negligible protein binding with a value

below 1% (0.9 ± 0.6). (Krause 1996)

Lysozyme InhibitionThe lysozyme inhibition test is an established

method to evaluate the potential of a compound for

interfering with macromolecules, e.g. enzymes.

The IC50 values recorded for iopromide in a compara-

tive study were identical with those found for other

non-ionic contrast media. When inhibition was

measured as a percentage at a contrast medium

concentration of 150 mg I/mL, again similar values

were measured for the non-ionic agents, whereas

diatrizoate produced complete inhibition of the

enzyme. (Krause 1996)

Acetylcholinesterase InhibitionCholinergic mechanisms may play a role in many

of the allergy-like side-effects of contrast agents.

Acetylcholinesterase inhibition is thought to be

responsible for adverse events such as vasodilata-

tion, bronchospasm, urticaria and gastrointestinal

symptoms.

45

Ultravist.indd 45 16.09.2009 14:04:51

Iopamidol

Diatrizoate

Ioxaglate

Iohexol

Iopentol

Iodixanol

Ultravist®

Iotrolan

Ioversol

Iomeprol

9.8 ± 1.4

77.5 ± 7.0

9.1 ± 2.3

11.7 ± 1.6

6.7 ± 2.8

5.4 ± 3.5

2.7 ± 0.5

1.3 ± 1.2

3.4 ± 1.0

3.0 ± 0.6

Histamine Release (100 mg I/mL)*

0 10 20 30 40 50 60 70 80

* Tested concentrations between 30 and 150 mg I/mL

Figure 19: Comprehensive investigation of histamine

release of key iodinated contrast media. (Krause 1996)

When iopromide and iopamidol were compared in

concentrations from 0 to 40 mg I/mL with respect to

acetylcholin-esterase inhibition, a dose-dependent

effect was demonstrable, reaching approximately

15% inhibition with both compounds at the highest

concentrations. (Krause 1994b)

Urokinase InhibitionUrokinase inhibition is another test to evaluate a

contrast agent’s potential to interact with macro-

molecules.

When several contrast media were tested for

urokinase inhibition, the ionic agents proved to be

considerably more effective than the non-ionic ones.

The values recorded for iopromide were similar to

those of other non-ionic monomers. (Krause 1996)

Interaction with the Complement SystemComplement activation is one of the established

laboratory indicators for a contrast agent’s capabil-

ity to induce anaphylactoid reactions.

Complement activation was determined in fresh hu-

man plasma as remaining complement activity after

incubation with various contrast media. It could be

demonstrated only at very high concentrations. No

significant differences between the tested agents

were detectable. (Krause 1994b)

The decrease in complement observed clinically is

low and remains within the range caused by hemo-

dilution. (Pinet 1988)

Histamine ReleaseHistamine release from mast cells is suspected to be

an important mechanism for severe adverse effects

observed after the administration of contrast media.

The effects can range from harmless cutaneous

reactions to life-threatening anaphylactoid shock.

(Schoebel 1994)

46

Ultravist.indd 46 16.09.2009 14:04:51

In an in vitro study, mast cells from the peritoneal

fluid of rats were incubated in buffer containing

increasing amounts of contrast agent. The amount

of histamine released from the cells was determined.

Iopromide 150 mg I/mL released approximately 7% of

the maximum amount of histamine. (Mützel 1983c)

Iopromide also released a small quantity of (4–6%)

histamine from canine mast cells obtained from

lung and liver. (Ennis 1989)

In a comparative study, iohexol and iopromide

were found to exhibit the lowest rates of histamine

release of all non-ionic monomeric contrast agents

tested (Figure 19). The amount of histamine release

was dose-dependent. (Krause 1996)

ToxicologyAcute and chronic toxicity of iopromide as well as its

reproductive toxicity and genotoxic potential have

been extensively studied in different species. There is

no risk of acute intoxication by use of iopromide in the

usual clinical setting at the approved dosages. Even

after repeated administration of high doses no toxic

organ lesions were observed. Likewise, no evidence

exists for a genotoxic, cytotoxic, or growth-promoting

potential of Ultravist®.

Systemic Tolerance on Single AdministrationThe acute toxicity of iopromide and other contrast

agents was determined in various species after

single intravenous injection. (Krause 1994b)

In rats, the acute LD50 of Ultravist® 300 was 12 g

iodine per kg body weight. This value compares fa-

vorably with those of iohexol (12 g I/kg), iopamidol

(11 g I/kg), iopentol (11 g I/kg) and ioversol (10 g I/

kg). In mice, the LD50 of the same preparation was

16.5 g I/kg. (Hughes 1991)

Systemic Tolerance on Repeated AdministrationSystemic tolerance of Ultravist® was studied in rats

and dogs. (Krause 1994d, e, f) The substance was

given using the intravenous route at doses up to

3.7 g I/kg per day for a total of four weeks. Even after

administration of the highest dose, no gross organic

damage was observed. The experiments revealed

only slight changes of the blood cell count, and in

animals having received the maximum dosage, an

increase in kidney weight and total cholesterol. Some

dogs vomited and consumed more water after doses

from 1.1 g I/kg onwards. Additionally vacuolization

of epithelial cells of the proximal tubules (in dogs)

and of hepatocytes (in rats) was observed. But these

morphologic lesions did not lead to functional conse-

quences. Moreover, these alterations are reversible.

Reproductive ToxicityReproductive toxicity studies with iopromide were per-

formed up to dose levels of 3.7 g I/kg/day in rats and

rabbits. (Krause 1994f) For that purpose, the substance

was administered intravenously (to test embryo-

toxicity) as well as intraperitoneally (to test fertility).

In the animals studied for embryotoxicity, neither em-

bryolethal nor teratogenic effects could be observed.

Maternal toxicity became apparent only at the high

dose by a reduction in body weight. Concomitantly,

the incidence of fetuses with supernumerary ribs was

47

Ultravist.indd 47 16.09.2009 14:04:52

increased. A slightly retarded ossification of head

bones was observed at all dose levels.

A series of embryotoxicity studies with similar de-

sign was carried out in rabbits to clarify the some-

what equivocal findings from the initial research.

Here, moderate to marked maternal toxicity and/or

mortality was observed at the dose of 3.7 g I/kg/day.

A slightly increased incidence of fetuses with abnor-

mal posture of limbs was recorded at the intermedi-

ate and high doses. Additionally, a slightly delayed

ossification at the intermediate dose and signs of a

slight developmental retardation at the high dose

became evident in one of the studies. In another ex-

periment, embryolethality was recorded at the high

dose along with increased morbidity and mortality

of the mother. In the fertility study performed with

rats, there was no sign of impairment at any dose

level.

Genotoxic PotentialThe genotoxic and mutagenic potential of iopro-

mide was examined by means of bacterial cell as-

says and in vivo tests using somatic and germ cells.

Not a single assay revealed gene, chromosomal or

genome mutations. (Krause 1994f)

48

Ultravist.indd 48 16.09.2009 14:04:52

Abbreviations Used in the Text

AAA Abdominal aortic aneurysm

AV (block) Atrioventricular

CIN Contrast-induced nephropathy

CM Contrast media

CT Computed tomography

CTA Computed tomography angiography

DSA Digital subtraction angiography

DSCT Dual-source computed tomography

ECG Electrocardiogram

EEG Electroencephalography

eGFR Estimated glomerular filtration rate

ERCP Endoscopic retrograde cholangio-

pancreatography

ESUR European Society of Urogenital

Radiology

FDA Food and Drug Administration

GFR Glomerular filtration rate

GI Gastrointestinal

HOCM High-osmolar contrast media

HSG Hysterosalpingography

HU Hounsfield unit

IDR Iodine delivery rate

IOCM Iso-osmolar contrast media

IVU Intravenous urography

LAD Left anterior descending artery

LOCM Low-osmolar contrast media

MCA Medium cerebral artery

MDRD formula Modification of Diet in Renal

Disease formula

MIP Maximum intensity projection

MDCT Multidetector computed tomography

MDCTA Multidetector computed tomogra-

phy angio graphy

MRI Magnetic resonance imaging

PMS Post-marketing surveillance

PTA Percutaneous transluminal angio-

plasty

PTCA Percutaneous transluminal coro-

nary angioplasty

SFA Superficial femoral artery

SMA Superior mesenteric artery

US Ultrasound

XR X-ray

49

Ultravist.indd 49 16.09.2009 14:04:52

References

Achenbach S, Kuettner A, Ropers D: Cardiac Coronary CT

Angiography. In: Seidensticker PR, Hofmann LK (eds). Dual

Source CT Imaging. Springer 2008

Adornato B, Winestock D: Acute renal failure. A complica-

tion of cerebral angiography. Arch Neurol 1976;33:687–688

Balzer JO, Seifried C, Herzog C, Thalhammer C, Pira A, Vogl TJ:

Evaluation of PAOD of the thigh and limb with multislice CT

angiography (MS-CTA). Radiology 2001;221(P):454–455

Barber PA, Auer RN, Buchan AM, Sutherland GR: Under-

standing and managing ischemic stroke. Can J Physiol Phar-

macol 2001;79(3):283–96

Barrett BJ, Parfrey PS: Clinical practice. Preventing

nephropathy induced by contrast medium. N Engl J Med

2006;354:379–386

Becker CR, Knez A, Leber A, Treede H, Ohnesorge B, Schoepf

UJ, Reiser MF: Detection of Coronary Artery Stenoses With

Multislice Helical CT Angiography. JCAT 2002;26:750–755

Behrendt FF, Mahnken AH, Keil S et al: Contrast enhance-

ment in multidetector-row computed tomography (MDCT) of

the abdomen. intraindividual comparison of contrast media

containing 300 mg versus 370 mg iodine per ml. Eur Radiol

2008a;18:1199–1205

Behrendt FF, Mahnken AH, Stanzel S et al: Intraindividual

comparison of contrast media concentrations for combined

abdominal and thoracic MDCT. Am J Roentgenol 2008b;

191:145–150

Bellin M-F, Jakobsen JÅ, Tomassin I, Thomsen HS, Morcos

SK and members of the Contrast Media Safety Committee

of the European Society of Urogenital Radiology (ESUR):

Contrast medium extravasation injury: guidelines for preven-

tion and management. Eur Radiol 2002;12:2807–2812

Ben Saad M, Rohnean A, Sigal-Cinqualbre A, Adler G,

Paul JF: Evaluation of image quality and radiation dose of

thoracic and coronary dual-source CT in 110 infants with

congenital heart disease. Pediatr Radiol 2009;39:668–676

Beresneva EA, Selina IE, Pakhomova GV, Lebedev AG,

Oranskii AV: Use of Ultravist to examine the gastrointestinal

tract in patients with emergency abdominal pathology. Vestn

Rentgenol Radiol 1997;3:51–52

Bergelson B, Bettmann MA, Wexler L, Wilson R, Dyet J:

Comparison of iopromide and iopamidol in coronary angiogra-

phy and left ventriculography. Invest Radiol 1994;29:107–111

Carraro M, Malalan F, Antonione R et al: Effects of a di-

meric vs a monomeric non-ionic contrast medium on renal

function in patients with mild to moderate renal insuffi-

ciency: a double-blind, randomized clinical trial. Eur Radiol

1998;8:144–147

Cohen M, Meyers AM, Milne FJ, Disler PB, van Blerk PJ:

Acute renal failure after use of radiographic contrast media.

S Afr Med J 1978;54:662–664

De Geeter P, Melchior H: Iomeprol versus iopromide for intra-

venous urography. Brit J Radiol 1994;67:958–963

50

Ultravist.indd 50 16.09.2009 14:04:52

Dembinski J, Arpe V, Kroll M, Hieronimi G, Bartmann P:

Thyroid function in very low birthweight infants after

intravenous administration of the iodinated contrast

medium iopromide. Arch Dis Child Fetal Neonatal Ed

2000;82:215–217

Dominik R, Keysser R, Taenzer V: Iopromide dosage and uro-

graphic image quality: Is there an optimal dose? In: Taenzer

V, Wende S (eds): Recent Developments in Non-ionic Contrast

Media. Thieme 1989;111–115

Eastwood JD, Provenzale JM, Hurwitz LM, Lee TY: Practi-

cal injection-rate CT perfusion imaging: deconvolution-

derived hemodynamics in a case of stroke. Neuroradiology

2001;43(3):223–226

Engeroff B, Kopka L, Harz C, Grabbe E: Impact of differ-

ent iodine concentrations on abdominal enhancement in

biphasic multislice helical CT (MS-CT). Fortschr Röntgenstr

2001;173:938–941

Engeroff B, Funke M, Grabbe EH: Optimization of arterial

enhancement in multi-slice CT angiography (MS-CTA) of the

entire aorta. Radiology 2002;225(P)Suppl:Abstract No 476

Ennis M, Ammon EU, Lorenz W: Histamine release from

canine lung and liver mast cells induced by radiographic

contrast media. Agents Actions 1989;27:101–103

Goebel C, Hardt P, Doppl W, Temme H, Hackstein N, Klör

HU: Frequency of pancreatitis after endoscopic retrograde

cholangiopancreatography with iopromid or iotrolan: a

randomized trial: Eur Radiol 2000;10:677–680

Grandy M, Schoenberg SO, Bischof H, Corvinus C, Manegold

V, von Kaick G: Multislice CT of patients with stage IIIa bron-

chial carcinoma for monitoring of neoadjuvant chemothera-

py and presurgical evaluation. Eur Radiol 2001;11

(2 suppl):370

Gregory MC: Acute renal failure after percutaneous cholan-

giography. Arch Intern Med 1984;144:1288–1289

Groell R, Willfurth P, Schaffler GJ, Mayer R, Schmidt F, Ug-

gowitzer MM, Tillich M, Genser B: Contrast-Enhanced Spiral

CT of the Head and Neck: Comparison of Contrast Material

Injection Rates. AJNR Am J Neuroradiol 1999;20:1732–1736

Gronewaller EF, Wahl HG, Kehlbach R, Rodemann HP,

Claussen C, Duda SH: Stability of iodinated contrast media in

UV-laser irradiation and toxicity of the photoproducts. RöFo

1998;169:537–541

Hacke W, Kaste M, Skyhoj Olsen T, Orgogozo JM, Bogous-

slavsky J: European Stroke Initiative (EUSI) recommendations

for stroke management. The European Stroke Initiative Writ-

ing Committee. Eur J Neurol 2000;7(6):607–623

Hagen B, Klink G: Contrast media and pain: hypo thesis on

the genesis of pain occurring on intra-arterial administration

of contrast media. In: Taenzer V, Zeitler E (eds): Contrast Me-

dia in Urography, Angiography and Computerized Tomogra-

phy. Thieme 1983a;50–56

Hagen B, Siefert HM, Mützel W, Speck U: Increased pain

reactions as hang-over phenomena after intra-arterial injec-

tions of contrast media in rats. In: Taenzer V, Zeitler E (eds):

Contrast Media in Urography, Angiography and Computer-

ized Tomography. Thieme 1983b;57–61

51

Ultravist.indd 51 16.09.2009 14:04:53

Hallett RL, Fleischmann D: Tools of Trade for CTA: MDCT

Scanners and Contrast Medium Injection Protocols. Tech Vasc

Interv Radio 2006;9:134–142

Hanninen EL, Vogl TJ, Felfe R, Pegios W, Balzer J, Clauss W,

Felix R: Detection of focal liver lesions at biphasic spiral CT:

randomized double-blind study of the effect of iodine concen-

tration in contrast materials. Radiology 2000;216:403–409

Haughton VM, Papke RA, Hyland D, Drayer BP, Osborn AG,

Maravilla K, Hilal SK: Safety and efficacy of iopromide in

cerebral arteriography. Invest Radiol 1994;29:S94–S97

Heinrich MC, Kuhlmann MK, Grgic A, Heckmann M, Kra-

mann B, Uder M: Cytotoxic effects of ionic high-osmolar,

non-ionic monomeric, and non-ionic iso-osmolar dimeric

iodinated contrast media on renal tubular cells in vitro. Radi-

ology 2005;235:843–849

Herbe E, Spaetling L, Hoetzinger H, Jaspers V: Hysterosal-

pingography by means of digital subtraction. Arch Gynecol

Obstetrics 1989;245:446–447

Hughes PM, Bisset R: Non-ionic contrast media: a compari-

son of iodine delivery rates during manual injection angio-

graphy. Br J Radiol 1991;64:417–419

Johnson TR, Nikolaou K, Wintersperger BJ et al: Dual-

source CT cardiac imaging: initial experience. Eur Radiol

2006;16:1409–1415

Jost G, Pietsch H, Sommer J, Sandner P, Lengsfeld P, Seiden-

sticker P, Lehr S, Hutter J, Sieber MA: Retention of iodine and

expression of biomarkers for renal damage in the kidney after

application of iodinated contrast media in rats. Invest Radiol

2009;44:114–123

Ju YM, Kim MH, Lee SK, Seo DW, Min YI, Kim JY: Compara-

tive cytotoxicity of low-osmolar non-ionic and high-osmolar

ionic contrast media to dog gallbladder epithelial cells.

Gastrointest Endosc 2002;55:382–386

Justesen P, Downes M, Grynne BH, Lang H, Rasch W, and

Seim E: Injection-associated pain in femoral arteriography:

a European multicenter study comparing safety, tolerability,

and efficacy of iodixanol and iopromide. Cardiovasc Inter-

vent Radiol 1997;20:251–256

Kalsch W: Biodegradation of the iodinated X-ray con-

trast media diatrizoate and iopromide. Sci Total Environ

1999;225:143–153

Kamel IR, Kruskal JB, Pomfret EA, Keogan MT, Warmbrand

G, Raptopoulos V et al: Impact of multidetector CT on donor

selection and surgical planning before living adult right lobe

liver transplantation. AJR 2001;176:193–200

Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P,

Matsuura K: Adverse reactions to ionic and nonionic contrast

media. A report from the Japanese Committee on the Safety

of Contrast Media. Radiology 1990;175:621–628

Kaufmann HJ, Bassir C: What advantages do non-ionic con-

trast media have for pediatric patients? In: Dawson P, Clauß W

(eds): Contrast Media in Practice. Springer 1994;222–225

Kaur JS, Goldberg JP, Schrier RW: Acute renal failure fol-

lowing arteriography in a patient with polyarteritis nodosa.

JAMA 1982;247:833–834

52

Ultravist.indd 52 16.09.2009 14:04:53

Kavukcu S, Tavli V, Fadiloglu M, Akhunlar H, Oran B,

Akcoral A: Urinary enzyme changes in children undergoing

cineangiographic evaluation using iopromid. Int Urol

Nephrol 1995;27:131–135

Kim KJ, Ahn JH, Park T, Ahn HJ, Kim CS, Cho KS et al: Virtual

cystoscopy of the contrast material-filled bladder in patients

with gross hematuria. AJR 2002;179:763–768

Klingebiel R, Zimmer C, Rogalla P et al: Assessment of

the arteriovenous cerebrovascular system by multi-slice

CT. A single-bolus monophasic protocol. Acta Radiol

2001;42:560–562

Koehler A, Reimer P: Possibilities of diagnosis of the swal-

lowing act in cases of contrast medium aspiration. Akt Radiol

1993;3:356–359

König M, Klotz E, Luka B, Venderink DJ, Spittler JF, Heuser

L: Perfusion CT of the brain: diagnostic approach for early

detection of ischemic stroke. Radiology 1998;209(1):85–93

Kopp AF, Heuschmid M, Claussen CD et al: Multidetector

helical CT of the liver for tumor detection and characteriza-

tion. Eur Radiol 2002;12:745–752

Kopp AF, Mortele KJ, Cho YD, Palkowitsch P, Bettmann MA,

Claussen CD: Prevalence of acute reactions to iopromide:

postmarketing surveillance study of 74,717 patients. Acta

Radiol 2008;49:902–911

Krause W, Miklautz H, Kollenkirchen U, Heimann G: Physi-

cochemical parameters of X-ray contrast media. Invest Radiol

1994a;29:72–80

Krause W: Preclinical characterization of iopromide. Invest

Radiol 1994b;29:21–32

Krause W, Schumann-Giampieri G, Staks T, Kaufmann J:

Dose proportionality of iopromide pharmakokinetics and

tolerability after IV injection in healthy volunteers. Eur J Clin

Pharmacol 1994c;46:339–343

Krause W, Muschick P, Wehrmann D: Cardiac and hemody-

namic tolerability of iopromide with or without sodium or

iloprost and of ioversol in the anesthetized rat. Invest Radiol

1994d;29:978–984

Krause W, Press WR, Frenzel T: Preclinical testing of iopro-

mide. 1st communication: pharmacological evaluation.

Arzneim Forschung/Drug Research 1994e;44:1162–1166

Krause W, Schoebel C, Press WR: Preclinical testing of iopro-

mide. 2nd communication: toxicological evaluation. Arzneim

Forschung/Drug Research 1994f;44:1275–1279

Krause W, Niehues D: Biochemical characterization of X-ray

contrast media. Invest Radiol 1996;31:30–42

Laghi A: Ultravist 370 Case Report: CT-Abdomen. Bayer

Schering Pharma 2006, EU 2006.0716

Lee CH, Goo JM, Lee HJ et al: Determination of optimal tim-

ing window for pulmonary artery MDCT angiography. Am J

Roentgenol 2007;188:313–317

Liss P, Persson PB, Hansell P, Lagerqvist B: Renal failure in

57 925 patients undergoing coronary procedures

using iso-osmolar or low-osmolar contrast media. Kidney Int

2006;70:1811–1817

53

Ultravist.indd 53 16.09.2009 14:04:53

Mahnken AH, Lautenschlager S, Fritz D, Koos R, Scheuering M:

Perfusion weighted color maps for enhanced visualization of

myocardial infarction by MSCT: preliminary experience. Int J

Cardiovasc Imaging 2008a;24:883–890

Mahnken AH: Ultravist 370 Case Report: Case Collection Dual

Source CT. Bayer Schering Pharma 2008b, EU 2008.1124

Mahnken AH, Wildberger JE, Das M: Abdominal CTA. In:

Seidensticker PR, Hofmann LK (eds). Dual Source CT Imaging.

Springer 2008c

Mainenti PP, Cirillo LC, Camera L, Persico F, Cantalupo T,

Pace L, De Palma GD, Persico G, Salvatore M: Accuracy of

single phase contrast enhanced multidetector CT colonog-

raphy in the preoperative staging of colo-rectal cancer. Eur J

Radiol 2006;60:453–459

Mallouhi A, Rieger M, Czermak B, Freund MC, Walden-

berger P, Jaschke WR: Volume-rendered multidetector CT

angiography: noninvasive follow-up of patients treated with

renal artery stents. AJR 2003;180:233–239

Manniesing R, Viergever MA, van der Lugt A, Niessen WJ:

Cerebral arteries: fully automated segmentation from CT

angiography – a feasibility study. Radiology 2008 Jun;247:841–

846

McCollough CH, Primak AN, Saba O, Bruder H, Stierstorfer

K, Raupach R, Suess C, Schmidt B, Ohnesorge BM, Flohr TG:

Dose performance of a 64-channel dual-source CT scanner.

Radiology 2007;243:775–784

McDonald E, Hartman RP, McCullough C: Body: Obese Mode.

In: Seidensticker PR, Hofmann LK (eds). Dual Source CT Imag-

ing. Springer 2008

Meijboom WB, Mollet NR, van Mieghem CA, Weustink AC,

Pugliese F, van Pelt N, Cademartiri F, Vourvouri E, de Jaegere

P, Krestin GP, de Feyter PJ: 64-slice computed tomography

coronary angiography in patients with non-ST elevation acute

coronary syndrome. Heart 2007;93(11):1386–1392

Miklautz H, Fichte K, Wegscheider K: Osmolality of nonionic

contrast media. Fortschr Geb Rontgenstrahlen Nuklearmed

Erganzungsbd 1989;128:16–20

Misawa M, Sato Y, Hara M, Karasawa K, Noto N, Sumimoto

N, Okada T, Harada K: Use of non-ionic contrast medium,

Iopromide (Proscope 370), in pediatric cardiovascular angio-

graphy. Nihon Shoni Hoshasen Gakkai Zasshi 2000;16:42–48

Misselt A, McCullough C, Williamson E: Dual Energy: CTA

Runoff. In: Seidensticker PR, Hofmann LK (eds). Dual Source

CT Imaging. Springer 2008

Mollet NR, Cademartiri F, Krestin GP, McFadden EP, Aram-

patzis CA, Serruys PW, de Feyter PJ: Improved diagnostic

accuracy with 16-row multislice computed tomography

coronary angiography. JACC 2005a;45:128–132

Mollet NR, Cademartiri F, van Mieghem CAG, Runza G,

McFadden EP, Baks T, Serruys PW, Krestin GP, de Feyter

PJ: High-resolution spiral computed tomography coronary

angiography in patients referred for diagnostic conventional

coronary angiography. Circulation 2005b;112:2318–2323

54

Ultravist.indd 54 16.09.2009 14:04:53

Mortele KJ, Oliva MR, Ondategui S, Ros PR, Silverman SG:

Universal use of nonionic iodinated contrast medium for CT:

evaluation of safety in a large urban teaching hospital. AJR

Am J Roentgenol 2005;184:31–34

Mützel W, Speck U, Weinmann HJ: Pharmacokinetics of io-

promide in rat and dog. In: Taenzer V, Zeitler E (eds): Contrast

media in urography, angiography and computerized tomo-

graphy. Thieme 1983a;85–91

Mützel W, Speck U: Pharmacological profile of iopromide.

AJNR 1983b;4:350–352

Mützel W, Speck U: Tolerance and biochemical pharmacol-

ogy of iopromide. In: Taenzer V, Zeitler E (eds): Contrast media

in urography, angiography and computerized tomography.

Thieme 1983c;11–17

Mützel W, Speck U: Effects of ionic and non-ionic contrast

media after selective peripheral and cerebral arterial injec-

tions in rats. In: Taenzer V, Zeitler E (eds): Contrast media in

urography, angiography and computerized tomography.

Thieme 1983d;62–66

Mützel W: Preclinical evaluation of Ultravist® a new non-

ionic contrast medium. In: Felix R, Fischer HW et al (eds): Con-

trast Media from the Past to the Future. Thieme 1987;33–40

Nabavi DG, Kloska St, Nam Eun Mi, Freund M, Gaus CG,

Klotz E, Heindel W: MOSAIC: Multimodal Stroke Assessment

Using Computed Tomography: novel diagnostic approach for

the prediction of infarction size and clinical outcome. Stroke

2002;33:2819–2826

Nauert C, Mützel W: Experimental urography in dogs:

diagnostic quality and pharmacokinetic behavior of iotrolan

in comparison to non-ionic and ionic, monomeric contrast

media. Fortschr Geb Röntgenstrahlen Nuklearmed Ergän-

zungsbd 1989;128:82–87

Newhouse JH, Landman J, Lang E, Amis ES, Goldman S,

Khazan R, Leder R, Hedgcock M: Efficacy and safety of iopro-

mide for excretory urography. Invest Radiol 1994;29:S68–S73

Newhouse JH, Kho D, Rao QA, Starren J: Frequency of Serum

Creatinine Changes in the Absence of Iodinated Contrast

Material: Implications for Studies of Contrast Nephrotoxicity.

AJR 2008;191:376–382

Nieman K, Rensing BJ, van Geuns RJM, Munne A, Ligthart

JMR, Pattynama PMT, Krestin GP, Serruys PW, de Feyter

PL et al: Usefulness of multislice computed tomography for

detecting obstructive coronary artery disease. Amer J Cardiol

2002;89:913–918

O’Malley ME, Halpern E, Mueller PR, Gazelle GS: Heli-

cal CT Protocols for the Abdomen and Pelvis: A Survey. AJR

2000;175:109–113

Papke K, Kuhl CK, Fruth M et al: Intracranial aneurysms: role

of multidetector CT angiography in diagnosis and endovascu-

lar therapy planning. Radiology 2007;244:532–540

Park SJ, Han JK, Kim TK, Choi BI: Three-dimensional spiral CT

cholangiography with minimum intensity projection in pa-

tients with suspected obstructive biliary disease: comparison

with percutaneous transhepatic cholangiography. Abdom

Imaging 2001;26:281–286

55

Ultravist.indd 55 16.09.2009 14:04:54

Persson PB, Hansell P, Liss P: Pathophysiology of contrast

medium-induced nephropathy. Kidney Int 2005;68:14–22

Pinet A, Corot C, Biot N, Elov R: Evaluation of histamine

release following intravenous injection of ionic and non-ionic

contrast media. Invest Radiol 1988;23(suppl1):174–177

PSUR 2009: Periodic Safety Update Report on Ultravist. Bayer

Schering Pharma AG, 2009

Pugliese F, Mollet NRA, Runza G, van Mieghem C, Meijboom

WB, Malagutti P, Baks T, Krestin GP, de Feyter PJ, Cade-

martiri F: Diagnostic accuracy of non-invasive 64-slice CT

coronary angiography in patients with stable angina pecto-

ris. Eur Radiol 2006;16:575–582

Puls R, Knollmann F, Werk M, Gebauer B, Gaffke G, Steinkamp

H, Stroszczynski C, Felix R: 3D multislice CT angiography for

the assessment of relevant stenoses in patients with peripheral

artery occlusive disease. Röntgenpraxis 2001;54:141–147

Putschew A, Wischnack S, Jekel M: Occurrence of triiodi-

nated X-ray contrast agents in the aquatic environment. Sci

Total Environ 2000;255:129–134

Riebel T, Wartner R: Use of non-ionic contrast media for

tracheobronchography in neonates and young infants. Eur J

Radiol 1990;11:120–124

Rieger M, Czermak BV, Bale RJ, Pechlaner S, Gabl M, Jasch ke

WR: Multislice CT-Angiography (MSCTA) of the hand. Radiol-

ogy 2001a;221(P)Suppl:Abstract No 079GM-p

Rieger M, Czermak BV, Bale RJ, Sparr H, Mallouhi A, Jaschke

WR: The Role of Multislice CT-Angiography (MSCTA) in Poly-

traumatized Patients with Suspected Arterial Injuries. Radiol-

ogy 2001b;221(P)Suppl:Abstract No 080GM-p

Ropers D, Ulzheimer S, Wenkel E, Baum U, Giesler T, Derlien

H, Moshage W, Bautz WA, Daniel WG, Kalender WA, Achen-

bach S: Investigation of Aortocoronary Artery Bypass Grafts

by Multislice Spiral Computed Tomography with Electro-

cardiographic-gated Image Reconstruction. Amer J Cardiol

2001;88:792–795

Rust GF, Holzknecht N, Olbrich D, Schöpf U, Brü ning R,

Reiser M: Multiplanar computed tomography of the small

intestine. Preliminary findings. Radiologe 1999;39:965–970

Rust GF, Eisele O, Hoffmann JN, Kopp R, Fürst H, Rei ser M:

Virtual colonoscopy with multi-slice computed tomography.

Radiologe 2000;40:274–282

Sahani D, Saini S, Pena C, Nichols S, Prasad SR, Hahn PF,

Halpern EF, Tanabe KK, Mueller PR: Using multidetector

CT for preoperative vascular evaluation of liver neoplasms:

Technique and results. AJR 2002;179:53–59

Sahin H, Bircan MK, Akay AF, Kuru AF: Acute side effects

of iopromide and diatrizoate in urography. Acta Radiol

1998;39:734–735

Sandstede JJ, Werner A, Kaupert C et al: A prospective study

comparing different iodine concentrations for triphasic multide-

tector row CT of the upper abdomen. Eur J Radiol 2006; 60:95–99

Schild HH, Kuhl CK, Hubner-Steiner U, Bohm I, Speck U:

Adverse events after unenhanced and monomeric and

dimeric contrast-enhanced CT: a prospective randomized

controlled trial. Radiology 2006;240:56–64

56

Ultravist.indd 56 16.09.2009 14:04:54

Schoebel C, Guenzel P: Results of toxicological tests assessing

the risk of non-ionic contrast media in humans. In: Dawson P,

Clauß W (eds): Contrast Media in Practice. Springer 1994;18,58

Schoellnast H, Tillich M, Deutschmann HA, Stessel U,

Deutschmann MJ, Schaffler GJ, Schoellnast R, Uggo witzer

MM: Improvement of parenchymal and vascular enhance-

ment using saline flush and power injection for multiple-

detector-row abdominal CT. Eur Radiol 2004;14:659–664

Sciascia N, Zompatori M, Di Scioscio V et al: Multidetector

CT-urography in the study of urological complications in

renal transplant. Radiol Med 2002;103:501–510

Seidensticker P, Ciceri M: Contrast Agent Application. In:

Cademartiri F, Casolo G, Midiri M (Eds): Clinical Application of

Cardiac CT. Springer 2007

Seidensticker PR, Hofmann LK (eds): Dual Source CT Imag-

ing. Springer 2008

Seifarth H, Fischer T, Fischbach R, Kloska S: Vascular Brain

Perfusion. In: Seidensticker PR, Hofmann LK (eds). Dual Source

CT Imaging. Springer 2008

Solomon R, Deray G: How to prevent contrast-induced ne-

phropathy and manage risk patients: practical recommenda-

tions. Kidney Int 2006;Suppl:S51–S53

Speck U, Siefert HM, Klink G: Contrast media and pain in

arterial arteriography. Invest Radiol 1980;15:335–339

Stacul F, Cova M, Pravato M, Floriani I: Comparison between

the efficacy of dimeric and monomeric non-ionic contrast

media (iodixanol vs iopromide) in urography in patients with

macroscopic haematuria. Eur Radiol 2003;13:810–814

Steger-Hartmann T, Lange R, Schweinfurth H: Environ-

mental risk assessment for the widely used iodinated X-ray

contrast agent iopromide (Ultravist). Ecotoxicol Environ Saf

1999;42:274–281

Steger-Hartmann T, Lange R, Schweinfurth H, Tschampel

M, Rehm I: Investigations into the environmental fate and

effects of iopromide (ultravist), a widely used iodinated X-ray

contrast medium. Water Res 2002;36:266–274

Sutton AGC, Finn P, Campbell PG, Price DJA, Hall JA, Stewart

MJ, Davies A, Linker NJ, Harcombe AA, de Belder MA: Early

and Late Reactions Following the Use of Iopamidol 340,

Iomeprol 350 and Iodixanol 320 in Cardiac Catheterization.

J Invas Cardiol 2003;15:133–138

Thomsen HS, Morcos SK: Contrast-medium-induced ne-

phropathy: is there a new consensus? A review of published

guidelines. Eur Radiol 2006a;16:1835–1840

Thomsen HS, Morcos SK: ESUR guidelines on contrast media.

Abdom Imaging 2006b;31:131–140

Tomandl BF, Klotz E, Handschu R, Stemper B, Reinhardt F,

Huk WJ, Eberhardt KE, Fateh-Moghadam S: Comprehensive

imaging of ischemic stroke with multi-section CT. Radio-

Graphics 2003;23:565–592

Verow P, Nossen JO, Sheppick A, Kjaersgaard P: A compari-

son of iodixanol with iopamidol in aorto-femoral angiogra-

phy. Br J Radiol 1995;68: 973–978

57

Ultravist.indd 57 16.09.2009 14:04:54

Vogel N, Kauczor HU, Heussel CP, Ries BG, Thelen M: Arte-

fact reducing in diagnosis of lung embolism during spiral CT

with saline bolus. Fortschr Röntgenstr 2001;173:460–465

Willmann JK, Weishaupt D, Boehm T, Pfammatter T, Ma-

rincek B, Bauernfeind P: Detection of submucosal gastric

fundal varices with multidetector row CT angio graphy. Radi-

ology 2002a;225(P) Suppl: Abstract No 1354

Willmann JK, Roos JE, Platz A et al: Multidetector CT: detec-

tion of active hemorrhage in patients with blunt abdominal

trauma. AJR 2002b;179:437–444

Wintermark M, Smith WS, Ko NU, Quist M, Schnyder P,

Dillon WP: Dynamic Perfusion CT: Optimizing the Temporal

Resolution and Contrast Volume for Calculation of Perfu-

sion CT Parameters in Stroke Patients. AJNR Am J Neuroradiol

2004;25:720–729

Wintersperger BJ, Nikolaou K, von Ziegler F et al: Image

quality, motion artifacts, and reconstruction timing of

64-slice coronary computed tomography angiography with

0.33-second rotation speed. Invest Radiol 2006;41:436–442

Wintersperger B, Nikolaou K: Ultravist 370 Case Report: CT-

Angiography. Bayer Schering Pharma 2007, EU 2007.0898

58

Ultravist.indd 58 16.09.2009 14:04:54

ACTIVE

Thomsen HS, Morcos SK, Erley CM, Grazioli L, Bonomo L, Ni

Z, Romano L: The ACTIVE Trial: comparison of the effects on

renal function of iomeprol-400 and iodixanol-320 in patients

with chronic kidney disease undergoing abdominal computed

tomography. Invest Radiol 2008;43(3):170–178

CARE

Solomon RJ, Natarajan MK, Doucet S, Sharma SK, Staniloae CS,

Katholi RE, Gelormini JL, Labinaz M, Moreyra AE: Cardiac Angi-

ography in Renally Impaired Patients (CARE) study: a randomized

double-blind trial of contrast-induced nephropathy in patients

with chronic kidney disease. Circulation 2007;115:3189–3196

Carraro et al.

Carraro M, Malalan F, Antonione R, Stacul F, Cova M, Petz S,

Assante M, Grynne B, Haider T, Palma LD, Faccini L: Effects of

a dimeric vs a monomeric non-ionic contrast medium on renal

function in patients with mild to moderate renal insufficiency: a

double-blind, randomized clinical trial. Eur Radiol 1998;8:144–147

Chalmers/Jackson

Chalmers N, Jackson RW: Comparison of iodixanol and iohe-

xol in renal impairment. Br J Radiol 1999;72:701–703

CONTRAST

Wessely et al: The Contrast Media and Nephrotoxicity Following

Coronary Revascularization by Angioplasty (CONTRAST). SCAI 2008

COURT

Davidson CJ, Laskey WK, Hermiller JB, Harrison JK, Matthai

W Jr, Vlietstra RE, Brinker JA, Kereiakes DJ, Muhlestein JB,

Lansky A, Popma JJ, Buchbinder M, Hirshfeld JW Jr: Ran-

domized trial of contrast media utilization in high-risk PTCA:

the COURT trial. Circulation 2000;101:2172–2177

Feldkamp et al.

Feldkamp T, Baumgart D, Elsner M, Herget-Rosenthal S,

Pietruck F, Erbel R, Philipp T, Kribben A: Nephrotoxicity of

iso-osmolar versus low-osmolar contrast media is equal in

low risk patients. Clin Nephrol 2006;66:322–330

From et al.

From AM, Bartholmai BJ, Williams AW, McDonald FS: Iodixa-

nol compared to iohexol for contrast procedures: a case-match-

ed retrospective cohort study Acta Radiol 2008;49:409–414

ICON

Mehran R, Nikolsky E, Kirtane AJ, Caixeta A, Wong SC,

Teirstein PS, Downey WE, Batchelor WB, Casterella PJ, Kim

YH, Fahy M, Dangas GD: Ionic low-osmolar versus nonionic

iso-osmolar contrast media to obviate worsening nephropa-

thy after angioplasty in chronic renal failure patients: the

ICON (Ionic versus non-ionic Contrast to Obviate worsening

Nephropathy after angioplasty in chronic renal failure pa-

tients) study. JACC Cardiovasc Interv 2009;2:415–421

IMPACT

Barrett BJ, Katzberg RW, Thomsen HS, Chen N, Sahani D,

Soulez G, Heiken JP, Lepanto L, Ni ZH, Nelson R: Contrast-

induced nephropathy in patients with chronic kidney disease

undergoing computed tomography: a double-blind comparison

of iodixanol and iopamidol. Invest Radiol 2006;41:815–821

Juergens et al.

Juergens CP, Winter JP, Nguyen-Do P, Lo S, French JK, Hal-

lani H, Fernandes C, Jepson N, Leung DY: Nephrotoxic effects

of iodixanol and iopromide in patients with abnormal renal

function receiving N-acetylcysteine and hydration before

coronary angiography and intervention: a randomized trial.

Intern Med J 2009;39:25–31

Head-to-Head Comparisons on Renal Tolerance LOCM vs. IOCM in Risk Patients

59

Ultravist.indd 59 16.09.2009 14:04:55

McCullough et al.

McCullough PA, Bertrand ME, Brinker JA, Stacul F: A

meta-analysis of the renal safety of isosmolar iodixanol

compared with low-osmolar contrast media. J Am Coll Cardiol

2006;48:692–699

NEPHRIC

Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R,

Berg KJ: Nephrotoxic effects in high-risk patients undergoing

angiography. N Engl J Med 2003;348:491–499

Ngyuen et al.

Nguyen SA, Suranyi P, Ravenel JG, Randall PK, Romano PB,

Strom KA, Costello P, Schoepf UJ: Iso-Osmolality versus

Low-Osmolality Iodinated Contrast Medium at Intravenous

Contrast-enhanced CT: Effect on Kidney Function. Radiology

2008;248(1): 97–105

Nie et al.

Nie B, Cheng WJ, Li YF, Cao Z, Yang Q, Zhao YX, Guo YH,

Zhou YJ: A prospective, double-blind, randomized, controlled

trial on the efficacy and cardiorenal safety of iodixanol vs.

iopromide in patients with chronic kidney disease undergoing

coronary angiography with or without percutaneous coronary

intervention. Catheter Cardiovasc Interv 2008;72:958–965

PREDICT

Kuhn MJ, Chen N, Sahani DV, Reimer D, van Beek EJ, Heiken

JP, So GJ: The PREDICT study: a randomized double-blind

comparison of contrast-induced nephropathy after low-

or isoosmolar contrast agent exposure. Am J Roentgenol

2008;191:151–157

RECOVER

Jo SH, Youn TJ, Koo BK, Park JS, Kang HJ, Cho YS, Chung WY,

Joo GW, Chae IH, Choi DJ, Oh BH, Lee MM, Park YB, Kim HS:

Renal toxicity evaluation and comparison between visipaque

(iodixanol) and hexabrix (ioxaglate) in patients with renal

insufficiency undergoing coronary angiography: the RECO-

VER study: a randomized controlled trial. J Am Coll Cardiol

2006;48:924–930

Solomon Pooled Analysis

Solomon R: The role of osmolality in the incidence of

contrast-induced nephropathy: a systematic review of

angiographic contrast media in high risk patients. Kidney Int

2005;68:2256–2263

Swedish Registry

Liss P, Persson PB, Hansell P, Lagerqvist B: Renal failure

in 57 925 patients undergoing coronary procedures using

iso-osmolar or low-osmolar contrast media. Kidney Int

2006;70:1811–1817

Uder Meta-analysis

Heinrich MC, Haberle L, Muller V, Bautz W, Uder M: Nephro-

toxicity of iso-osmolar iodixanol compared with non-ionic

low-osmolar contrast media: meta-analysis of randomized

controlled trials. Radiology 2009;250:68–86

VALOR

Rudnick MR, Davidson C, Laskey W, Stafford JL, Sherwin PF:

Nephrotoxicity of iodixanol versus ioversol in patients with

chronic kidney disease: the Visipaque Angiography/Interven-

tions with Laboratory Outcomes in Renal Insufficiency (VALOR)

Trial. Am Heart J 2008;156:776–782

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Index

Aabdomen 17, 42

abdominal viscera 17

acetylcholinesterase inhibition 45

adverse drug reactions (ADR) 31

–, rates 32

adverse effects 25f

aneurysm(s) 9

–, of the aorta 23

angiography 4, 11, 24

–, cardio- 25

–, cine- 28

–, coronary 14, 25

–, peripheral 25

angioplasty

–, laser 25

–, percutaneous transluminal (PTA) 5

–, percutaneous transluminal coronary (PTCA) 5

arrhythmia 34

arterial phase 8

–, late 8

arteriography, cerebral 25

artery

–, carotid 11

–, coronary 14

arthrography 5, 28

aspiration 27

Bbiliary duct system 19

biodistribution 44

bladder 18

blood flow 11

blood pressure 32

–, decrease 32

–, increase 32

blood volume 11

body cavities 27

bolus 14

–, geometry 11

–, tracking 11f

bowel obstruction 28

bronchial carcinoma 13

bronchospasm 32

bypass 14

Ccardiac cycle 14

cardioangiography 25

catheter 42

–, angiography 20

central blood volume 9

chemistry 40

chemotoxicity 42

chest 13

chills 34

cholangiography 19

cholangitis 27

clearance 44

colonoscopy, virtual 17f

complement system 46

computed tomography see also CT 4, 7, 11

–, multidetector (MDCT) see MDCT

contrast agent 11

contrast application 7

contrast distribution 17

contrast enhancement 3

contrast medium (CM) 3, 32, 36

–, high osmolar (HOCM) see also HOCM 35

–, low-osmolar, extracellular X-ray(LOCM) see also LOCM 3, 36

–, non-ionic 3

–, monomeric 3

contrast nephropathy 35

–, pathogenesis 35

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–, prophylaxis 39

coughing 32, 34

CT 11

–, abdomen 17

–, angiography (CTA) 20

–, chest 13

–, ECD-gated 14

–, head 11

–, heart 14

–, liver 19

–, pediatric 29

Ddensity 26

detector rows 7

digital subtraction angiography (DSA) 21, 24

–, technique 21

dimers 36

–, iso-osmolar non-ionic (IOCM) 36, 38

dizziness 34

dose 31

dual-energy technique 19

dual-head injector system 13

dual-head power injector 10

dual-source CT (DSCT) 5, 7, 15

duct systems 27

dyspnea 32

Eecochemistry 43

edema 32

efficacy 26

endoscopic retrograde cholangiopancreatography (ERCP) 5, 27

eGFR values 39

electrical charge 40

enhancement, vascular 14

erythema 32

ESUR 30

evidence, preclinical 36

examinations, non-invasive 24

exanthema 32

extravasation 8, 30

extremities 42

Ffailure, acute renal 35

filtration, glomerular 35, 44

fistulography 5

flow rate 10

formulations 40

GGFR 37

GI tract 27

Hhalf-life 44

handling 30

head 11

heart 14

–, failure 39

heat sensation 32

hemorrhage 17

histamine release 46

HOCM 41

hydration 37, 39

hypersensitivity 31, 34

hypertension 39

hysterosalpingography 5, 27

Iimpairment, renal 34, 37

injection

–, flow rate 14

–, duration 15

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inspection, optical 30

interaction(s) 43

–, with biomolecules 5

intervention, coronary 37

intestine 17

intrathecal use 35

IOCM 38

iodine 3, 14

–, concentration 5

–, delivery rate (IDR) 8, 25

iopromide 3

itching 32f

Kkidney 8, 35

–, function 28

Llaser angioplasty see angioplasty

late phase 8

liver 8, 19

–, focal lesions 19

–, transplantation 19

LOCM 38, 41

lysozyme inhibition 45

Mmalaise 34

MDCT 7, 13

–, multiplanar 17

mean transit time 11

metabolization 44

molecular formula 40

molecular weight 40

monomers 36

–, non-ionic 36

morbidity 48

mortality 48

myelography 35

myeloma 39

NN-Acetylsteine 37

nausea 32

nephropathy 39

–, contrast-induced (CIN) 37

nephroureterolithiasis 26

Oocclusions 21

opacification 7f

osmolality 3, 5, 35, 40

oxygenation 35

Ppackage insert 33

pain 32

pancreatitis 27

patient(s)

–, comfort 42

–, renally impaired 35

–, traumatized 21

pelvis 42

perfusion 11

peripheral arterial occlusive disease 21

pH 6

pharmaceutics 40

pharmacokinetics 6, 43

pharmacology 44

physicochemistry 40

portal-venous phase 8

post-marketing surveillance 31f

procedures, interventional 24

product characteristics 5

product profile 4

properties 5

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protein binding 45

pruritus 34

PTA 25

pyelonephritis 26

Rradiography 4

–, conventional 4, 26

radiology, pediatric 28

rash 34

reactions

–, anaphylactoid 31, 34

–, delayed 31

–, skin 33

–, vasovagal 34

recommendation, general 30

renal artery stenoses see stenoses

restlessness 34

risk factors 39

Ssafety 3, 26, 28

–, profile 31

saline flush 10, 13

salpingography 27

scan

–, spiral 10

–, timing 9

side effects 43

structural formula 40

serum creatinine 35

skin rash 33

sneezing 32, 34

sodium bicarbonate 37

spatial resolution 15

stenoses 21

–, coronary artery 14

–, renal artery 20

stomach 17

streak artifacts 13

stroke assessment 11

surrogate marker 37

sweating 34

Ttaste disturbance 34

test bolus 10

–, method 11

thromboembolic events 30

thrombosis 26

time-to-peak 11

–, enhancement 10

timing 11

toxicity 47

toxicology 44, 47

tracheobronchography 28

Uurography 17

–, intravenous 26

urokinase inhibition 46

urticaria 32, 34

Vvariability 9

vascular malformations 11

vasodilation 34

vein of Galen 11

venography 26

venous phase 8

viscosity 3, 6, 30, 35, 42

vision, disturbed 34

vomiting 32, 34

Wwarming 30

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