Contrast Media in Practice
Springer
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P. DAWSON· W. CLAUSS
(EDS.)
Contrast Media in Practice
Questions and Answers
2
nd
Edition
With 60 Figures
Springer
PROF. DR. PETER DAWSON
Hammersmith Hospital
Department of Radiology
Du Cane Road
London W 12 oHS
United Kingdom
DR. WOLFRAM CLAUSS
ScheringAG
Klinische Entwicklung Diagnostika
D-13324 Berlin
ISBN-13: 978-3-540-64759-1
Springer-Verlag Berlin Heidelberg New York
Library of Congress Cataloging-in-Publication Data
Contrast media in practice: questions and answers / P. Dawson, W. Clauss, editors. - 2nd ed.
p.cm.
Includes bibliographical references and index.
ISBN -13: 978-3-540-64759-1
e- ISBN-13: 978-3-642-59957-6
DOl: 10.1007/978-3-642-59957-6
1. Contrast media.
1. Dawson, Peter H.
RC78.7.C65C665 1998
616.07'54-dc21
II. Clauss, W. (Wolfram), 194098-44436
CIP
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Table of Contents
1
General Fundamentals
1.1
A Historical Overview of the Development of Contrast Media
for Diagnostic Imaging Procedures in Radiology
H.J. MAURER and W. CLAUSS
1
Chemistry of Positive X-Ray Contrast Media
P. BLASZKIEWICZ . . . . . . . . . . . . . . .
6
Structure - Toxicity Relationships and Molecule Design
P.DAWSON
.
15
Relevant Results of Toxicity Studies of Non-Ionic X-Ray Contrast
Media for Estimating the Risk to Man
C.STARK
16
Physicochemical Properties of Contrast Media: Osmotic Pressure,
Viscosity, Solubility, Lipophilicity, Hydrophylicity, Electrical Charge
V.SPECK
24
Pharmacokinetics of Contrast Media
W. KRAUSE and G. SCHUHMANN-GAMPIERI
31
Clinical Documentation of the Tolerance, Safety and Efficacy
of X-Ray Contrast Media
E. ANDREW, W. CLAUSS, A. ALHASSAN and H. P. BOHN . . . . .
40
1.2
1.3
1.4
1.5
1.6
1.7
1.8
Statistical Considerations in the Design and Analysis of Clinical Trials
J. KAUFMANN . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
43
VI
Table of Contents
2
2.1
2.2
2.3
2.4
Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
What are the Steps in the Production of X-Ray Contrast Media?
D. HERRMANN • • • • . • • . • • • • • • • • • . . . • • • • • •
58
Which Chemical Degradation Products are Formed?
D. HERRMANN • • • • . • • • • • • • • • • • • • • .
59
What Additives do X-Ray Contrast Media Solutions Contain?
D. HERRMANN • • • • • • • • • • • • • • • • • • • • • . •
60
What is the Importance of Additives in Contrast Medium
Formulations?
••••.••••••••••••••••••
61
How is the Sterility of X-Ray Contrast Media Assured?
D. HERRMANN • • • • • • • • • • • • • • • • . • • • •
62
How is the Chemical Stability of Contrast Media Checked?
D. HERRMANN • • • • • • • • • • • • • • • • • • . • •
63
How are X-Ray Contrast Media Checked for Freedom
from Pyrogens?
D. HERRMANN • • • • • • • • • • • • • • • • • • • • •
65
To What are Colour Changes of Contrast Media Attributable?
D. HERRMANN • • • • • • • • • • • • • • • . • • • • • • • • •
65
P.DAWSON
2.5
2.6
2.7
2.8
2.9
Does Particulate Contamination Occur in X-Ray Contrast Media,
and How Important Is It?
D. HERRMANN
2.10
2.12
66
Which Factors Reduce the Stability of X-Ray Contrast Media,
and What Are the Implications of Storage Recommendations?
D. HERRMANN
2.11
•••••••••••.••••.••••••••
•••••••••••••••••••••••••
67
What Precautions Are Necessary in Drawing Up X-Ray Contrast
Media into Syringes and in Administering Them Using Infusion
Devices and Motorised Pumps?
D. HERRMANN • • • • • • • • • • • • • • • • • • • • • • • • • • • •
70
How Long Do X-Ray Contrast Media Remain Usable
After the Original Container Has Been Opened?
D. HERRMANN • • • • • • • . • • • • • • • • . • •
71
2.13 May X-Ray Contrast Media be Resterilised, Diluted
or Mixed with Other Drugs?
D. HERRMANN • • • • • • • • • • • • • • • • • • .
71
Table of Contents
2.14 Can the Re-Use of Disposable Catheters for Angiography
be Justified?
M. THELEN
.••.....••..•..••.•.•••.
3
Influence of Contrast Media on Organs and Vessels
3.1
What are the Mechanisms of Toxicity Associated with Contrast Media?
P. DAWSON
••••••••.•••.•••••••••••••...•
3.2
Do Contrast Media Affect the Viscosity of Blood?
N.H. STRICKLAND • • . . • • . . • • • • • • • .
3.3
Are there any Differences Between Ionic and Nonionic Contrast
Media in Their Effect on Coagulation?
P. DAWSON
••••••..••..••.••.•.•••..•••
73
75
79
3-4 Do Contrast Media Affect Cardiovascular Function?
P.DAWSON
3.5
••••••••••••••••••
. . . • • . . . . . . . ; • • • . .
Do Contrast Media Lead to Impaired Kidney Function?
J. E. SCHERBERICH
3.8
••••.••••••••••••..
84
Do Iodinated X-Ray Contrast Media Affect Thyroid Function?
B. GLOBEL
3.9
81
Do Contrast Media Affect Hepatic Function?
V. TAENZER
3.7
80
Do Contrast Media Affect Pulmonary Function?
P.DAWSON
3.6
••.•••••••••.•••••••
•••.•.•.••..••••••••••••••
86
What Is the Relationship Between Iodinated Contrast Media
and the Blood-Brain Barrier?
M. R. SAGE • • . • • • • • • • • • . • • • • • • • • . •
87
3.10 Do Contrast Media Affect the Central Nervous System?
M.R. SAGE
.••.••••..••••••••••••.
3.11 Do Contrast Media Affect Blood Vessel Walls?
F. LAERUM • • • • . • . . . • • . • • • • • .
92
3.12 Can X-Ray Contrast Media Affect the Results of Laboratory Tests?
W. JUNGE. . • • • . • • . . • • • . • • • • . • . . . . . . • • ••
94
VII
VIII
Table of Contents
4
Determination of Risk Factors Regarding the Administration
of Contrast Media
4.1
In Which Patients is the Administration of X-Ray Contrast Media
Associated with an Increased Risk?
W.
4.2
4.4
•••••••••••••••••••••••••••••
96
How Big is the Risk of an Examination with X-Ray Contrast Media
of Patients with Known Hypersensitivity to CM
and for Allergic Patients?
W.
4.3
CLAUSS
••••••••••••••••••••••••••
98
Does an Existing Allergy to Iodine Mean an Increased Risk
for an X-Ray Contrast Medium Examination?
W. CLAUSS • • • • • • • • • • • • • • • • • • • • • • • • • •
99
CLAUSS
Why does the Administration of Iodinated Contrast Media to
Patients with Manifest or Latent Hyperthyroidism Represent a Risk?
B. GLOEBEL • • • • • • • • • • • • • • • • • • • • • • • • • • • • ••
100
4.5 Why does the Administration of Iodinated Contrast Media
Represent a Risk to Patients with Non-Toxic Nodular Goitre?
B. GLOEBEL • • • • • • • • • • • • • • • • • • • • • • • • • •
101
4.6 How Do I Recognise Hyperthyroidism or the Presence of Non-Toxic
Nodular Goitre?
B. GLOEBEL • •
• • • • • • • • • • • • • • • • • • • • • • • • • •.
102
4.7 Does Underlying Cardiovascular Disease Constitute an Increased
Risk in Contrast Media Administration?
P. DAWSON • • • • • • • • • • • • • • • • • • • • • • • • • • • •
103
4.8 Why is Pre-Existing Lung Disease a Risk for the Administration
of Contrast Media?
P. DAWSON • • • • • • • • • • . • • • • • • • • • • • • • • • • • • •
104
4.9 Why Does Previous Renal Failure Represent a Risk?
J. E. SCHERBERICH
• • • • ••
104
4.10 Why Does Previous Diabetes Mellitus Represent a Risk?
J. E. SCHERBER1CH • • • • • • • • • . • • • • • • • • • • • • • • • .
106
••••••••••••••••••
4.11 Why Does Previous Paraproteinaemia Represent a Risk?
J.E. SCHERBERICH
••••••••••••••••••••
107
4.12 How Can the Risk of Provoking a Hypertensive Crisis in Patients
with Phaeochromocytoma be Reduced?
P. DAWSON • • • • • • • • • • • • • • • • • • • • • • • • • • • . • •
108
Table of Contents
4.13 Does the Examination of Dehydrated Patients
Represent an Increased Risk?
J. E. SCHERBERICH
.
.,
4.14 Are Patients with Autoimmune Disorders at Any Particular Risk
on Contrast Media Administration?
P. DAWSON
Does the Administration of Iodinated Contrast Media to Patients
with Sickle Cell Anaemia Result in Further Change in Erythrocytic
Shape?
R. DICKERHOFF
109
110
111
4.16 Are Contrast Media-Induced Side Effects Dependent on Age?
H. KATAYAMA
112
4.17 Can Contrast Media Procedures Be Carried Out Despite Defined Risks?
P. DAWSON
113
4.18 What Interactions are Known Between Contrast Media
and Other Medications?
P.DAWSON
.
114
4.19 What Effects Do Iodinated Contrast Media Have
When Administered During Pregnancy or Lactation?
K. A. WANDL-VERGESSLICH and H. IMHOF . . . . . .
116
5
Prophylactic Measures
5.1
What Is the Place of Fasting and Dehydration Before Contrast
Media Administration?
W. CLAUSS
118
Can Hypersensitivity Reactions to Contrast Media be Predicted
Through Preliminary Testing?
W. CLAUSS and V. TAENZER
..
120
Is Sedation Indicated Before Administering Contrast Media?
G. WISSER
121
5.2
5.3
5.4 Does General Anaesthesia Prevent the Occurrence
of Contrast Media-Induced Side Effects?
G. WISSER
.
5.5
Can the Rate of Contrast Media-Induced Side Effects be Lowered
by Premedication with Antihistamines?
R. TAUBER
122
123
IX
X
Table of Contents
5.6
5.7
Can the Adverse Reaction Rate Be Reduced by Administration
of Corticosteroids?
W. CLAUSS
124
How Important is Pharmacoprophylaxis of Hyperthyroidism
and How Can it Be Performed?
B. GLOEBEL . . . . . . . . . . . . . . . . . . . . . . . . . . .
126
6
Informing the Patient Prior to Contrast Media Administration
6.1
What is the Patient's "Right to Know" Prior to an X-Ray
Examination Using Contrast Media?
H. J. MAURER and W. SPANN
6.2 What Special Information Should a Healthy Volunteer/Patient
Receive Who is Participating in a Clinical Study of a New Drug?
W. CLAUSS and E. ANDREW
127
129
7
Administration of Contrast Media
7.1
Are Contrast Media Heated to Body Temperature Better Tolerated?
P. DAWSON
131
Are There Any Guidelines for Maximum Doses in Angiography?
P. DAWSON
132
Are There Any Guidelines for Maximum Doses in Myelography?
1. O. SKALPE . . . . . . . . . . . . . . . . . . . . . . . . . . . .
133
Are There Any Guidelines for Maximum Doses in Cholegraphy?
V. TAENZER . . . . . . . . . . . . . . . . . . . . . . . . . . . .
133
Can "Maximum" Doses be Exceeded?
P.DAWSON
.
134
Does the Injection Rate Affect the Tolerance?
P.DAWSON
.
135
What Fluids Can Be Recommended for Flushing Catheters?
P. DAWSON
136
Are Contrast Media Dialysable?
.
J.E. SCHERBERICH
137
What are the Sequelae of Inadverted Paravascular Administration
of Iodinated Contrast Media?
W. CLAUSS
138
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
Table of Contents
8
Adverse Reactions and Their Pathophysiology and Management
8.1
What Adverse Reactions Can Be Expected After Intravascular
Administration of Iodial Containing Contrast Media?
R. G. GRAINGER
8.2 Do Late-Occuring Adverse Reaction to Contrast Media Necessitate
Longer Supervision of the Patient?
P. DAVIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
141
144
8.3 What Adverse Reactions to Contrast Media are Dose Independent
or Dependent?
H.KATAYAMA
. 146
8.4 What Are the Mediators of Anaphylactoid Reactions to Iodinated
Contrast Media?
P.DAWSON
.
8.5
How Often Can Late Reactions be Expected After Administration
of Radiographic Contrast Media
K. BROCKOW and J. RING . . . . . . . . . . . . . . . . . . . . . . . 149
8.6 Which Are the Clinical Manifestations of Late Reactions
to Radiographic Contrast Media?
K. BROCKOW and J. RING . . . . . . . . . . . . . . . . .
150
8.7 What Is the Pathophysiology of Late Reactions
to Radiographic Contrast Media?
K. BROCKOW and J. RING . . . . . . . . . . . .
15 1
8.8 Are Antibodies to Radiographic Contrast Media Known?
R. C. BRASCH . . . . . . . . . . . . . . . . . . . . . . .
151
8.9 Are There Allergies to Contrast Media?
R. C. BRASCH . . . . . . . . . . . . . .
15 2
8.10 Can Sensitization Due to Frequent Contrast Media Administration
be Observed?
R. C. BRASCH .. . . . . . . . . . . . . . . . . . . . . . . . . . ..
153
8.11 Can Epileptogenicity and Arachnoiditis be Observed
After Myelography with Nonionic Contrast Media?
I. O. SKALPE . . . . . . . . . . . . . . . . . . . . . .
154
XI
XII
Table of Contents
9
Clinical Use of Iodinated Contrast Media for the Visualization
of Vessels, Organs and Organ Systems
9.1
Cerebral Angiography
1. O. SKALPE . . . . . .
155
9.2 Spinal Angiography and Phlebography
A. THRON
.
9.3
Angiography of the Extremities
H. J. MAURER . . . . . . . . . .
9.4 Phlebography
B. HAGEN . . .
9.5
. . . . ..
Direct Lymphography and Indirect Lymphangiography
H. WEISSLEDER . . . . . . . . . . . . . . . . . . . . . .
169
174
9.6 Angiocardiography
M. J. THORNTON and P. WILDE
180
9.7 Angiographic Procedures for the Liver, Spleen, Pancreas and Portal
Venous System
W.RODL
189
9.8 Computed Tomography in the Liver, Pancreas and Spleen
A. ADAM and P. DAWSON . . . . . . . . . . . . . . . . . .
197
9.9 Visualization of the Gastrointestinal Tract
C. 1. BARTRAM, B. LAERMANN and P. O'BRIEN . . . . . . . . . . ..
203
9.10 Cholecystography and Cholangiography
V. TAENZER
.
218
9.11 Intravenous Urography
P.DAWSON
.
. 220
9.12 Urethrography and Micturating Cystrography, Cavernosography,
and Seminal Vesiculography and Vasography
D. RICKARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
224
9.13 Visualization of the Kidneys and the Adrenal Glands
G.P. KRESTIN . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
229
9.14 Contrast Media in Gynaecology
H. J. MAURER AND J. G. HEEP
235
9.15 Arthrography
V. PAPASSOTIRIOU
239
Table of Contents
9.16 Contrast Media for Paediatric Patients
J. TROGER
.
. ...
249
9.17 What is the Role of Newer Contrast Media in Interventional
Radiology?
P. DAWSON
253
9.18 Computer Tomography Angiography (CTA)
S. C. RANKIN
.
255
9.19 Magnetic Resonance Angiography (MRA)
J. F. M. MEANEY . . . . . . . . . . . . . . . . . . . . . . . . . . ..
265
9.20 Carbon Dioxide Angiography
S. HASHIMOTO and K. HIRAMATSU
273
10
Contrast Media for Magnetic Resonance Imaging and Ultrasound
10.1 Contrast Media for Clinical Magnetic Resonance Imaging
H. P. NIENDORF, T. WELS and V. GEENS . . . . . . . . . . . . . . ..
10.2
Ultrasonographic Contrast Media
A. BAUER, R. SCHLIEF and H. P. NIENDORF
276
290
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 299
XIII
List of Contributors
ADAM, A., PROF.
Guy's Hospital
Department of Radiology
London Bridge
London SEI 9RT
United Kingdom
BLASZKIEWICZ, PETER, DR.
ScheringAG
Chemischer Versuchsbetrieb II
Miillerstrasse 178
13342 Berlin
Germany
ALHASSAN, A., DR.
ScheringAG
Arzneimittelsicherheit
Miillerstrasse 178
13342 Berlin
Germany
BOHN, H.P., DR.
Nycomed Amersham, Nycomed
Imaging AS
Sandakerveien 100 c
P. O. Box 4220 Torshov
0401 Oslo
Norway
ANDREW, E., DR.
Nycomed Amersham,
Nycomed Imaging AS
Sandakerveien 100 c
P. O. Box 4220 Torshov
0401 Oslo
Norway
BRASCH, ROBERT C., PROF. DR.
University of California
Department of Radiology
Contrast Media Laboratory
Third and Pamassus Street
San Francisco, CA 94143
USA
BARTRAM, CLIVE, DR.
St. Mark's Hospital
Intestinal Imaging 4V
Northwick Park
Watford Road
Harrow HAl 3UJ
United Kingdom
BROCKOW, KNUT, DR.
Klinik und Poliklinik fiir
Dermatologie und Allergologie
Biedersteiner Strasse 29
80802 Miinchen
Germany
BAUER, A., DR.
Schering AG
Clinical Development Diagnostics I
Miillerstrasse 178
13342 Berlin
Germany
CLAUSS, WOLFRAM, DR.
ScheringAG
Medical and Scientific Affairs
Diagnostics
Miillerstrasse 178
13342 Berlin
Germany
XVI
List of Contributors
DAVIES, PETER, DR.
HASHIMOTO, SUBARU, DR.
City Hospital
Department of Radiology
Nottingham
United Kingdom
Keio University Hospital
Department of Diagnostic Radiology
School of Medicine
35 Shinanomachi
Shinjukuku, Tokyo 160
Japan
DAWSON, PETER, PROF. DR.
Hammersmith Hospital
Department of Radiology
Du Cane Road
London W12 oNN
United Kingdom
HEEP, JOSEF, PROF. DR.
St. Josefskrankenhaus
Gynakologische Abteilung
Landhausstrasse 25
69115 Heidelberg
DICKERHOFF, ROSWITHA, DR.
HERRMANN, DIRK, DR.
Johanniter-Kinderklinik
Arnold-Janssen-Strasse 29
53757 St. Augustin
Germany
Fasanenstrasse 55
14612 Falkensee
Germany
HIRAMATSU, KYOICHI, DR.
GEENS, V., DR.
ScheringAG
Clinical Development Diagnostics II
Miillerstrasse 178
13341 Berlin
Germany
Keio University Hospital
Department of Diagnostic Radiology
School of Medicine
35 Shinanomachi
Shinjukuku, Tokyo 160
Japan
IMHOF, H., PROF.
B., PROF. DR. DR.
UniversiUitskliniken Homburg
Abteilung Medizintechnik
66421 Homburg/Saar
Germany
GLOEBEL,
GRAINGER, RONALD G., PROF.
Consultant Radiologist
"Little Orchard"
8 Clumber Road
Sheffield SIO 3L£
United Kingdom
Universita.tsklinik fur Radiodiagnostik
Abteilung fur Osteologie
Allgemeines Krankenhaus Wien
Wahringer Gurtel18 - 20
1090 Wien
Austria
JUNGE, WOLFGANG, PROF. DR.
LKF-Laboratorium fur Klinische
Forschung GmbH
Lise-Meitner-Strasse 25 - 29
24223 Raisdorf bei Kiel
Germany
HAGEN, BERND, DR.
KATAYAMA, HITOSHI, PROF. DR.
Martin-Luther-Krankenhaus
Rontgen- und Strahlenabteilung
Caspar-Theyss-Strasse 27 - 31
14193 Berlin
Germany
Juntendo School of Medicine
Department of Radiology
Hongo 2-1-1 Bunkyo-ku
Tokyo 113
Japan
List of Contributors XVII
KAUFMANN, JORG, DR.
NIENDORF, HANS-PETER, DR.
Schering AG
Biometry Diagnostics
Miillerstrasse 178
13342 Berlin
Germany
ScheringAG
Clinical Development Diagnostics
Miillerstrasse 178
13342 Berlin
Germany
KRAUSE, W., PROF. DR.
O'BRIEN, PAUL, PROF.
ScheringAG
Forschung Rontgenkontrastmittel
Miillerstrasse 178
13342 Berlin
Germany
Imperial College of Science,
Technology and Medicine
Department of Chemistry
London SW7 2AY
United Kingdom
PAPASSOTIRIOU, V., DR.
KRESTIN, GABRIEL P., PROF. DR.
Academisch Ziekenhuis Rotterdam
Dr. Molewaterplein 40
3015 GD Rotterdam
The Netherlands
LAERMANN, BARBARA, DR.
Imperial College of Science,
Technology and Medicine
Department of Chemistry
London SW7 2AY
United Kingdom
LAERUM, FRODE, PROF.
Rikshospitalet
Department of Diagnostic Radiology
Section for Experimental Radiology
0027 Oslo
Norway
MAURER, H.-J., PROF. DR.
Obere Flurstrasse 11
88131 Bodolz-Enzisweiler
Germany
MEANEY, JAMES
F. M., DR.
Leeds General Infirmary
CT Unit, Jubilee Building
Great George Street
Leeds LSI 3EX
United Kingdom
Ubierstrasse 4
14052 Berlin
Germany
RANKIN, SHEILA, DR.
Guy's Hospital
Department of Radiology
St. Thomas Street
London SEI 9RT
United Kingdom
RICKARDS, DAVID, DR.
Middlesex Hospital
Department of Radiology
Mortimer Street
London WIN 8AA
United Kingdom
RING, JOHANNES, PROF. DR.
Klinik und Poliklinik ffir
Dermatologie und Allergologie
Biedersteiner Strasse 29
80802 Mfinchen
Germany
RODL, W., PROF. DR.
Klinikum Weiden
Strahleninstitut
Abteilung ffir Radiologische
Diagnostik
Sollnerstrasse 16
92637 Weiden
Germany
XVIII List of Contributors
c., DR.
SAGE, MICHAEL R., DR.
STARK,
The Flinders University of South
Australia
Flinders Medical Centre
Division of Medical Imaging
Bedford Park
South Australia 5042
Australia
ScheringAG
Kurz- und Langzeittoxikologie
Miillerstrasse 178
13342 Berlin
Germany
SCHERBERICH, J. E., PROF. DR.
Stadtisches Krankenhaus MiinchenHarlaching
II. Medizinische Abteilung, Nephrologie
Sanatoriumsplatz 2
81545 Miinchen
Germany
SCHLIEF, REINHARD, DR.
ScheringAG
Clinical Development Diagnostics I
Miillerstrasse 178
13342 Berlin
Germany
SKALPE, INGAR 0., PROF. DR.
The National Hospital University of
Oslo
Rikshospitalet
Department of Radiology
Pilestredet 32
0027 Oslo
Norway
SPANN, W., PROF. DR.
Institut flir Rechtsmedizin der
Universitat Miinchen
Frauenlobstrasse 7a
80337 Miinchen
Germany
SPECK,
u., PROF. DR.
ScheringAG
SGE Diagnostika Forschung
Miillerstrasse 178
13342 Berlin
Germany
H., DR.
Imperial College of Science,
Technology and Medicine
Department of Imaging
Du Cane Road
London, W12 oNN
United Kingdom
STRICKLAND, NICOLA
TAENZER, V., PROF. DR.
Krankenhaus Moabit GbR
Turmstrasse 21
10559 Berlin
Germany
TAUBER, R., PROF. DR.
Allgemeines Krankenhaus Barmbeck
Urologische Abteilung
Riibenkamp 148
22291 Hamburg
Germany
THELEN, MANFRED, PROF. DR.
Klinikum der Universitat Mainz
Klinik und Poliklinik fiir Radiologie
Langenbeckstrasse 1
55131 Mainz
Germany
THORNTON, MARK, DR.
Bristol Royal Infirmary
Clinical Radiology
Mandlin Street
Bristol BS2 8HW
United Kingdom
THRON, A., PROF. DR.
Neurologische Klinik der RWTH
Abteilung Neuroradiologie
Pauwelstrasse 30
52074 Aachen
Germany
List of Contributors
TROGER, JOCHEN, PROF. DR.
WILDE, PETER, DR.
Universitatsklinik Heidelberg
Abteilung Padiatrische Radiologie
1m Neuenheimer Feld 153
69120 Heidelberg
Germany
Bristol Royal Infirmary
Clinical Radiology
Mandlin Street
Bristol BS2 8HW
United Kingdom
WANDL-VERGESSLICH, KLARA
A., DR.
Universitatskinderklinik Wien
Wahringer Gurtel18 - 20
1090 Wien
Austria
WEISSLEDER, HORST, PROF. DR.
Stephanienstrasse 8
79100 Freiburg
Germany
WELS, T., DR.
ScheringAG
Medical and Scientific Affairs
Diagnostics
Miillerstrasse 178
13342 Berlin
Germany
WISSER, GREGOR, DR.
Klinikum der Johahnes-GutenbergUniversitat
Klinik fur Anaesthesiologie
Langenbeckstrasse 1
55131 Mainz
Germany
XIX
CHAPTER 1
General Fundamentals
1.1
A Historical Overview of the Development of Contrast
Media for Diagnostic Imaging Procedures in Radiology
H.J. MAURER and W. CLAUSS
In diagnostic imaging, a distinction is made between negative X-ray (air, 02'
CO 2), positive X-ray (barium, BaS04; iodine, I), paramagnetic, and ultrasonographic contrast media (CM). Barium sulphate (BaS04 ) had already been used
in 1896 for investigations on peristalsis, but it was forgotten again once the
study was concluded. It was only about a decade later that BaS04 , "newly"
developed by the pharmacist and final-year medical student Fritz Munk, was
introduced into X-ray investigations of the gastrointestinal tract as the socalled Rieder meal (barium mixed with gruel). It has been able to maintain its
predominant position up to the present day, albeit with certain modifications
such as taste corrigents and changes in density and particle size, though
occasionally it is replaced by tri-iodinated ionic or nonionic X-ray CM, which
are used, for example, in suspected perforation fistulae, ileus, or for an array of
purposes in children.
Iodine was recognized as an X-ray-absorber, i.e., as a positive X-ray CM, as
early as 1896 (Haschek and Lindenthal), but the implications of this were not
immediately recognized. The iodized oil Lipiodol was successfully introduced
into myelography by Sicard as the first usable X-ray CM other than air in 1921.
This oily X-ray CM, used at the same time for bronchography, and later for
hysterosalpingography, pyelography, and, above all, lymphography, was poorly
absorbed, largely because of its molecular size; this often led to foreign-body
granulomata. Because of the occurrence of pulmonary and peripheral fat
microemboli, oily X-ray CM are hardly ever indicated today, except in such conditions as destructive chronic pulmonary diseases, pulmonary hypertension
and selctive angiographies of the liver before embolisation. Sicard and Jacobaeus also used Lipiodol for ventriculography, but the complications arising
were one reason why this did not become an established procedure.
2
CHAPTER 1
General Fundamentals
Water-soluble X-ray CM are subdivided into renal and biliary X-ray CM,
which are chiefly distinguished by the ways in which they bind to proteins. In
contrast to uroangiographic media, which are excreted by the kidney after passive glomerular fIltration, cholegraphic agents reach the liver only after binding
to serum proteins and are excreted via the gallbladder after metabolism. Since
toxicity increases along with increasing protein binding, the objective must be
to develop renal X-ray CM with minimal protein binding and biliary X-ray CM
with optimised protein binding. Oral cholecystography, still occasionally used
today despite the good results of ultrasonography (US), allows visualization of
the gallbladder if the small intestine absorbs the CM; it cannot, however, do the
same for the bile ducts. If the whole of the biliary system, i.e., the intra- and
extrahepatic biliary tree including the gallbladder, must be visualized, this
should be attempted using a rapid-infusion cholecystocholangiography, possibly in conjunction with tomography or thick-section tomography ("zonography") and/or computed tomography (CT).
Oral Biliary X-Ray Contrast Media
In 1909, it was shown that phenoltetrachlorophthalein is excreted by the gallbladder. This effect was then used for testing liver function from 1916 into the
1950S. In 1923, the gallbladder was demonstrated using orally administered
halogenated phenolphthalein. In 1924 iodophthalein sodium (Iodtetragnost)
was put on the market and then in 1940 Dohrn and Diedrich developed iodoalphionic acid (Biliselectan), which had only half the toxicity of iodophthalein
sodium. The development of a series of oral cholecystographic agents such as
sodium ipodate (Biloptin) then followed. These new agents were all based on
the same basic structure, but with different side chains, and were characterized
by their better tolerability.
Biliary Intravenous X-Ray Contrast Media
While attempting to synthesize a better renal X-ray CM, Priewe administered
intravenously a compound consisting of two molecules of acetrizoate connected by an aliphatic chain, and was surprised to find excretion occurring via
the liver and biliary system. From this, Langecker, Hawart and Junkmann [5]
developed the first hepatic-biliary X-ray CM, iodipamide (adipiodone; Biligrafin); in 1953, W. Frommhold introduced it into routine practice. Due to
the relatively high toxicity of Biligrafin and similar preparations, further
substances were subsequently synthesized and developed which, ultimately, led
to iotroxic acid (Biliscopin), a medium which displays good tolerability when
used in the short-infusion cholecystocholangiogram.
1.1
A Historical Overview of the Development of Contrast Media
Renal X-Ray Contrast Media
Even though iodine was recognized very early as a positive X-ray CM (1896), it
still took about 30 years for a clinically acceptable X-ray CM to be developed.
The experiment to visualize blood vessels by Haschek and Lindenthal in 1896
failed to be used in men because of the high toxicity of the contrast medium (a
mixture of minerals).
In 1904, Lexter, too, was not successful in carrying out angiographic examinations due to both the CM toxicity and the unsufficient technical equipment.
The procedure that Berberich and Hirsch as well as Moniz chose, namely, to
administer strontium or bromide compounds (SBr, LiBr, KBr, NaBr) intravenously and intraarterially in order to image the blood vessels, resulted in some
cases in technically successful arteriographies and phlebographies. In the same
year in Paris, Sicard and Forestier succeeded in performing angiographies of
satisfactory diagnostic qualitiy using the oily Lipiodol. The inadequate vessel
demonstration and the severe intolerance reactions, especially following
intraarterial administration, prompted Moniz to try sodium iodide, which
Osborne, Sutherland, Scholl [8] and Roundtree had already used for intravenous urography in 1923. In spite of the high toxicity of the 25 % sodium iodide
solution used, the good contrast-enhancing properties of iodine were demonstrated. These are chiefly the result of the high mass absorption coefficient that
iodine possesses at the wavelengths used in diagnostic radiology.
In a completely different context, in 1925, Binz and Riith [2] synthesized
various pyridone compounds, some of which also contained iodine. Swick [11],
investigated a series of these pyridones in 1928 and 1929, first with 1. Lichtwitz
(City Hospital of Altona, Hamburg, Germany) and later with A. von Lichtenberg
(St. Hedwig's Hospital, Berlin, Germany) [6]. In conjunction with Schering AG,
he then developed Selectan Neutral in 1929, which was very quickly supplemented by Uroselectan (1 iodine atom) and Uroselectan B (2 iodine atoms). At
about the same time (1930), Bronner, Hecht and SchUller at Bayer AG developed
Abrodil (methiodal sodium - iodomethanesulfonic acid as the sodium salt) and
Per-Abrodil (iodopyracet - 3,5-iodo-4-pyridone-N-acetic acid). The diiodinated X-ray CM, Uroselectan and Per-Abrodil, provided adequate imaging of
the efferent urinary tract and of the blood vessels with satisfactory tolerability;
they were used for almost 20 years in diagnostic radiology.
In 1929, Moniz [7] introduced a thorium-dioxide suspension for cerebral
angiography; it provided excellent contrast and was very well tolerated. However,
a great proportion of the thorium is stored in the reticuloendothelial system and
leads, because of its radioactivity, to the formation of benign tumours, which in
time become malignant. In extravascular injections, considerable fibrosis develops, which may compress vessels and may also become malignant. Even though
these serious complications were known in 1942, thorium dioxide continued to
be used, although increasingly less often, into the 1950S.
At the beginning of the 1950S, the change was made from diiodinated
pyridine derivatives to benzene derivatives with three substituted iodine
atoms, i. e.) triiodinated benzoic acid derivatives. Hydrophilic side groups and
the meglumine cation improved the tolerability of the ionic CM considerably,
3
4
CHAPTER 1
General Fundamentals
while the third iodine atom bound to the molecule led to higher contrast
density.
The development of these triiodinated X-ray CM was initiated by Wallingford's synthesis [12] of acetrizoate sodium (Urokon Sodium, Mallinckrodt,
1950). Diedrich (Schering) and chemists at Sterling-Winthrop simultaneously
succeeded in making a decisive further improvement in tolerance by synthesizing meglumine diatrizoate (Urografin and Hypaque, 1954). By starting with
meglumine diatrizoate and varying the side chains, the following preparations
were then developed: metrizoic acid (Isopaque, 1962), iothalamic acid (Conray,
1962), iodamide (Uromiro, 1965), ioxitalamic acid (Telebrix, 1972) and ioglicic
acid (Rayvist, 1978). For more than 30 years, these X-ray CM formed the basis for
diagnostic studies of the blood vessels, the renal tract, and various body cavities.
They are still used today, although primarily intravenously and for intracaritarily. What they have in common are their dissociation into anions and cations (as
ionic X-ray CM) and their consequent high osmotic pressure (up to seven times
that of blood). Almen [1] was the first, at the end of the 1960s, to recognize the
decisive role that hyperosmolatity and electrical charge play in triggering certain
side effects of ionic X-ray CM. His suggestion of replacing the ionic carboxyl
radical in the triiodinated benzoic-acid derivatives with a nondissociating group
and to guarantee the required water solubility by means of substituting hydrophilic OH groups represented the birth of nonionic X-ray CM.
The osmolality, more closely approaching that of the blood, and the lack of
electrical charge clearly improved tolerability. Amipaque was chiefly used for
myelography and occasionally peripheral angiography; nevertheless, it still had
to be made up into solution immediately prior to use. The introduction of
nonionic triiodinated X-ray CM in ready-to-use form, such as iohexol (Omnipaque), iopamidol (Solutrast, Niopam, Isovue, Iopamiron), iopromide (Ultravist), ioversol (Optiray) and iopentol (Imagopaque), made the use of nonionic
X-ray CM easier and thus promoted such use. The effort to achieve similarly
favourable results by using the ionic dimer ioxaglic acid (Hexabrix) was, however, not quite as successful. Although the osmolality was likewise reduced by the
dirrieric structure, the "ionic character" of the molecule remained unchanged.
Nonionic X-ray CM can be used in all regions of the body, except for the biliary
and lymphatic systems.
Numerous publications based on clinically monitored comparative studies
have demonstrated the significantly lower rates of mild and moderate side
effects that nonionic X-ray CM have in comparison to ionic ones. However, as
yet, only three large-scale, multicentre studies have been carried out with the
goal of differentiating X-ray CM in terms of the severe reactions they all, rarely,
trigger. Independent of statistical design, the results of all three studies attest to
the reduced risk of severe, life-threatening reactions occurring when nonionic
X-ray CM are used. This reduction in risk varies from a factor of 1: 2 to 1: 10,
depending upon the type and degree of prior risk level of the patient [4, 9, 10].
The synthesis of the hexaiodinated nonionic dimers iotrolan (Isovist),
iodecol and iodixanol (Visipaque) represents the most recent advance in X-ray
CM development. The osmolality of these media in all concentrations matches
that of circulating blood; indeed, their osmolality has to be adjusted upwards to
1.1
A Historical Overview of the Development of Contrast Media
achieve this. It is possible to reduce significantly the neurotoxic symptoms associated with myelography by using iotrolan, which is already commercially
available. In the mid 90ies, the two nonionic dimeric contrast media received
marketing authorization for intravascular use. Mainly due to their isotonicity,
local and cardiovascular tolerance have been improved and the reduced osmotic effects lead to an increased contrast quality.
Unfortunately, postmarketing surveillance resulted in detecting a relatively
high rate of late occurring reactions, mostly pseudoallergic reactions of the skin
and mucosa. On the basis of a risk-benefit decision Schering withdrew Isovist®280 for intravascular use from the market while Nycomed Amersham preferred
currently to perform a very close monitoring of all reactions occurring after the
application ofVispaque®-270 and 320.
The attempt to replace the contrast-enhancing element, iodine, with lithium,
widely used in psychiatry, had to be abandoned after animal experiments in
spite of the good contrast it provided, since considerable cystic degeneration of
the kidneys was observed.
Negative X-Ray CM
Negative CM such as air, O2 and CO 2 do not absorb X-rays as strongly as body
tissues do; this allows one to achieve a negative contrast effect in certain body
cavities. Very early, prior to US and CT, use was made of air in imaging the kidney, ureter and bladder. Following presacral insufflation, air, O2 and CO 2 also
allowed the imaging of retroperitoneal and mediastinal structures, especially in
combination with tomography. In addition, CO 2 is used clinically for angiography and, in order to avoid administering iodinated X-ray CM to patients
at risk. Difficulties in its administration and often inadequate contrast have
hindered its routine use.
Negative CM were primarily administered in ventriculography and
ascending lumbar or basal cisternography. However, their use was first reduced
by the introduction of cerebral angiography; then, later, CT and, today,
magnetic resonance imaging (MRI), have completely superceded them. In the
same way, the use of pneumomyelography was considerably reduced on the
introduction of Lipiodol-based myelography, later replaced by di- and triiodinated ionic X-ray CM. Today, myelography is performed exclusively using
nonionic monomeric and dimeric X-ray CM that are eliminated via the urine.
Summary
Seen as a whole, the history of iodinated X-ray CM represents a successful and
happy example of collaboration between the chemical-pharmaceutical industry
and clinicians. As a result, diagnostic radiology has available very well tolerated,
nonionic X-ray CM for all applications.
In order to complete the picture, it should be mentioned that for MRI extracellular paramagnetic CM such as Gd-DTPA (Magnevist), Gd-DOTA (Dotarem), Gd-DTPA-BMA (Omniscan) and Gd-D03A (Prohance) as well as intra-
5
6
CHAPTER 1 General Fundamentals
cellular superparamagnetic CM such as Magnetites (Endorem) have been developed and made commercially available (see chapter 10.1). For ultrasound,
CM based on microbubbles such as Echovist, Lelovist and Albunex have been
developed to increase the signal intensity (see chapter 10.2). The use of these
CM has made it possible to increase considerably the sensitivity and specificity
of these diagnostic procedures.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Almen T (1969) Contrast agent design. Some aspects of the synthesis of water-soluble
agents of low osmolality. J Theor BioI 24: 216 - 226
Binz A, Riith A, von Lichtenberg A (1931) The chemistry of proselectan. Z Urol 25: 297 - 301
Grainger RG (1982) Intravascular contrast media - the past, the present and the future. Br
J Radiol55 :1-18
Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K (1990) Adverse
reactions to ionic and nonionic contrast media. A report from the Japanese Committee on
the Safety of Contrast Media. Radiology 175 : 621- 628
Langecker H, Harwart A, Junkmann K (1954) 3,5-Diacetylamino-2,4,6-triiodbenzoesiiure
als Rontgenkontrastmittel. Naunyn-Schmiedebergs Arch Exp Pathol 222: 584 - 590
Lichtenberg A von, Swick M (1929) Klinische Prufung des Uroselectans. Klin Wochenschr
8: 2089 - 2091
Moniz E (1934) L'angiographie cerebrale. Masson, Paris
Osborne ED, Sutherland CG, Scholl AF, Rowntree LG (1923) Roentgenography of urinary
tract during excretion of sodium iodide. JAMA 80: 368 - 373
Palmer FJ (1988) The RACR survey of intravenous contrast media reactions: final report.
Austral Radiol 32 : 426 - 428
Schrott KM, Behrends B, ClauB W, Kaufmann J, Lehnert J (1986) Iohexol in der Ausscheidungsurographie: Ergebnisse des Drug monitorings. Fortschr Med 7: 53 -156
Swick M (1929) Darstellung der Niere und Harnwege im Rontgenbild durch intravenose
Einbringung eines neuen Kontraststoffes, des Uroselectans. Klin Wochenschr 8: 20872089
Wallingford VH (1953) The development of organic iodide compounds as X-ray contrast
media. J Am Pharmacol Assoc (Sci Ed) 42: 721-728
1.2
The Chemistry of Positive X-Ray Contrast Media
P. BLASZKIEWICZ
Basic Molecular Structure
When an X-ray penetrates a chemical element, it interacts with the electrons of
the element. Due to this interaction, the X-ray emerging from the layer has a
lower energy than before.
1.2
The Chemistry of Positive X-Ray Contrast Media
The degree of interaction depends on the wavelength/energy of the X-ray
and the energy of the electrons. The energy of the electrons is determined by
the actual electron orbital they belong to. The number of electrons and orbitals
and their energy content increase as the atomic number, Z, rises. Generally, the
degree of interaction between an X-ray and the electrons of an element increases with the atomic number of the element.
Certain combinations of X-ray wavelength and atomic numbers do not
follow this general rule. In the range of wavelengths used for diagnostic purposes, the elements iodine (Z = 53) and barium (Z = 56), for example, absorb
more X-ray energy than mercury (Z = 80) orlead (Z = 82), in spite of their considerably higher atomic numbers.
The body organs consist mainly of the elements carbon (Z = 6), oxygen
(Z = 8), hydrogen (Z = 1) and nitrogen (Z = 7), while the bones additionally contain calcium (Z = 20) and phosphorus (Z =15). Carbon, oxygen, hydrogen and
nitrogen differ very little in their absorption of X-ray energy. Their concentrations in the soft tissue differ also only minimally. Bone contrasts with the soft
tissue only in far as the greater number of electron orbitals of the calcium and
phosphorus interact more intensely with the X-rays.
To differentiate certain areas of soft tissue from each other, one has to introduce an element with a higher absorption of X-ray energy. As mentioned above,
in the diagnostic range of X-ray wavelengths, the elements iodine and barium
are physically suitable. However, they must first be integrated in physiologically acceptable compounds. For parenteral application, this is possible only with
iodine. The use of barium is limited to the water-insoluble barium sulphate,
BaS04 , for enteral application.
Iodine can be integrated fairly easily and copiously into organic compounds
suitable for parenteral, and also enteral, application.
For pharmacological reasons, several iodine atoms have to be kept in one
molecular unit to meet requirements such as water-solubility, stability, physiological inertness and low osmotic pressure of the solution. This is done most
effectively by binding the iodine atoms to the aromatic compound benzene.
Iodinated heterocyclic compounds are no longer in use.
All current X-ray contrast media (CM) are derivatives of symmetrically
iodinated benzene, with three iodine atoms bonded to the six available carbons
(triiodobenzene: see Fig. 1.2.1). This basic structure exhibits the most stable carbon-iodine bond combined with a high iodine content and offers a sufficient
potential for structural variations of the three further possible sites on the
benzene ring. The other three substituents (A, B, C) have the function of making
the molecule water-soluble, and pharmacologically inert and facilitating its
elimination pathway from the organism.
Fig.
1.2.1.
Molecular structure of symmetrically iodinated
benzene (triiodobenzene)
IYvI
A
C~B
I
7
8
CHAPTER 1
General Fundamentals
Triiodobenzene Derivatives
Depending on the structural variation of the substituents A, Band C the
iodinated CM are classified in groups with different properties and applications
shown in general formulae (Figs. 1.2.2-1.2.6).
The Water Solubility of CM
Very high solubility in water is the primary requirement for CM used in intravascular applications. This is especially the case in angiography, where fairly
large quantities of a highly concentrated solution are administered in a short
time. For other applications such as urography or i. v. cholangiography where
infusion is possible or even necessary, the solubility of the CM can be lower.
However, high water-solubility is also a safety factor to ensure that no CM precipitates from the solution.
There are two general options for achieving water-solubility. The chemically
simpler one is the formation of a salt. A salt is always the combination of an acid
and a base and consists of at least two parts with opposite electrical charges.
The charges are covered with water molecules, thus leading to solubility. The
formation of a salt is a rather simple procedure. The acid part of the salt is, in
the case of the iodinated CM, always the benzene-carrying acidic carboxylic
function -COOH (Fig. 1.2.7).
This acid is practically insoluble in water. The water-soluble salt is formed by
reaction with a base. This reaction is called neutralisation. It indicates that the
salt solution has a pH value in the range of 7. The bases in use are sodium hydroxide and/or the amine, N-methy-glucamine (Fig. 1.2.8).
The molecular region where the electrical charge is located is intensely
solvated with water molecules, leading to solubility. Anion and cation are
separated from each other by the solvation. All ionic CM solutions are of the
type described here.
The more demanding method of obtaining a water-soluble material is the
construction of an electrically neutral, non-ionic compound of such a hydrophilicity that the solvation with water molecules is sufficient to keep the compound in solution. Hydrophilic properties are obtained by the introduction of
functional groups such as hydroxy, ether and amido groups into the molecule.
The water-solubility of the non-ionic CM is based on the intrinsic hydrophilicity of the molecule structure.
The Osmotic Pressure of CM Solutions
The osmotic pressure of CM solutions is of great importance, for the same
reason as the water-solubility, especially in the case of angiographic application.
For infused solutions the osmotic pressure is less critical but not negligible.
The osmotic pressure is approximately proportional to the number of free
mobile particles in a solution. It is measured in mosm/kg, in Megapascal and
1.2
The Chemistry of Positive X-Ray Contrast Media
---
lriiodobezene derivati,-es
ionic
monomeric
Compounds ha ing
an aci d funct ion
for all formation
directly linked 10
tile benzene ring:
~
nonionic
dimeric
!
Compounds ha ing
an acid function
for salt fonnation
in a side chain:
one ub tiluenl
al Ihc benzene ring
mllSl be hydrogen:
A. B and
arc
trongly hydrophilic.
leading 10 a
waler-soluble
electrically neulral
compound:
!
~
monomeric
dimerie
Two benzene
rings wiIII
Irongly hydropluhe
ob lilUenlS
arC linked
\\~Ih each other:
1
1
O_H
I
C
I
""
.&
I
B
Derivatives of
benzoic acid
and
isophthalic acid.
renal elimination
hiJ:h osmolar
rO"lngiograllhic
agent.
salls of:
DIATRIZOI
TRIZOI ACID
10DAMI A ID
10THALA IC ACID
10XfTIlALAMIC ACtO
10GUCI IC ACID
ome oflhcsc
compounds arc
inlestinally ab orbed after
oral administration and
biliary eliminated:
Oral cholegraphic
lIgcnt.
salls of:
10PODATE
lOBE ZAMIC A lD
10PRONIC ACID
10PA OIC ACID
10 ETAMIC ACID
molar
non-ionic
ro I anwo'
myelographic
agent
10PAMIDOL
10H XOL
10PROMIDE
lOVER OL
10PENTOL
IOB1TRlDOL
101\' 0
isotonic
non..ionic
aogio' myelographic
agents
10DIXANOL
10TROLAN
dimcric ionic C 1
\\~thlwo
acid functions
c
B
c
h drogen
low osmo!;,r
ionic
ro I angiographie
agents
sailS of
10XAGLIC ACID
angio- and
myelographic
agents
sail of
10CARMI A ID
i. v. cholCJ:rallhie
agents
sail of
10DIPAMIC ACID
10GLY AMI A 10
IQTROXI A ID
10DOXAMIC ACID
Fig. 1.2.2. The general chemical structures of the current triiodobenzene derivatives
9
10
General Fundamentals
CHAPTER 1
,"J-:~:~
V
31
1
H
I
I
I
H
.'3
D1ATRIZOIC ACID
°
IX;C0
O-~
I ""
CH?-N b
hH:3 I
°
0
~Jl..CH:3
H
METRIZOIC ACID
I,~O
O-~
CH)lN
3
I
H
I ""
A
2
~~H:3
n
H
I
IODAMlC ACID
°
I~O
O-~
°
I ""
CH)lN A ~~N/CH:3
H
3
I
H
0
0
I
H
IOGLICINIC ACID
Fig. 1.2.3. The high osmolar uro/angiographic agents
IOHEXOL
IOVERSOL
IOPENTOL
Fig. 1.2..4. The complete chemical structures of the low osmolar non ionic uro-/angio/myelographic agents
Fig. 1.2..5.
The low osmolar ionic agents
The Chemistry of Positive X-Ray Contrast Media
1.2
IODIXANOL
Fig. l.2.6. The isotonic angio/myelographic agents
o
Fig. 1.2.7.
Triiodobenzoic acid derivative
~
I
C
I
OH
"'"
.&
I
B
I
+
*
0
I
C
I
o
O-H
"'"
.&
I
I
B
+ .+OW
or
.melhyl g1ucaminc
~
0- No'
I
I "'"
C
A'
~"'3
0' H'~'CH2(CHOHl
H
5
CH OH
2
Nom ethyl gluClIlTlIne
I
B
+ H20
Fig. 1.2.8. The neutralisation process
also in atmospheres. The conversion is: 1000 mosm/kg = 2.58 MPa = 25.5 at. The
osmotic pressure (= osmolality) of blood is about 290 mosm/kg. The ideal CM
solution should have the same, or should not deviate too much. The correlation
290 mosm/kg means that 290 mmol = 0.29 mol of an osmotically active substance is dissolved in 1 kg of water.
For diagnostic purposes an average iodine content of 300 mg iodine/ml is
required. The osmolality of a CM solution is indicated by the number of mmol
of a CM required to bind these 300 mg iodine. Table 1.2.1 shows this correlation.
In solutions of monomeric ionic CM, two particles are necessary to keep
three iodine atoms in solution. The two particles are the negatively charged
anion of the iodinated benzoic acid and the positively charged cation Na+
and/or N-methyl-glucamine (positively charged). Both ions are separately
solvated with water molecules, and both are osmotically active.
In solutions of monomeric non-ionic CM, only one particle is necessary to
keep three iodine atoms in solution. At the same iodine content, the osmolality
of such a solution is about half as high as that of the salt solution of an ionic
monomeric CM. The same result is achieved by the ionic dimer with only one
11
12
CHAPTER 1 General Fundamentals
Table 1.2.1. The osmotic pressure of CM solutions
Average
molecular
weight
mgper
mmol
Average mmolofCM
iodine
required to bind
content 300 mg iodine
per
mrnol
Resulting
osmolality
of the solution
in mosm/kg
water
%
mg
Ionic monomeric CM
633
60.2
381
approx.0.79
about 1500
anion
containing the iodine
+ 0.79 cation
without iodine
Ionic dimeric CM with
1 acid function =
low 0 molar ionic dimer
IOXAGLAT
on-ionic monomeric CM
1269
60
762
804
Non-ionic dimeric CM
1603
47.4
381
47.5
762
approx. 0.4 anion
about 500
containing the iodine
+ 0.4 cation
without iodine
about 645
approx.0.79
approx. 0.48
about 290
acid function, where six iodine atoms are bound to the acid anion and one cation contributes to the osmolality.
At the same iodine concentration the osmolality of a solution of a dimeric
nonionic CM is aproximately the same as that of blood. The osmolality of
monomeric nonionic CM and an ionic dimer with one acid function is twice as
high and that of an ionic monomer is three times as high.
The Viscosity of CM Solutions
The viscosity - the internal fluid friction - of CM solutions is a measure of their
flow properties. It depends mainly on the concentration of the solution, the
temperature and the molecule size of the CM. With increasing concentration
the amount of water in the solution decreases. The water molecules separate the
CM molecules from each other. When this separation is insufficient, adhesive
forces between the CM molecules become effective. Smaller CM molecules are
more easily separated from each other than larger molecules. The adhesive
forces depend on the molecular structure of the CM. They are not readily
predictable.
Small rises in temperature increase the motion of the molecules in the
solution, compensating for the adhesive forces and lowering the viscosity very
effectively.
The Chemistry of Positive X-Ray Contrast Media
1.2
The Synthesis of CM
Though the current CM are all derivatives of triiodobenzene, this compound is
not a suitable starting material for the synthesis. It itself is not easily manufactured and does not offer any reasonable possibility for introducing the other
three (or two) substituents.
It is therefore useful to start with benzene derivatives already containing
simple atom groups which allow the introduction of iodine and the construction of the other substituents. The introduction of iodine requires the
activation of the benzene ring to make it more readily accessible to the iodine.
The best activation and further chemical variability is provided by the amino
group. The two other possible substituents on the benzene ring, in regard to
stability, chemical variability, solubility and hydrophilicity, are carboxylic acid
or carboxylic acid-amide groups.
The most suitable starting materials to obtain the structures described are
the readily available nitrobenzoic acid and nitroisophthalic acid (Fig. 1.2.9).
The nitro compounds are easily reduced to the amino compounds, and the
iodine is then smoothly introduced, using iodine monochloride in aqueous
solution. The triiodinated intermediate is almost always of low water-solubility,
precipitates from the reaction mixture and can be purified. The synthesis of
ionic CM is almost complete at this stage. After acylation of the amino function
the iodine is "locked" into the ring because deiodination of the acyl compound
is very difficult. The chemistry of an ionic CM is complete at this stage. As an
example, see the synthesis of diatrizoic acid presented in Fig. 1.2.10.
Ionic CM are usually purified as salts dissolved in water. They are easily
reconstituted by precipitation through acidification.
Non-ionic CM do not lend themselves to this simple process. They require
elaborate methods like recrystallization, extraction or even chromatography. In
the case of a non-ionic CM, considerably more chemistry has to be done. Before
and/or after iodination the other three substituents have to be constructed via
a number of intermediate steps based on several chemical, physicochemical,
Fig. 1.2.9.
Suitable starting materials
Hq°,<:::o-:
- I
O'N'
A
N' O
g
H
g
-
di-nitro-benzoic
acic
H ....
hydrogenation
Fig.
1.2.10.
iodination
The sythesis of diatrozoic acid
I:~O
,<:::O-~
I
N
b
N"H
I
I
H
H
acetylation
13
14
CHAPTER 1
General Fundamentals
I
:I:
x~
f K : t : I : - Z0
~ ~
o
o
_
-
I
Z-:I:
:I:
:I:
I
\~
:I:~:I:_Z
6 ~ ~
o
:I:
-
:I:
I
Z-:I:
:I:
:I:
I
\~
:*/ =q
b$o
o
~
-
:I:
)=0
'ct=o
: I:
Ob~:I:-Z
~:I:
·z=o
I
o
I
~
0
~
0
:I:
:I:
I
:I:
Z-:I:
1.3 Structure - Toxicity Relationships and Molecule Design
pharmacological, economical and ecological aspects. Apart from the expenditure on materials and labor involved in each individual step, some of the material employed - including some of the usually already iodinated precursors - is
lost at each step in the synthesis. In addition, the isolation and purification of
intermediates and the final product require more sophisticated methods in
comparison with ionic CM because the structures involved show more particular solubilities and reactivities.
All non-ionic CM must be desalinated, a procedure which is not necessary
with ionic CM. Ionic CM are isolated and also purified from salts and other
impurities by precipitation from water. Non-ionic CM are intrinsically watersoluble and have to be desalinated and purified by laborious and expensive
methods such as ion exchange and crystallization from organic solvents. The
desalination is done with ion exchange resins in aqueous solution. Much attention must be paid to the quality of the water in this process. To reduce the
expense, the preceding reaction steps should produce a minimum of ionic
byproducts. Finally, the product is obtained in a rather large quantity of water.
This solution has to be protected from contamination with micro-organisms,
and the water removed carefully by vacuum distillation, spray or freeze-drying.
These processes result in an amorphous material rather than a crystalline product. Very often, further treatment is necessary, because the product is not sufficiently pure, is hygroscopic or has other disadvantages. Crystallization from
an organic solvent bearing no toxicological hazards might lead to the required
quality. There are also other very individually adapted procedures which fulfil
this goal.
For an example of a non-ionic CM, see the presentation of the synthesis of
iopromide in Fig. 1.2.11.
1.3
Structure - Toxicity Relationships and Molecule Design
P.DAWSON
There are two components to CM toxicity, one of which is well understood,
namely high osmolality, and one of which is much less well understood, namely
chemotoxicity. The former is a nonspecific effect which is a function only of the
strength of the solution; the second is molecule - specific and depends on a
number parameters of molecular structure.
It seems that CM exert their molecule-specific toxicity by way of weak, nonspecific binding to biological macromolecules. This binding appears to be
largely mediated through the hydrophobic portions of the molecule, the hydrophilic portions being solvated in water solution. The benzene ring - iodine core
of the molecule is the principal hydrophobic portion. The extent to which this
is available for interactions with biological molecules is variously measured as
15
16
CHAPTER 1
General Fundamentals
the partition coefficient (a measure of relative hydrophilicity/hydrophobicity),
as protein binding capacity (e. g. with albumin) or, indirectly, as the magnitude
of the effect on functional proteins, namely enzymes. A second and very important mechanisms of interaction between some contrast agents and biological macromolecules is the charge or Coulomb effect. This is not present, of
course, with the nonionic agents which, by definition therefore, can be expected
to be more inert, before any other considerations are taken into account.
Studies in this area have led to the conclusion that the design principles for
a low-toxicity CM include the following:
The agent should be nonionic.
Hydrophilic substituents should be many and should mask the benzene ring
- iodine core of the molecule.
3. The molecule should be compact so that the viscosity is not too high.
4. There should be isomerism in the molecule for reasons of entropy and
solubility.
1.
2.
This subject is incomplelety understood but recent progress has been significant and the point may soon be reached where computer-aided design of molecules will be a realistic proposition.
1.4
Relevant Results of Toxicity Studies of Non-Ionic X-Ray
Contrast Media for Estimating the Risk to Man
C.
STARK
The results of animal-experimental studies are an important aid in estimating
the risk of new iodinated X-ray contrast media (CM) and a vital precondition
for their clinical investigation in man. The toxicity study programmes for CM
are centred on the recommendations for the toxicity study of drugs intended
only for acute use in man. They normally cover the following parameters:
-
Systemic tolerance after a single dose (acute toxicity),
systemic tolerance after repeated administration (subacute toxicity),
mutagenic potential,
reproduction-toxicological potential,
local tolerance.
Because many reports have already been published on the nature and performance of such studies (13 -17, 36, 46, 51- 53), only representative results of
animal-experimental studies conducted with the non-ionic CM listed in
Table 141 for estimating the risk to man are presented and discussed in the
following.
l.4 Relevant Results of Toxicity Studies of Non-Ionic X-Ray Contrast Media
Table 1.4.1.
Non-ionic X-ray contrast
media (CM)
Short chemical name
Trade name
lohexol
lopamidol
Omnipaquee
lopamiro(n)e
Solutraste
Ultravist e
Amipaque e
Isovist e
lopromide
Metrizamide
lotrolan
Acute Toxicity
Iodinated non-ionic CM are characterised by low acute toxicity. For all the CM
mentioned in Table 1-4-1, the LD 50 values after intravenous administration in rat,
mouse and dog are higher than 10 g iodine/kg.
Non-ionic CM are less toxic than ionic CM. The reasons for this are their
lower osmolality, the absence of an electrical charge and greater hydrophilicity,
which make these compounds even more inert than ionic CM. In common with
all iodinated CM, they are metabolically stable, display a low protein-binding
capacity and are excreted quickly and completely [6].
Systemic Tolerance on Repeated Administration
The study of systemic tolerance after repeated administration helps, inter alia,
to estimate the dose range in which no clinically relevant adverse events are
likely. In addition, this type of study provides important information about the
toxicological profile of action, in particular about the organotoxic potential of
a compound. The doses are chosen so that the low dose is only slightly above the
proposed human dose and the intermediate dose permits an estimate of possible first side effects. The high dose, on the other hand, is always a big multiple
of the human dose in order that the broadest possible spectrum of toxic effects
can be detected after considerable overdosage as well [51].
The route of administration for repeated use is guided by the proposed
diagnostic use in man. The intravenous route is normally chosen for parenteral
diagnostic agents. The systemic tolerance after intrathecal administration is also
studied if it is intended to use the CM as a myelographic agent. On the other hand,
systemic tolerance studies after repeated oral administration are often dispensed
with because of the very low systemic availability of iodinated CM after oral
administration, even if a CM is to be employed as a gastroenterographic agent.
Intravenous Administration
No unequivocal organotoxic findings have been observed for any of the CM
listed in Table 1.4.1 even after repeated administration (over 3-5 weeks) of the
highest dose tested (~2.4 - ~ 4 g iodine/kg) in rats, dogs and/or monkeys.
17
18
CHAPTER 1
General Fundamentals
Minor, toxicologically irrelevant changes of clinico-chemical or haematological parameters occurred for individual CM from the intermediate and/or high
dose onwards.
In addition, all the CM listed in Table 1.4.1 led to dose-dependent vacuolation
of the epithelial cells of the proximal renal tubules after repeated administration (3 - 5 weeks) of 1.4 - 5 times the diagnostic dose. These changes were not associated with any impairment of kidney function. Moreover, additionally
performed reversibility studies in rats showed these changes to be reversible,
the time taken for complete reversibility to be achieved being dependent on the
size of the dose and the frequency of administration.
Vacuolation of the proximal renal epithelium is a well-documented phenomenon after single or multiple administration of X-ray contrast media which has
also been described in man [40]. The reason for these vacuoles is not yet fully
understood, but recent studies in the rat conducted with the model substance
iotrolan (non-ionic dimer) suggest that the development of these vacuoles is a
biphasic process. In this study, the first vacuoles were demonstrable in the
epithelial cells of the proximal renal tubules just a few minutes after administration of the CM. The ultrastructure and site of the vacuoles in the cells (mainly
apical) suggest that they are endosomes created by endocytosis and the resorption of material from the ultraflltrate. Fusion of the vacuoles with lisosomes then
occurred in a second, slower step [48]. These observations are consistent with
other studies in the rat in which other ionic and non-ionic CM (ioxaglate,
iohexol, iopamidol and iobitriol) were used [4,5,57]. Because all the studies consistently showed that the vacuolation of the cells was not accompanied by damage to vital cell organelles, it can be assumed that the vacuolation of the proximal tubular epithelium is not a pathological process, but that it reflects a
physiological cellular event in the processing of endogenous or exogenous material in the kidney. Vacuolation of the proximal renal tubular epithelium after CM
administration should not, therefore, be equated with the term "osmotic nephrosis", which was originally coined for the typical renal changes which occurred after Lv. administration of hyperosmolar sugar solutions; although vacuolation of the renal tubular epithelium was among these changes, it was also
accompanied by distinct signs of cellular degeneration.
Because neither functional impairment nor degenerative changes of vital cell
organelles were demonstrable in animal-experimental studies even on highgrade vacuolation of the renal epithelium, it appears doubtful whether vacuolation of the proximal renal epithelium is associated with the impairment of renal
function covered by the term "contrast medium nephropathy" in man [7, 12,34,
50]. Although the latter involves primarily a transient impairment of kidney
function, cases of acute renal failure have also been reported. The pathophysiology of contrast medium nephropathy is not yet known in all detail, but
it appears to be a multifactorial process for which there is no reliable animal
model available [28].
Vacuolation of the hepatocytes has also been observed under the highest
dose (3.7 g iodine/kg) of iopromide (a non-ionic monomer) tested in rats.
Because this vacuolation did not correlate with an increase of the liver-specific
serum parameters or with signs of impaired liver function, hepatocyte vacuo-
1.4 Relevant Results of Toxicity Studies of Non-Ionic X-Ray Contrast Media
lation - like vacuolation of the proximal renal tubular cells - was not interpreted as an indication of an organotoxic effect.
Intrathecal Administration
Our own animal-experimental studies with non-ionic CM, which are indicated
for the diagnosis in the CNS, were performed in the dog and rat. In the rat,
repeated intracisternal administration of iotrolan (4 injections within 14 days)
did not lead to any iotrolan-related findings even at the highest dosage tested
(60 mg iodine/rat corresponding to approx. 25 mg iodine/kg). Repeated
subarachnoid administration (4 injections at intervals of 1 week) of iotrolan (up
to 250 mg iodine/kg) and iopromide (180 mg iodine/kg) was also well tolerated
in the dog. In particular, no leptomeningeal changes occurred.
Convulsions were observed in individual animals on the day of treatment
after a single subarachnoid injection of iopromide and iopamidol in the dog
under brief anaesthesia. This side effect in the dog has also been described after
the diagnostic administration of iohexol and iopamidol [10] and is also known
after intrathecal administration of CM in man [49].
Mutagenic Potential
The mutagenic potential is assessed on the basis of several tests covering
various genetic end-points. The "standard test battery" shown in Table 1-4-2
examines mutations of both genes and chromosomes. The micronucleus test
covers not only chromosome-breaking, i.e. clastogenic effects (chromosomal
mutation), but also aneugenic effects, which lead to the maldistribution of
chromosomes (genome mutation), since micronuclei can consist both of
chromosomal fragments and of whole chromosomes which were not integrated
in one of the two daughter cell nuclei on mitosis.
None of the different tests conducted to determine the mutagenic potential
produced any evidence for a pertinent risk on administration of non-ionic CM.
Table 1.4.2. Standard test systems used for determining the mutagenic potential as part of
drug registration studies
Test system
Ames test (in vitro)
HPRT test (in vitro)
Chromosome aberration test
(in vitro)
Micronucleus test (in vivo)
Indicator ceUs/organi m
Salmonella typhimurium
V79 ceUs of the Chine e
hamster
Human lymphocytes from
peripheral blood
Erythrocytes from the bone
marrow of the mou e
Genetic end-point
Gene mutation
Gene mutation
Chromosome mutation
Chromosome/genome
mutation
19
20
CHAPTER 1
General Fundamentals
Reproduction Toxicology
X-ray examinations of pregnant women are performed only after careful consideration of the benefits and risks, and the radiation load is then kept as low as possible.
Embryotoxicity studies were conducted in two laboratory animal species
with all the substances listed in Table 1.4.1 in order to detect any negative effects
of iodinated CM on intrauterine development. The CM were administered
intravenously and daily during the main phase of organogenesis (rat day 6 -15
post coitum, rabbit day 6 -18 post coitum). The experiments failed to furnish
any evidence for a relevant embryotoxic or teratogenic potential of any of the
substances. Iohexol, iopromide and iotrolan were each examined additionally in
a fertility study (treatment of the parent animals of both sexes followed by
mating to determine fertility) and a peri/postnatal development study (treatment of the maternal animals during gestation and the lactation phase,
observation of the physical and functional development of the offspring) in the
rat. These experiments, too, produced no evidence for specific reproductiontoxicological effects of the non-ionic, iodinated CM.
Any reproduction-toxicological risk in the use of iodinated X-ray contrast
media is more likely to come from the radiation insult during the examination
than from the diagnostic agent used.
Local Tolerance
The local tolerance is studied both at the proposed site of administration and in
the tissues with which the CM might inadvertently come into contact (e. g. as a
result of incorrect injection, swallowing, aspiration, perforation etc.). The
concentration used diagnostically is normally employed in these studies.
The good vascular tolerance of all the CM listed in Table 1-4-3 has been
demonstrated by clinical assessment and histological examination of the sites
of administration both in local tolerance studies of the rabbit ear (intravenous,
intraarterial) and in systemic tolerance studies on repeated intravenous administration in two or, in individual cases, three animal species.
Comparative local tolerance studies were conducted in muscle tissue - which
is regarded as particularly sensitive to local irritative effects - and after
perivenous injection in the rabbit as well as after intraperitoneal administration
in the rat. The non-ionic compounds iotrolan, iopamidol, iopromide and
iohexol (iodine content of each 300 mg iodine/ml) did not differ from each
other as regards their tissue tolerance in perivenous and peritoneal tissue.
Differences between the non-ionic study preparations were observed only in
the muscle tissue of the rabbit (see Table 1.4.3). Of the CM tested, iotrolan was
found to be the best tolerated in this regard, its effect being about the same as
that of the simultaneously tested 0.9% (w/v) saline solution. The ionic CM
diatrizoate (Angiografin®, 306 mg iodine/ml) included as a reference substance
in the comparative studies described was tolerated much worse after
perivenous administration than the non-ionic CM.
If it is also intended to use a CM for myelography, the local tolerance after
intrathecal injection is also tested, since it has been reported that some CM can
1.4 Relevant Results of Toxicity Studies of Non-Ionic X-Ray Contrast Media
Table 1.4.3. Results of the comparative local tolerance study in the rabbit after intramuscular
administration of X-ray contrast media (8 injection sites per test solution: Histological
examinations of 4 injection sites each on day 3 and 7 after administration)
Sub tance name (trade name)
o molality at 37°C
(0 mlkg H 20)
Very light
0.9% (w/v) aline olution
(control)
lotrolan
(Isovist-)
lohexol
(Omnipaque-·300)
lopromide
(Ullravist-·300)
lopamidol
( olutra t--3OO)
Diatrizoate
(Angiografin-)
Severity of local irritative
effect
320
Very light to light
690
light
610
light to moderate
640
Moderate
1530
Moderate
cause not only acute signs of irritation, but also chronic leptomeningeal
reactions such as proliferation of granulation tissue after intrathecal injection
in the lumbosacral region. The leptomeningeal reactions are seen at radiology
as obliteration of the nerve root sacs or as narrowing or shortening of the
lumbar sac [1,2,18,29,31- 33,37,39,55].
In studies in the monkey, leptomeningeal changes were found in the lumbar
region after intrathecal administration of the monomeric non-ionic CM
metrizamide, iopamidol and iohexol and of the dimeric ionic CM iocarmate
[19-27,32]. Slight to moderate local reactions were observed under the nonionic CM (300 mg iodine/ml) from an injection volume of 1.2 mlJmonkey (corresponding to approx. 0.3 mlJkg). The tolerance of the ionic CM iocarmate was
graded as worse on the basis of much more pronounced reactions. No differences in the local tolerance were observed between metrizamide, iopamidol
and iohexol at an injection volume of 1.2 mlJmonkey and an iodine concentration of 300 mg/ml [23,26]. It was found on increasing the injection volume
(3.6 mlJmonkey) and the iodine content (370 mg iodine/ml) that the local
tolerance of iohexol was superior to that of metrizamide [27].
In dogs, on the other hand, no leptomeningeal changes were observed after
intrathecal administration of iopamidol and iohexol (each 300 mg iodine/ml) at
an injection volume of 3 ml per animal (corresponding to approx. 0.2 mlJkg)
[45]. Our own studies have shown that iotrolan and iopromide (each 300 mg
iodine/ml) also cause no leptomeningeal changes in the dog after either single
or repeated administration (4 injections at intervals of 1 week) of high volumes
(0.6 - 0.83 mlJkg). Rats also showed no leptomeningeal reactions after repeated
intracisternal administration (4 injections) of up to 0.2 ml iotrolan per rat
(corresponding to approx. 0.8 mlJkg) [47].
21
22
CHAPTER 1 General Fundamentals
Numerous studies [2,3,8,11,18,30,38,54-56] have shown that metrizamide,
which has long been used for myelography, is locally well tolerated after
intrathecal administration in man. No local irritative effects have so far been
reported after intrathecal administration of iotrolan, either.
A local tolerance study after intratracheal administration is required for the
risk estimation both of CM intended for use in bronchography and for orally
administered CM which might enter the lungs after inadvertent aspiration.
A comparative study of the pulmonary tolerance has been performed in
dogs after a single intrabronchial dose of 0.6 ml/kg iotrolan (Isovist®-300),
iopromide (Ultravist®-300) and diatrizoate (Angiografin®,306 mg iodine/ml)
[44]. For the assessment of the pulmonary tolerance, the weights of the lungs
and the oxygen partial pressure in arterial blood were determined and histological studies performed. The results of this study showed that the tolerance of
the two non-ionic CM is much better than that of the ionic CM tested.
Estimate of the Risk of Occurrence of Anaphylactoid Reactions
Although it has long been known for man that anaphylactic reactions in the
form of cutaneous reactions, nausea, vomiting, bronchoconstriction and even
circulatory failure can occur after administration of iodinated CM, the pathogenesis of these reactions is still not known. This is one of the reasons why no
animal model is available even today which permits an estimate of the risk
regarding the occurrence of anaphylactoid reactions.
In systemic tolerance studies, no comparable reactions were observed in any
of the animal species tested (rat, dog and monkey) even after repeated administration over a period of up to 4 weeks. Studying histamine release from mast
cells and testing complement activation in vitro have likewise produced only
few reliable indications of just how likely a CM is to trigger such reactions. Nonionic CM appear to be less active than ionic compounds in these two test
systems [9,35,41-43,58]. Because of the absence of a suitable preclinical test
model, a reliable estimate of the risk regarding the occurrence of anaphylactoid
reactions can be made only in clinical studies in man on the basis of the incidence and severity of such reactions.
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28. Irstam L, Rosencrantz M (1974) Water-soluble contrast media and adhesive arachnoiditis.
Acta Radiol15: 1-15
29. Irstam L (1978) Lumbar myelography with amipaque. Spine 3: 70 - 82
30. Irstam L et al. (1974) Lumbar myelography and adhesive arachnoiditis. Acta Radiol Diagn
15:356-368
31. Johansen JG et al. (1984) Arachnoiditis from myelography and laminectomy in
experimental animals. Am J Neuroradiol5 : 97 - 9
23
24
CHAPTER 1 General Fundamentals
32. Jorgensen J et al. (1975) A clinical and radiological study of chronic lower spinal
arachnoiditis. Neuroradiology 9 : 139 -144
33. Kropelin T et al. (1983) The risk liability of nephrotropic contrast media: Clinical and
experimental results. In: Taenzer V, Zeitler E (eds) Contrast media in urography, angiography and computerised tomography. Thieme, Stuttgart, pp 129 -142
34. Lang JH et al. (1976) Activation of serum complement by contrast media. Invest Radiol
11: 303-308
35. Lang R (1990) Priifung auf genotoxische Wirkung. In: Kuemmerle HP et al. (eds).
Klinische Pharmakologie Bd 1, 11-2.4.5., 4. Aufl, 24. Erg Lfg 2/90 Ecomen, Landsberg
36. Liliequist B, Lundstrom B (1974) Lumbar myelography and arachnoiditis. Neuroradiology
7:91-94
37. McCormick CC et al. (1981) Myelography with metrizarnide. An analysis of the complications encountered in cervical, thoracic and lumbar myelography. Aust NZ J Med
11: 645-650
38. Mc Neill TW et al. (1976) A new advance in water-soluble myelography. Spine 1: 72- 84
39. Moreau JF et al. (1980) Tubular nephrotoxicity of water-soluble iodinated contrast media.
Invest Radiol15 (Supp16): S54-S60
40. Muetzel W, Speck U (1983) Tolerance and biochemical pharmacology of iopromide. In:
Taenzer V, Zeitler E (eds) Contrast media in Urography, Angiography and Computerised
Tomography. Thieme, Stuttgart, New York, pp 11-17
41. Muetzel W, Speck U (1983) Tolerance and biochemical pharmacology of iopromide.
Fortschr Geb Rontgenstr Nuklearmed 118 : 11-17
42. Muetzel W, Speck U (1983) Pharmacochemical profile of iopromide. Am J Neuroradiol
4: 350-352
43. MiiIler N et al. (1991) Results of comparative pulrnonal tolerance study in the dog following a single intrapulrnonal application of three iodine-containing X-ray contrast
media (Isovist-300, Ultravist-300, Angiografin) Poster, Eurotox-Kongress, Maastricht,
01- 04 Sep. 1991
44. Pasaouglu A et al. (1988) An experimental evaluation of response to contrast media. Pantopaque, iopamidol and iohexol in the subarachnoid space. Invest Radiol 23: 762-766
45. Poggel HA (1984) Reproduktionstoxikologische Untersuchungen. In: Kuemmerle HP et al.
(eds) Klinische Pharmakologie, Bd 1,11-2.4.6.,4. Aufl. Ecomed, Landsberg
46. Press WR et al. (1989) Tolerance to iotrolan after subarachnoid injection in animals. Fortschr Geb Rontgenstr Nuklearmed 128 :126 -133
47. Rees JA et al. (1997) An ultrastructural histochemistry and light microscopy study of the
early development of renal proximal tubular vacuolation after a single administration of
the contrast enhancement medium "iotrolan". Toxicologic Pathology 24: 158 -164
48. Sage MR (1989) Neuroangiography. In: Skucas J (ed) Radiographic contrast agents, 2nd
edn. Aspen, Rockville, pp 170 -188
49. Scherberich JE et al. (1991) Unerwiinschte Kontrastmitteleinwirkungen an der Niere. In:
Peters PE, Zeitler E (eds) Rontgenkontrastmittel. Springer, Berlin, Heidelberg, New York,
pp 65-69
50. SchObel C, Giinzel P (1984) Systemische Vertraglichkeitspriifungen bei wiederholter Verabreichung subakute und chronische Toxizitatspriifung. In: Kuemmerle HP et al. (eds)
Klinische Pharmakologie. Bd. 1, 11-2.4.3., 4. Aufl. Ecomed, Landsberg
51. Schobel C, Siegmund F (1984) Lokale Vertraglichkeitspriifungen. In: Kuemmerle HP et al.
(eds) Klinische Pharmakologie. Bd. 1, 11-2.4.7., 4 Aufl. Ecomed, Landsberg
52. Schobel C, Giinzel P (1991) Methoden und Ergebnisse toxikologischer Priifungen von
nichtionischen Rontgenkontrastmitteln. In: Peters PE, Zeitler E (eds). Rontgenkontrastmittel. Springer, Berlin, Heidelberg, New York, pp 5-7
53. Schmidt RC (1980) Mental disorders after myelography with metrizamide and other
water-soluble contrast media. Neuroradiology 19: 153-157
54. Skalpe 10 (1978) Adhesive arachnoiditis following lumbar myelography. Spine 3: 61- 64
55. Skalpe 10 (1977) Lumbale Myelographie mit wasserloslichen Kontrastmittein (Metrizamid). Akt Neurol 4: 179 -183
1.5 Physicochemical Properties of Contrast Media
56. Tervahariala P et al. (1997) Structural changes in the renal proximal tubular cells induced
by iodinated contrast media. Studies in dehydrated rats. Nephron 76 :96 -102
57. Tirone P, Boldrini E (1983) Effects of radiographic contrast media on the serum complement system. Arch Toxicol (SuppI6): 37-41
1.5
Physicochemical Properties of Contrast Media:
Osmotic Pressure, Viscosity, Solubility, Lipophilicity,
Hydrophilicity, Electrical Charge
U. SPECK
Introduction
The most important physicochemical features of water-soluble, iodinated CM are
their solubility, the viscosity and osmolality of their solutions, the lipophilic or
hydrophilic qualities of the molecules carrying the iodine, their electrical charge
(Table 1.5.1) and the ability to interact with biomolecules through hydrogen
bonding. This section describes the practical significance of these features [9]:
Water Solubility
Very high water solubility is an absolute requirement for the production of
highly concentrated CM of good X-ray density. Meglumine salts are generally
Table 1.5.1 The most important physicochemical features of water-soluble iodinated contrast
media
Feature
Significance
Solubility
Maximum po sible concentration; sometimes means dissolving
crystals before use
Speed of injection, infusion.
In selective angiography, very viscous solutions can disturb
microcirculation
Pain in some angiographic indications, endothelial damage,
arachnoiditis (?) in myelography,
bradycardia in cardioangiography,
hypervolaemia after administration of high doses, diuresis
Frequent general reactions (nausea, vomiting, allergy-like reactions),
especially in high doses and with rapid injection; protein binding,
hindrance of glomerular filtration, tubular ecretion and of biliary
excretion; permeation through cell membranes, enteral absorption
Improvement of solubility, increase in hydrophilicity,
epileptogenicity
Viscosity
Osmotic pre sure
Lipophilia,
hydrogen bonding
Electrical charge
25
26
CHAPTER 1
General Fundamentals
more soluble than sodium salts. The solubility of nonionic CM results, as in
sugars or peptides, from hydrophilic groups such as -OH and -CONH-. Some
CM on the market may crystallize at low temperatures: To dissolve these
crystals, they have to be warmed before use.
Viscosity
Viscosity is a measure of the fluidity of solutions. It is measured in millipascals
(mPa) per second, which are identical to the older unit, the centipoise (cP). Viscosity increases greatly with rising concentration and with falling temperature
(Fig. 1.5-1, 1.5.2).
Low viscosity means above all that the CM in question can be quickly injected without too much effort or pressure. This is advantageous in urography,
allowing high plasma levels and subsequent rapid excretion to be achieved [5].
In some angiographic techniques (narrow catheter lumen, high rates of flow),
low viscosity is crucial. Moreover, low-viscosity CM mix more rapidly and
homogeneously with the blood and, in selective arteriography, flow better
through the smaller vessels and capillaries when undiluted or slightly diluted
[6]. Preparations containing iopromide or iopamidol are suitable low-viscosity
CM for angiography, CT and urography. The sodium salts of ionic CM should
also be mentioned here, although not without strong reservations, since they
are so poorly tolerated by patients.
In certain investigations, high viscosity can be advantageous, for example if
one seeks to coat surfaces or prevent too rapid dilution. In angiography, more
viscous CM can produce somewhat longer-lasting and thus better contrast [8].
Since contact time with blood vessels is lengthened in this way, implementation
mPa·s (=cP)
mPa·s (=cP)
24
20
20·C
30
16
•
20
12
•
37"C
8
4
o ¥===:;::::=--,....-----,----r--o
100
200
300
400 mg lod/ml
Fig. 1.5.1. Viscosity of Ultravist in relation
to the concentration
10
o
5
10
15
20
25
30
35
Fig. 1.5.2. Viscosity of Ultravist
relation to the temperature
4O·C
370
in
1.5 Physicochemical Properties of Contrast Media
Fig. 1.5.3. Viscosity of different CM at 300 mgl/ml>37°C
Solutions
ViscosIty
Blood
Meglumlne diatrizoale
Sodium d;atn.oate
i==
Meglumlne lodipamlde
Meglumine loca,male
Meglumlne io.eglale
Metrlzam,de
lopemidcl
lohe.ol
lop,omide
lotrelan
2
4
6
8
mPa s (-
10
cPl
of this principle presupposes very good local tolerance. CM with higher viscosity are the so-called dimers (hexaiodinated substances): these include, in addition to the intravenous biliary CM (e.g. iodipamide), the ionic compound
sodium meglumine ioxaglate (Hexabrix) and the nonionic CM iotrolan (Isovist) and iodixanol (Visipaque). At the same temperature and with the same
iodine concentration, different CM have different viscosities (Fig. 1.5.3).
Osmolality
The osmolalities of CM solutions are indicated in milliosmoles per kilogram of
water, in megapascals or in atmospheres (1000 mOsmlkg = 2.58 MPa = 25.5 atm).
The osmolality is roughly proportional to the number of freely moving parFig. 1.5.4.
Relationsship of the osmolality of Ultravist to the CM
concentration
Osmolality at 37"C; mosm/kg water
800
700
600
500
400
300 --
---------------blood--
200
100
0-1"----,--.,....---,--.,----o
100
200
300
400 mg Ilml
27
28
CHAPTER
1
General Fundamentals
tides (molecules, ions) per kilogram water. It is strongly dependent upon the
concentration and weakly dependent upon temperature (Fig. 1.5.4). Different
CM with identical iodine concentrations can display very different osmolalities
(Table 1.5.2). Most of the CM currently on the market are hypertonic compared
to the blood at concentrations commonly used in angiography. Exceptions to
this are diluted, so-called low-osmolar CM such as Ultravist 150 and Hexabrix
160 and, in particular, Isovist and Visipaque; the latter, even at 300 mg IIml, are
practically isotonic with blood and body fluids [4].
The high osmotic activity of standard ionic CM was one of the most important causes of side effects in vascular imaging when the solutions were not
heavily diluted before use (phlebography and intraarterial digital subtraction
angiography). In high intravenous doses and in body cavity imaging, many of
the undesired effects can be ascribed to the high osmolality of most CM (Table
1.5.3) [1]. On the other hand, reactions such as nausea, vomiting, allergy-like
Table 1.5.2.
Osmolality of ionic and
nonionic contrast media at
37°C; mean ±950/0 confidence interval)
Fluid
mg 11m!
Blood
Osmolality
mOsmlkg water
290
lonicCM
Urografin 30%
45%
60%
76%
370
Angiografin
306
1530
Urovist
306
1530
loxaglate
(sodium meglumine)
320
160
150
577 ± 13
ca. 300
ca. 300
240
300
301
483 ± 17
586 ± 5
774 ± 10
lopamidol
200
300
370
437 ± 16
653 ± 7
832 ± 34
Omnipaque
240
300
350
525 ± IS
685 ± 10
823 ± 23
Nonionic CM
Ultravist
146
219
292
710
1050
1500
2100
Amipaque
300
480
Optiray
300
661
Imagopaque
300
684
lomeron
300
540
Xenetix
300
724
Isovisl
300
294
Visipaque
270
290
1.5 Physicochemical Properties of Contrast Media
Table 1.5.3. Pharmacological effects based on the hyperosmolality of CM
Angiography
Myelography
Pain
Depression/Sedation
Damage to endothelium
Pain
Damage to blood-brain barrier
Arachnoiditis
Thrombo i and thrombophlebitis
Bradycardia and increase in contractility
in angiocardiography
Increa e in the pulmonary blood pre ure
Va odilatation and hypotension
In any intravascular application of high CM doses
Other body cavities
Vasodilatation and drop in blood pressure
Fast dilution
Hypervolemia
Increase in diure is
Local inflammatory reactions
Pulmonary edema
Increased peristalsis
reactions and certain cardiovascular effects are clearly not osmotically induced.
They can also occur with highly diluted or even isotonic CM (such as cholegraphic media) or when very small amounts of CM are administered.
Lipophilicity
Lipophilicity refers to the affinity of molecules containing iodine for fats or
lipid-dissolving agents and hydrophilicity to their affinity for water. The lipophilicity of CM acids containing iodine or of nonionic CM is determined by the
way they distribute themselves between solvents non-miscible with water
(Octanol, butanol) and an aqueous buffer with physiological pH value (distribu-tion coefficient) (Fig. 1.5.5). By the 1950S, the connection between increasing
tolerance and decreasing lipophilicity had been recognized [3]. At the same
time, it was found that lipophilic CM (acids) tended to be excreted by means of
active transport processes, for example, biliary CM through the liver and the
previously common urographic media through glomerular excretion in the
kidneys. Moreover, oral cholegraphic media have to be highly lipophilic in
order to be enterally absorbed.
These features-toxicity and active transport-are obviously mediated by the
increased binding to proteins in the body, including the transport proteins, that
results from the lipophilicity of the molecules. The acid group of ionic CM plays
a decisive role in this binding, even though their hydrophilicity is increased to
a tremendous extent by it.
Nonionic X-ray CM are more lipophilic than comparable ionic urographic
agents since they lack an acid group. They are, nevertheless, clearly better
tolerated than the latter. Presumably, the low level of interaction between the
29
30
CHAPTER 1
General Fundamentals
Fig. 1.5.5.
Partition coefficients of different X-ray CM between
n-butanol and a buffer
(pH 7.6)
Substance
Diatrizoate
lodiPamide• • • •
locarmate
loxaglate • • •
lotrolan
lopromide _ r - - Metrizamide
lopodate -I
II.
+1-..--r---,-----tI
o 0.1 0.2 0.3
7
8
Partition coefficient
neutral nonionic molecules and proteins, membranes and other biological
substrates is more significant than lipophilic or hydrophilic factors.
Hydrogen bonding
On a molecular level most biological interactions are mediated by hydrogen
bonding (e.g. folding of polypeptides, DNA). Hydrophilic CM contain important structural elements to initiate or participate in hydrogen bonding.
As hydrogen bonding results in reversible binding to proteins it can be easily
measured.
Electrical Charge
Ionic CM are salts of electrically negatively charged acids containing iodine.
Positively charged cations do not contain any heavy elements; they thus do not
contribute to the contrast density of the substances on the market, but can
influence tolerance. Negatively charged CM acids and positively charged cations
(e.g., Na+ and meglumine+) move independently of one another in the body
and can also be excreted in different ways. The ionic character of the molecules
influences their biological behaviour in a host of ways. In biliary CM, the use of
the hepatic acid transport mechanism is, of course, premised upon it. In contrast, electrical charge is undesirable in CM used in angiography, urography and
CT. It contributes to protein binding and the inhibition of enzymes. The calcium
binding of CM acids increases the negative inotropic effect on the heart [7]. The
better tolerance in many regards of nonionic CM has also been indisputably
proven in the meantime in clinical tests [2]. Finally, the completely unsatisfactory tolerance of ionic CM in myelography should also be emphasized.
1.6 Pharmacokinetics of Contrast Media
References
1. Grainger RG (1987) Osmolality and osmolality-related side effects. In: Contrast media
from the past to the future. Berlin, March 27 - 28. Thieme, Stuttgart
2. Katayama H, Tanaka T (1988) Clinical survey of adverse reactions to contrast media. Invest
Radiol 23 : S88 - S89
3. Knoefel PK, Huang KC (1956) The biochemorphology of renal tubular transport: iodinated
benzoic acids. J Pharm Exp Ther 117: 307 - 316
4. Krause W, Niehues D (1996) Biochemical characterization of contast media. Invest Radiol
31: 30-42
5. Mitchell DG, Friedman AC (1985) Viscosity of iodinated contrast agents: significance for
peripheral venous injection. J Comput Tomogr 9 :77 -78
6. Morris TW, Kern MA, Katzberg RW (1982) The effects of media viscosity on hemodynamics in selective arteriography. Invest Radiol17: 70 -76
7. Morris TW, SalIIer LG, Fischer HW (1982) Calcium binding by radiopaque media. Invest
RadioI17:501-505
8. Nauert CM, Langer M, Miitzel W (1989) Hemorrheologic effects of Iotrolan after intraarterial injection in rabbits: comparison with other types of contrast media. Fortschr Geb
Rontgenstrahl Nuklearmed SUppl128 : 40 - 45
9. Speck U (1987) Newer perspectives in contrast media chemistry. In: Parvez Z, Moncada R,
Sovak M (eds) Contrast media: biological effects and clinical application, vol 1. CRC Press,
Boca Raton
1.6
Pharmacokinetics of Contrast Media
W. KRAUSE and
G. SCHUHMANN-GAMPIERI
Introduction
CM can be classified according to their contrast mechanism and the imaging
technique with which they are to be used. For instance, iodinated CM are used
for X-ray CM imaging, paramagnetic CM for MRI, radiopharmaceuticals for
nuclear medicine and gas-containing micro bubbles for US. From a pharmacokinetic point of view, however, the pattern of biodistribution of CM is the
most suitable form of classifications, distinguishing between extracellular fluid
CM (ECF-CM; angiography, urography, myelography), hepatocellular or tissuespecific CM (e. g. cholangiography, liver imaging) and macromolecular CM or
micro bubbles that are confined to the vascular space (blood pool). At present,
however, CM of this last type are only available for US and for nuclear
diagnostics whereas macromolecular CM for X-ray and MR imaging are at an
early research stage. Therefore at present blood pool enhancement for
modalities other than US or nuclear diagnostics has to be performed with
extracellular fluid CM applying high doses and fast imaging techniques.
31
32
CHAPTER 1
General Fundamentals
Extracellular Fluid Contrast Media
In general, ECF-CM are either negatively charged ionic molecules (Urografin,
Angiografm, Urovist, Hexabrix for X-ray; Magnevist for MRI) or nonionic
molecules (Ultravist, Niopam, Iopamiron, Omnipaque, Isovist for X-ray, Prohance, Omniscan for MRI, Table 1.6.1). Very high water solubility, low distribution coefficients between butanol and buffer and low binding to plasma proteins (< 5 %) are the main features of ECF-CM. After intravenous administration
ECF-CM are rapidly distributed between the vascular and the interstitial spaces
with a distribution half-life of about 3-10 min [22, 34, 36]. Time-density curves
for a number of different vessel and tissue systems obtained after rapid i. v.
injection (5 mL/sec) of a total dose of 13.5 g iodine and subsequent scanning by
ultrafast CT are given in Fig. 1.6.1. The ECF-CM are cleared from the blood with
an elimination halflife of about 1.5-2 h [22,34,36]. The major organ of elimination is the kidney, glomerular filtration being the main process of renal
elimination. The renal and total blood clearance are therefore close to the
individual's creatinine clearance. Consequently, attempts have been made to use
Table 1.6.1. Overview of contrast media (X-ray, MRI and nuclear medicine) with respect to
their biodistribution
Tissue-specific (hepatobiliary) CM
Extracellular fluid CM
Trade name
Chemical name
Trade name
Chemical name
Amipaque
Angiografin, Urografm,
Urovison, Urovi t
DOTAREM
Hexabrix
lmagopaque
lopamiron, iopam,
Solutrast
lomeron
lsovist
Magnevist
Omnipaque
Omniscan
Optiray
Prohance
U1travist
Visipaque
Xenetix
Metrizamide
Diatrizoate
Bili.Jnjro
Biliscopin
lopronic acid
lotroxic acid
Gd-DOTA
loxaglate
ropentol
ropamidol
Biloptin
Cholebrine
Endomirabil
Telepaque
lopodate
locetamic acid
lodoxamic acid
lopanoic acid
lomeprol
lotrolan
Gd-DTPA
Iohexol
Gadodiamide
Ioversol
Gadoteridol
lopromide
lodixanol
lobitridol
51Cr-EDTA
99mTc-DTPA
Eovist
Gd-EOB-DTPA
Gadobenate
Mn-DPDP
Teslascan
Abbreviations: Gd-DTPA: gadolinium diethylenetriaminepentaacetate (gadopentetate)
EDTA: ethylenediaminetetraacetate
Gd-EOB-DTPA: Gd-ethoxybenzyl-DTPA
Mn-DPDP: manganese dipyridoxyldiphosphate.
1.6 Pharmacokinetics of Contrast Media
150
100
5
E
?:'
';;;
c
a
C1I
50
Portal vein
o-t--...-::::,.-----,r---,....----r------,---,---.,...----,
o
20
40
60
80
100
120
140
160
TIme (5)
Fig. 1.6.1. CT enhanced curves in different vessels and tissues of patients after intravenous
injection of 13.5 g iodine at a rate of 5 mL/sec. Data are means of 25-27 patients and were
obtained by ultrafast CT followed by fitting curves to measured enhancement values using
the computer program TOPFIT [11]
ECF-CM for assessment of renal function [6,8]. In patients with normal renal
function the extrarenal elimination of ECF-CM is low (< 2%).
Since ECF-CM are not distributed to any great extent into the intracellular
compartment, the volume of distribution of an ECF-CM is about 0.2sllkg, a
value which typically represents the extracellular fluid space. No passage
through the erythrocyte membrane occurs, and in man biotransformation has
not been observed for any ECF-CM so far. Neither does measurable enterohepatic recirculation occur. In the dose ranges investigated, the pharmacokinetics were found to be linear or proportional to the dose [34]. In general,
transfer of ECF-CM to human milk is low. Thus the daily dose a suckling infant
would ingest is reported to be at most o.os % of the administered dose for the
ionic CM Angiografin and Magnevist, while for the nonionic CM Omnipaque a
maximum of o.s% was reported [S, 26]. Results from animal studies clearly
indicate that passage through the intact blood-brain barrier can mostly be
excluded for ECF-CM, whereas the placental barrier is somewhat more leaky.
After oral use, absorption of ECF-CM from the gastrointestinal mucosa is low
and so diatrizoate could not only be developed for intravascular use (Urografin,
Angigrafin) but also as a drinking solution (Gastrografin) to fIll the bowel for
imaging of the gastrointestinal tract. Since glomerular fIltration is the predominant route of elimination, the renal clearance of ECF-CM is reduced in
renally impaired patients, thus increasing the elimination half-life. For Magnevist the renal clearance was reduced from 120 ml/min (normal renal function) to
20 ml/min or less, depending on the degree of renal failure and the patient's
glomerular fIltration rate (GFR) [14]. Consequently, the typical value of 1.S h for
33
34
CHAPTER 1
General Fundamentals
100
Gd-DTPA HALF-LIFE IN SERUM (h)
10
*
*
*
*--------
1-+---.----,-----.-----,-----,-----,
o
20
40
60
80
100
120
CREATININE CLEARANCE (ml/min)
Fig. 1.6.2. Relation between creatinine clearance and elimination half-life of Magnevist
(Gd-DTPA) in serum after single intravenous administration of 0.1 mmollkg in patients with
chronic renal failure. The fitted line approaches the elimination half-life of 1.5 h when renal
function is normal (creatinine clearance of 120 ml/min). The same curve was observed when
iopamidol (Niopam) was given to patients with chronic renal failure at a dose of 18 g I [16)
the elimination half-life of an ECF-CM increased to 10 h or more, as is demonstrated in Figure 1.6.2 for both Magnevist and Iopamidol [7,28]. Nevertheless,
despite the increased residence time of the ECF-CM in the body of the renaliy
impaired patient, elimination was prolonged but complete for both nonionic
X-ray CM and Magnevist [7,28] and renal tolerance was good. Only in patients
with severely impaired renal function (GFR < 20 rnI/min) might haemodialysis
be necessary for shortening the elimination half-life and it has proved to be
efficient and safe for many ECF-CM, e. g. Angiografin, Omnipaque, Ultravist
and Magnevist [1,10,14,33]. 51Cr and 99mTc are often used as radionuclides in
nuclear medicine. Intravenous administration of the free metal ions would
result in uptake in the liver, spleen and bone, but complexing with the hydrophilic chelates diethylenetriaminepentaacetate (DTPA) and ethylenediaminetetraacetate (EDTA) changes the pharmacokinetics in the desired way. 99mTcDTPA or 51Cr-EDTA show very high water solubility, low protein binding,
distribution into the extracellular fluid space and rapid elimination from the
body by glomerular flltration when administered intravenously. From a
pharmacokinetic point of view these chelates are ECF-CM as well, and consequently the basic pharmacokinetic principles and features outlined above can
be applied to 99mTC-DTPA or 51Cr-EDTA. The basic pharmacokinetic features
of ECF-CM are summarized in Table 1.6.2.
1.6 Pharmacokinetics of Contrast Media
Table 1.6.2.
Summary of the pharmacokinetic features of extracellular fluid contrast media
High hydrophilicity
Very low binding to plasma proteins « 5%)
Predominantly renal elimination through glomerular
filtration
Elimination half-life of 1.5-2 h
Very little extrarenal elimination « 2 %)
Pharmacokinetics linear or proportional to dose
o biotransformation
o enterohepatic circulation
Prolonged but complete elimination in renal insufficiency
Dialysable
egligible pas age of the blood-brain and placental barrier
Little enteral absorption
Tissue-Specific Contrast Media
Hepatobiliary Contrast Media
Tissue specificity has been the goal for many therapeutic and diagnostic drugs.
Targeting of the drug to the tissue of interest should reduce both the dose
necessary to yield a certain drug concentration there and the side effects since
no major distribution to, and interaction with, other tissues should occur. Interestingly, this goal has essentially been reached for the iodinated hepatobiliary
CM: apart from being distributed into the extracellular fluid space, these agents
are only distributed intracellularly in the hepatocytes. Although they are useful
for cholecystography and cholangiography, the concentration achieved in the
hepatocytes is not sufficient to provide useful contrast enhancement in the
liver. In general, iodinated hepatobiliary CM are negatively charged ionic molecules that are less hydrophilic than ECF-CM due to an appropriate chemical
substitution [2]. This balance between hydrophilic and lipophilic features allows the iodinated hepatobiliary CM to dissolve in the intestinal lumen, be
absorbed and distributed into the extracellular fluid space and be taken up by
the hepatocytes and excreted via the bile. The monomeric hepatobiliary CM are
designed for oral use (Biloptin, Cholebrine, Bilimiro, Telepaque; Table 1.6.1)
whereas the dimeric hepatobiliary CM are for intravenous use (Biliscopin,
Endomirabil; Table 1.6.1).
In general, the solubility in water of the oral iodinated hepatobiliary CM at
physiological pH values is low, ranging from 0.6 mmolll to about 30 mmolll (the
water solubility of ECF-CM is in the order of 500 to 1000 nmolll). As a consequence of the lower hydrophilicity, iodinated hepatobiliary CM exhibit considerable plasma protein binding, which at the same time, however, seems to be
important in increasing the solubility in plasma and prevents premature renal
excretion. Plasma binding of iodinated hepatobiliary CM is of the order of
35
36
CHAPTER 1
General Fundamentals
70 % - 95 % and appears to be saturable (nonlinear) since binding clearly
depends on the CM concentration bO,31].
Administered intravenously, iodinated hepatobiliary CM are reversibly and
nonspecifically bound to plasma proteins, and an equilibrium is established
between the free, unbound CM concentration and the bound CM concentration
in the blood. The free, unbound CM is better able to leave the intravascular
space, is freely distributed into the interstitial space and at the same time undergoes glomerular filtration via the kidneys. Of the total dose of iodinated hepatobiliary CM administered, 10 % - 35 % is excreted renally [30]. Besides being eliminated renally - a process which for most iodinated hepatobiliary CM has been
shown to be linear or nonsaturable [2] - the majority of the free unbound CM is
specifically taken up by the hepatocytes and excreted into the bile, which makes
the CM suitable for cholangiography. This process of biliary excretion, however,
proved to be saturable for all iodinated hepatobiliary CM in the diagnostic dose
range applied. Saturation or inhibition of biliary excretion was reported from
intensive studies using increasing doses or coadministering compounds competing for the same transport mechanism across the hepatocyte membrane,
e.g. sulphobromophthalein bilirubin or even other hepatobiliary CM [17].
Extrarenal elimination due to biliary excretion plays a major role in the disposition of the iodinated hepatobiliary CM in the body. The liver can clear the
blood of compounds in a single pass. This phenomenom is called a "first-pass
effect": it occurs especially with the orally administered iodinated hepatobiliary
CM since a substantial proportion of the dose is cleared by the liver before the
CM reaches the systemic circulation. However, it must be taken into consideration that for a drug with high hepatic clearance this parameter, and consequently the plasma concentration, is heavily dependent on the liver blood
flow of the individual. Because of this and because of interindividual variations
in plasma protein binding, greater variability is observed in the pharmacokinetics of the iodinated hepatobiliary CM than with ECF-CM.
Iodinated hepatobiliary CM for oral use are less water soluble than the corresponding intravenous compounds. They are subject to biotransformation. Iopodate (Biloptin) undergoes glucuronidation in the liver and is excreted via the bile
as the more water soluble glucuronide species [2]. The glucuronidation also
prevents reabsorption from the intestinal lumen (enterohepatic recirculation).
Probably due to their higher lipophilicity, iodinated hepatobiliary CM are able to
pass into human milk to a slightly greater extent than ECF-CM. For iopanoic acid
the maximum amount an infant would ingest is reported to be 6.9 % of the dose.
Exposure of the infant may be limited by delaying breastfeeding for 24 h [5].
For MRI too, tissue-specific hepatobiliary contrast agents (lipophilic derivatives of the hyrophilic paramagnetic chelates) are under development and will
soon be available. The three most advanced hepatobiliary CM for MRI are gadolinium-ethoxybenzyl-diethylenetriaminepentaacetate (Gd-EOB-DTPA), gadobenate dimeglumine, and manganese dipyridoxyldiphosphate (Mn-DPDP) [9,16,
19,20,23,24,29,32]. Two basic differences favor the hepatobiliary MRI CM: first,
higher sensitivity of MRI means that the CM concentration necessary to obtain
an increase in signal intensity in the liver is ten-fold lower, thus decreasing the
diagnostic tissue concentration significantly; secondly, hepatobiliary MR CM are
1.6 Pharmacokinetics of Contrast Media
only slightly bound to plasma (about 10 %) and there is no saturation in plasma
binding within the clinically useful range of doses and concentrations. This
results in less variability in the pharmacokinetics between individual patients.
The basic pharmacokinetic features of hepatobiliary CM are summarized in
Table 1.6.3. Surprisingly, it has been found that Gd or Dy-EOB-DTPA at high
dodes (0.3-0.5 mmollkg) are also suitable for CT imaging [4,13,27].
Contrast Media for the Reticuloendothelial System
CM for the reticuloendothelial system (RES CM) are not commercially available
yet. However, many attempts have been made to direct particulate CM selectively to the Kupffer cells of the liver and spleen, basically in order to avoid distribution of the CM into the extracellular fluid space and thus decrease the dose
needed for sufficient enhancement of liver and spleen. Three major approaches
(Table 1.6.4) have been undertaken to obtain RES CM particles: first, encapsulation of the CM (Gd-DTPA as well as iopromide or diatrizoate) into liposomes
[12]; secondly, the synthesis of iron oxide particles (magnetites) for MRI [3,18,
21,35]; and third, making gas-containing microcapsules for ultrasound (US).
From a pharmacokinetic standpoint, targeting of CM to the reticuloendothelial
system raises many questions: Are there species differences in the relative
Table 1.6.3. Summary of the pharmacokinetic properties of hepatocellular contrast media
Hydrophiliciry
Plasma binding
Renal elimination
Extrarenal (biliary) elimination
Saturabiliry of biliary excretion
Dose-dependent kinetics
Biotransformation
Enterohepatic recirculation
X-ray
MRI
Moderate
High (70%-95%, saturable)
Low (10%-35%)
High
Yes
Yes
Only oral CM
Only oral CM
High
Low (10%)
Moderate to high
Low to moderate
Yes
Yes
No
No
Table 1.6.4. Characteristic of particulate contrast media for liver imaging
Modality
X-rayfMRI
Type of particle
Liposomes
Entrapment of
iodinated CM/Gd
chelate
Preparation
MRI
US
Magnetites
Microcapsules
Superparamagnetic
particles (Fe,04)
with hydrophilic
coating
tabilized air bubble
(polymer coating)
Target Tissue
Elimination
RES
RES
RES
CM
Renal excretion
Biodegradation
Biodegradation
Dissolution
Biodegradat ion
Biodegradation
Coating
37
38
CHAPTER 1 General Fundamentals
weight of the liver and/or in the phagocytic activity? How does the particle size
influence biodistribution? What is the effect of particle surface charge? Does
saturation of uptake in the reticuloendothelial system occur or, in other words,
are the pharmacokinetics of RES eM nonlinear and dose dependent?
For MRI the first particulate contrast agent has already reached the market
(Endorem) and the next generation of better tolerated substances (Resovist) is
under clinical development. For the extremely low doses used in MRI (lower
micromol range per kg), saturability does not seem to be an issue. However, for
X-ray imaging, where at present several liposome preparations are being
developed, the high doses necessary for this modality (upper milligram range
per kg) not only seems to imply saturation phenomena but also significant
tolerability problems so that, at present, no preparation has reached phase II. A
reduction of liposome size to 100 - 200 nm or a modification of the surface by
attaching long pegylated chains resulted in prolonged circulation times (bloodpool imaging) [IS, 25]. However, these liposome preparations have not yet
passed the preclinical stage. The future will show whether modifications of the
available liposomes will be possible to achieve sufficient tolerance in this interesting approach to tissue specifity.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Ackrill P, McIntosh S, Nimmon C et al. (1976) A comparison of the clearance of urographic
contrast medium sodium diatrizoate by peritoneal and haemodialysis. Clin Sci Med 50: 69 -74
Barnhart JL (1984) Hepatic disposition and elimination of biliary contrast media. In:
Sovak M (ed) Radiocontrast agents. Springer, Berlin Heidelberg New York, pp 367 - 418
Bengele HH, Palmacci S, Rogers J et al. (1994) Biodistribution of an ultrasmall superparamagnetic iron oxid colloid, BMS 180549, by different routes of administration. Magn
Reson Imaging 12: 433 - 442
Benness G, Khangure, Morris I et al. (1993) Hepatic kinetics and magnetic resonance
imaging of gadolinium ethoxybenzyl diethylenetriaminepentacetic acid Gd-EOB-DTPA
in dogs. Australas Radiol 37: 252 - 255
Bennett PN, Bath FRCP (1988) Drugs and human lactation. Elsevier, Amsterdam
Choyke PL, Austin AH, Frank JA et al. (1992) Hydrated clearance of gadolinium-DTPA as
a measurement of glomerular fIltration rate. Kidney Int 41: 1595 -1598
Corradi A, Menta R, Cambi Vet al. (1990) Pharmacokinetics of iopamidol in adults with
renal failure. Arzneimittelforschung/Drug Res 40 (II): 830 - 832
Effersoe H, Rosenkilde R, Groth S et al. (1990) Measurement of renal function with iohexol or
a comparison of iohexol, 99mTc-DTPA, and 51Cr-EDTA clearance. Invest Radiol 25: 778 -782
Hamm B, Staks T, Miihler A et al. (1995) Phase I clinical evaluation of Gd-EOB-DTPA as a
hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging. Radiology
195: 785 -792
Kierdorf H, Kindler J, Winterscheid R et al. (1989) Elimination of the nonionic contrast
medium iopromide in end-stage renal failure by haemodialysis. In: Taenzer V, Wende S (eds)
Recent developments in nonionic contrast media. Thieme, Stuttgart New York, pp 119 -123
Krause W (1996) Applications of pharmacokinetics to computed tomography. Injection
rates and schemes: mono-, bi- or multiphasic. Invest Radiol 31 : 91-100
Krause W, Klopp R, Leike J et al. (1995) Liposomes in diagnostic imaging - Comparison of
modalities - In-vitro visualization of liposomes. J Liposome Res 5 (1): 1- 26
Krause W, Schuhmann-Giampieri G, Bauer M et al. (1996) Ytterbium- and dysprosiumEOB-DTPA: A new prototype of liver-specific contrast agents for computed tomography.
Invest Radiol 31 : 502 - 511
1.6 Pharmacokinetics of Contrast Media
14. Lackner K, Krahe T, G6tz R, Haustein J (1990) The dialysability of gadolinium-DTPA. In:
Bydder G, Felix R, BlicWer E et al. (eds) Contrast media in MR!. Medicom Europe, Bussum,
PP3 21 -3 26
15. Leike J, Sachse A, Ehritt C, Krause W (1996) Biodistribution and CT-imaging characteristics of iopromide-carrying liposomes in rats. J Liposome Res 6 (4) 665 - 680
16. Lim KL, Stark DD, Leese PT et al. (1991) Hepatobiliary MR imaging: first human experience with MnDPDP. Radiology 178: 79 - 82
17. Lin KS, Moss AA, Riegelmann S (1979) Kinetics of drug-drug interactions: biliary excretion
of iodoxamic acid and iopanoic acid in rhesus monkeys. J Pharm Sci 68: 1430 - 1433
18. Majumdar S, Zoghbi SS, Gore JC (1990) Pharmacokinetics of superparamagnetic iron
oxide MR contrast agents in the rat. Invest Radiol 25: 771-777
19. Misselwitz B, MliWer A, Weinmann HJ (1995) A toxicologic risk for using manganese complexes? A literature survey of existing data through several medical specialties. Invest
Radiol 30 : 611- 620
20. Mlihler A, Elferink RPJ, Weinmann HJ (1993) Complete elimination of the hepatobiliary
MR contrast agent Gd-EOB-DTPA in hepatic dysfunction: an experimental study using
transport deficient, mutant rats. MAGMA (N.Y.) 1: 134 -139
21. MiiWer A, Zhang X, Wang H et al. (1995) Investigation of mechanisms influencing the
accumulation of ultrasmall superparamagnetic iron oxid particles in lymph nodes. Invest
Radiol 30 : 98 -103
22. Mlitzel W, Nagel R, Kemper JD, Claufi W (1984) Pharmakokinetik des nichtionischen
R6ntgenkontrastmittels Iohexol. Akt Uro115: 154-156
23. Nelson RC, Chezmar JL, Newberry LB et al. (1991) Manganese dipyridoxyl diphosphate. Effects of dose, time, and pulse sequence on hepatic enhancement in rats. Invest Radiol 26 : 569 - 573
24. Patrizio G, Pavone P, Cardone G et al. (1990) A comparative study between Gd-BOPTA, a
biliary excretion contrast medium, and Gd-DTPA in the magnetic resonance imaging of
the rat. Radiol Med (Torino) 79 : 458 - 462
25. Sachse A, Leike J, Schneider T et al. (1997) Biodistribution and computed tomography
blood-pool imaging properties of polyethylene glycol-coated iopromide-carrying liposomes. Invest Radiol 32 : 44 - 50
26. Schmiedl U, Maravilla KR, Gerlach R, Dowling CA (1990) Excretion of gadopentetate
dimeglumine in human breast milk. AJR 154: 1305 -1306
27. Schmitz SA, Wagner S, Schuhmann-Giampieri G et al. (1997) A prototype liver-specific
contrast medium for CT: preclinical evaluation of gadoxetic acid disodium, or Gd-EOBDTPA. Radiology 202 : 407 - 412
28. Schuhmann-Giampieri G, Krestin G (1991) Pharmacokinetics of Gd-DTPA in patients
with chronic renal failure. Invest Radiol 26 : 975 - 979
29. Schuhmann-Giampieri G, Schmitt-Willich H, Press WR et al. (1992) Preclinical evaluation
of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology 183 : 59 - 64
30. Speck U, Mlitzel W, Herz-Hlibner U, Siefert HM (1978) Pharmakologie der Iotroxinsaure eines
neuen intraven6sen Cholegraphikums. ArzneimittelforschunglDrug Res 28 (II):2143 - 2149
31. Taenzer V, Speck U, Wolf R (1977) Pharmakokinetik and Plasmaeiweifibindung von Iotroxinsaure. Fortschr R6ntgenstr 126 : 262 - 267
32. Vogi TJ, Pegios W, McMahon C et al. (1992) Gadobenate dimeglumine - a new contrast
agent for MR imaging: preliminary evaluation in healthy volunteers. AJR 158 : 887 - 892
33. Waaler A, Svaland M, Fauchald P et al. (1990) Elimination of iohexol, a low osmolar
nonionic contrast medium, by hemodialysis in patients with chronic renal failure.
Nephron 56: 81- 85
34. Weinmann HJ, Laniado M, Mlitzel W (1984) Pharmacokinetics of Gd-DTPAldimeglumine
after intravenous injection into healthy volunteers. Physiol Chern Phys Med NMR 16: 167 -172
35. Weissleder R, Stark DD, Engelstad BL et al. (1989) Superparamagnetic iron oxide: pharmacokinetics and toxicity. Am J Radiol152 : 167 -173
36. Wolf KJ, Steidle B, Skutta T, Mlitzel W (1983) Iopromide. Clinical experience with a new
non-ionic contrast medium. Acta Radiol 24: 55 - 62
39
40
CHAPTER 1
General Fundamentals
1.7
Clinical Documentation of the Tolerance, Safety
and Efficacy of X-Ray Contrast Media
E. ANDREW, W. CLAUSS, A. ALHASSAN, and H. P. BOHN
Prior to release for clinical use, a new X-ray CM must undergo comprehensive
preclinical in vitro and in vivo tests. Although LD50 assessments of X-ray CM
in animals seem, in contrast to therapeutic drugs in general, to correlate well
with the tolerance experienced in patients, it is clinical experience [1] that really counts when the X-ray CM finally reaches human trials and clinical use.
The diagnostic use of X-ray CM is based on the physical ability of iodine to
absorb X-rays not on pharmacological effects, and is similar for all vascular CM
based on iodinated chemical structures. Clinical trials with CM have therefore
concentrated on the recording of adverse reactions and assessment of safety.
However, diagnostic efficacy has also to be confirmed clinically.
Since clinical comparative trials, and particularly randomized double-blind
trials, are the accepted scientific method for evaluating safety and efficacy in
man, the results serve as the basis for important decisions on CM by pharmaceutical companies, regulatory authorities and physicians.
New CM undergoing clinical testing have to pass through a very strict and
meticulous clinical programme with step-wise advancement for safety reasons.
Human beings with increasing range of disease are gradually included as the
clinical trial programme progresses. For new CM, as for other drugs, the clinical
trials up to marketing authorization are generally divided into three phases
(Table 1.7.1). Each phase has to answer specially defined questions and so they
are, in general, conducted sequentially (i. e., knowing the results of the previous
phase), although they may overlap.
For the whole clinical trial programme up to submission of an NDA (New
Drug Application) a time of 4- 6 years is usually needed, although compared to
long-term therapeutic drugs the clinical documentation of vascular CM is
relatively uncomplicated.
The size of the patient population that a CM needs to be tested on to achieve
release or market approval depends on the claims, the indications included and
the regulatory authority involved. Usually, the number of the patients given the
new CM varies roughly between 500 and 1500 patients in the first registration
file. Additional indications documented later on may require fewer patients,
depending on the claim. Today, in most of the countries, documentation of relative tolerability/safety and efficacy is usually required for registration purposes.
As a matter of principle, every clinical trial has to fulfIl the ethical recommendations of the current version of the Declaration of Helsinki (World
Medical Association Declaration of Helsinki in 1976). In addition, the health
authorities of most countries have published regulations and/or guidelines.
Guidelines for the planning, execution, documentation, and reporting of
clinical studies have been published by the International Conference on
1.7 Clinical Documentation of the Tolerance, Safety and Efficacy of X-Ray Contrast Media
Table 1.7.1. Clinical testing of contrast media
Clinical phase
ClassificationJdefinition
Aim
Initial introduction of a new CM
into humans. The CM is given to
a small number of preferably
healthy male volunteers.
To gain a preliminary elucidation
of the human pharmacological
properties (pharmacokinetics,
tolerance) before advance to
diseased subjects.
To determine the intended effect
of the CM for a certain
indication by approximating the
doses used for the other CM to
a ess patient safety and
tolerance.
II
Noncomparative, later possibly
comparative, trials in the first
small number of patients.
III
Expanded, usually comparative,
trials in larger (and possibly
varied) patient group for the
same indication as in phase II.
To gain additional and preferably
comparative documentation
about the efficacy and safety
and, to evaluate the overall
benefit-risk relationship.
Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH), which in the meantime have been accepted worldwide as
the guidelines for Good Clinical Practice (GCP). They, together with the
Standard Operation Procedures that derive from them, today form the basis for
the correct procedure during the clinical exmination of new pharmaceuticals
[3]. Clinical studies conducted according to these guidelines guarantee, for the
first time in a standard fashion and at a high level of quality independent of
where the study is conducted, optimal protection of the healthy volunteers/patients and reliable data which will be accepted by all registration authorities
(European Union, USA, Japan). According to the GCP all trials must be approved by an ethical committee, and in most European countries, the regulatory
authorities will also assess the protocol before the trial starts.
Even after marketing of the drugs, the documentation process will continue
in order to evaluate their usefulness in clinical practice and further assess the
relative safety and effectiveness and cost-benefit ratio (phase IV clinical trials,
surveillance of applications, and postmarketing surveillance, PMS). Although
phase-IV trials are subject to the GCP guidelines and are employed to clarify
specific issues, the goal of the surveillance of applications is to provide information about the use of medication under standard conditions (doctors are
not given instructions in this regard by a study protocoll). Such studies must
include a surveillance and evaluation scheme that provides data on the number
of patients observed, the period of surveillance, the features to be noted, the
kind of documentation, and the parameters of the statistical and the medical
evaluations. Also studied are other possible side effects that might be caused by
a medication, in order to determine the severity, frequency of occurrence, dose
relationship, sequelae, risk factors, and optimal treatment. Furthermore, drug-
41
42
CHAPTER 1
General Fundamentals
drug interactions, long-term effects, quality of life, and the costs to society are
also considered. This pharmacoepidemiological information is used to minimize the risk of such injuries and in risk-benefit assessments. All methods for
monitoring the safety and efficacy of marketed drugs are included under PMS.
They are classified as follows:
A Nonanalytical, Descriptive Methods
1.
2.
Voluntary or mandatory spontaneous reporting.
Uncontrolled studies.
B Analytical Methods
1.
2.
Experimental (clinical and toxicological).
Nonexperimental (epidemiological)
a) Cohort survey (prospective or retrospective),
b) Case-control study (prospective or retrospective),
c) Cross-sectional study,
d) Ecological study,
e) Disease trend study.
( Literature Surveillance
The spontaneous reporting system is the method generally used for recording
side effects of marketed drugs. The medical legislation of many countries
makes this system obligatory. Doctors are requested to report events and
adverse reactions occurring after the use of drugs. Special adverse drug
reaction forms are used and are generally sent to the pharmaceutical company
responsible. However, in some cases and in some countries the reports are sent
directly to the drug regulatory authorities or to other agencies set up for monitoring such adverse events or reactions.
The pharmaceutical companies in most countries are obliged to forward
such reports, either periodically or without delay, depending on the type of
reaction and country, to the responsible health authority. Yearly periodic safety
updates for the renewal of a marketing licence are also often requested from the
pharmaceutical companies.
Under this system it is possible to monitor adverse events and reactions and
suspected adverse reactions connected with the administration of a given drug.
This contributes to the creation of a broader adverse reaction profile and updating of package inserts or data sheets, since the clinical trials usually detect
only the more common adverse reactions. It also facilitates a risk-benefit assessment. Major disadvantages worth mentioning are that it does not enable the
assessment of causality and it is extremely sensitive to bias, e. g. due to adverse
publicity.
The other methods listed are generally employed for specific purposes when
further clarification of questions arising from the spontaneous adverse event or
reaction monitoring is necessary.
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
Interestingly, the incidence of CM adverse reactions in preregistration trials
is 2 -10 times higher than that recorded in PMS. The pattern of reaction is the
same, so the difference probably reflects the greater scrutiny and vigilance in
early clinical phases [2] compared with daily clinical routine.
The nonionic X-ray CM have a very low incidence of adverse effects,
particularly of mild and moderate reactions. Accordingly, in order to establish
a safety profile based on more medically important reactions, patient populations larger than those surveyed in preregistration trials are needed. The drug
monitoring performed by Schrott et al. in Germany on 50,000 patients [6] and
the cohort surveys performed by Katayama et al. in Japan on 338,000 patients
[4] and Palmer in Australia on 110,000 [5] patients have not only documented
the superiority of nonionic over ionic CM in the incidence of the usual mild and
moderate adverse effects found in preregistration trials, but have also convincingly demonstrated that there are fewer medically relevant reactions.
References
1. Andrew E (1989) Clinical relevance of toxicological experiments on drugs (in Norwegian,
English summary). Nor Lregeforening 106 : 1935 -1938
2. Andrew E (1990) Adverse reactions of x-ray contrast media in pre-registration trials versus
post-marketing surveillance (PMS). 2nd international symposium of CM, Osaka, Japan,
November 1990
3. Good clinical practice for trials on medicinal products in the European Community.
COMEUR, Brussels, 1990
4. Katayama H, Yamaguchi K, Kozuka T et al. (1990) Adverse reactions to ionic and non-ionic
contrast media. A report from the Japanese Committee on the Safety of Contrast Media.
Radiology 11 : 52 - 66
5. Palmer FJ (1989) The Royal Australian College of Radiologists (RACR) survey of reactions
to intravenous ionic and non-ionic media. In: Enge I, Edgren J (eds) Patient safety and
adverse events in contrast medium examination. Elsevier, Amsterdam, pp 137 -141
(Excerpta medica international Congress series, vol 816)
6. Schmitt KM, Behrends B, ClauB W, Kaufmann J, Lehnert J (1986) Iohexol in der Ausscheidungsurographie. Ergebnisse des Drug-monitoring. Fortschr Med 7: 153 -156
1.8
Statistical Considerations in the Design and Analysis
of Clinical Trials
J.KAUFMANN
Introduction
Clinical trials should be conducted in accordance with ethical principles that
have their origin in the Declaration of Helsinki and that are consistent with
Good Clinical Practice (GCP).
43
44
CHAPTER 1
General Fundamentals
GCP is a standard for the design, conduct, performance, monitoring,
auditing, recording, analysis, and reporting of clinical trials that provides
assurance that the data and reported results are credible and accurate.
The efficacy and safety of medicinal products should be demonstrated by
clinical trials. Clinical trials should be designed, conducted, and analysed according to scientific principles to achieve their objectives and should be
reported appropriately. The essence of rational drug development is to ask
questions and answer them with appropriate studies. The primary objectives of
any study should be clear and explicitly stated.
The proliferation of statistical research in the area of clinical trials coupled
with the critical role of clinical research in the drug-approval process and
health care in general necessitates a succinct document on statistical issues
related to clinical trials. This paper is based on ICH E9, "Statistical Principles for
Clinical Trials:' which is written primarily to harmonise the principles of
statistical methodology applied to clinical trials for marketing applications submitted in Europe, Japan, and the United States [1].
The following important principles should be followed in planning the
objectives, design, and analysis of a clinical trial; each part should be defined in
a written protocol before the study starts.
Considerations for Overall Clinical Development
Study Context
Confirmatory Trial. A confirmatory trial is a controlled trial in which a hypothesis is stated in advance and evaluated. As a rule, confirmatory trials are
necessary to provide firm evidence of efficacy or safety. In such trials the key
hypothesis of interest follows directly from the trial's primary objective, is
always pre-defined, and is the hypothesis that is subsequently tested when the
trial is complete. In a confirmatory trial it is equally important to estimate with
due precision the size of the effects attributable to the treatment of interest and
to relate these effects to their clinical significance.
Exploratory Trial. The rationale and design of confirmatory trials nearly always
refers to earlier clinical work carried out in a series of exploratory studies. Like
all clinical trials, these exploratory studies should have clear and precise
objectives. However, in contrast to confirmatory trials, their objectives may not
always lead to simple tests of pre-defined hypotheses. In addition, exploratory
trials may sometimes require a more flexible approach to design, so that
changes can be made in response to accumulating results. Their analysis may
entail data exploration; tests of hypothesis may be carried out, but the choice of
hypothesis may be data dependent. Such trials cannot be the basis of the formal
proof of efficacy, although they may contribute to the relevant evidence.
Any individual trial may have both confirmatory and exploratory aspects.
For example, in most confirmatory trials the data are also subjected to exploratory analyses which serve as a basis for explaining or supporting their findings
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
and for suggesting further hypotheses for later research. The protocol should
make a clear distinction between the aspects of a trial which will be used for
confirmatory proof and the aspects which will provide data for exploratory
analysis.
Study Scope
Population. In the earlier phases of drug development the choice of patients for
a clinical trial may be heavily influenced by the wish to maximise the chance of
observing specific clinical effects of interest, and hence the patients may come
from a very narrow sub-group of the total patient population for which the drug
may eventually be indicated. However, by the time the confirmatory trials are
undertaken, the patients in the trials should more closely mirror the intended
users. Hence, in these trials it is generally helpful to relax the inclusion and
exlusion criteria as much as possible within the target indication, whilst maintaining sufficient homogeneity to permit a successful trial to be carried out.
Primary and Secondary Variables. The primary variable ("target" variable,
primary endpoint) should be the variable capable of providing the most
clinically relevant and convincing evidence directly related to the primary
objective of the trial. There should generally be only one primary variable. This
will usually be an efficacy variable, because the primary objective of most confirmatory trials is to provide strong scientific evidence regarding efficacy. The
selection of the primary variable should reflect the accepted norms and
standards in the relevant field of research. The use of a reliable and validated
variable with which experience has been gained either in earlier studies or in
published literature is recommended. The primary variable should generally be
the one used when estimating the sample size (see section "Sample Size").
Categorisation of continuous or ordinal variables may sometimes be desirable. Criteria of "success" and "response" are common examples of dichotomies
which require precise specification in terms of, for example, a minimum
percentage improvement (relative to the baseline) in a continuous variable, or a
ranking categorised as at or above some threshold level (e.g., "good") on an
ordinal rating scale. The reduction of diastolic blood pressure below 90 mmHg
is a common dichotomy. Categorisations are most useful when they have clear
clinical relevance. The criteria for categorisation should be pre-defined and specified in the protocol, as knowledge of trial results could easily bias the choice
of such criteria. Because categorisation normally implies a loss of information,
a consequence will be a loss of power in the analysis; this should be accounted
for in the sample-size calculation.
Design Techniques to Avoid Bias
The two most important design techniques for avoiding bias in clinical trials
are blinding and randomisation, and these should be a normal feature of most
controlled clinical trails intended to be included in a marketing application.
Most such trials follow a double-blind approach in which treatments are pre-
45
46
CHAPTER 1
General Fundamentals
packed in accordance with a suitable randomisation schedule and supplied to
the trial centre(s) labelled only with the patient's number and the treatment
period so that no one involved in the conduct of the trial is aware of the specific
treatment allocated to any particular not even as a code letter.
Blinding. Blinding is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from
the influence which the knowledge of treatment may have on the recruitment
and allocation of patients, their subsequent care, the attitudes of patients to the
treatments, the assessment of end points, the handling of withdrawals, the
exclusion of data from analysis, and so on. The essential aim is to prevent identification of the treatments until all such opportunities for bias have passed.
A double-blind trial is one in which neither the volunteer/patient nor any of
the investigator or sponsor staff who are involved in the treatment or clinical
evaluation of the patients are aware of the treatment received. In a single-blind
trial the investigator and/or his/her staff are aware of the treatment, but the
patient is not. In an open-label trial the identity of treatment is known to all.
The double-blind trial is the optimal approach. This requires that the treatments to be applied during the trial cannot be distinguished in any way.
If a double-blind trial is not feasible, then the single-blind option should be
considered. In some cases only an open-label trial is practically or ethically possible. Single-blind and open-label trials provide additional flexibility, but it is
particularly important that the investigator's knowledge of the next treatment
should not influence the decision to select the patient for the trial; this decision
should precede knowledge of the randomised treatment. Also, under either of
these circumstances, clinical assessments should be made by medical staff who
are not involved in treating the patients and who remain blind to treatment. In
single-blind or open-label trials, every effort should be made to minimise the
various known sources of bias, and primary variables should be as objective as
possible.
Randomisation. Randomisation introduces a deliberate element of chance into
the assignment of treatments to patients in a clinical trial. During subsequent
analysis of the trial data, it provides a sound statistical basis for the quantitative
evaluation of the evidence relating to treatment effects. It also tends to produce
treatment groups in which the distributions of prognostic factors (known and
unknown) are similar. In combination with blinding, randomisation helps to
avoid possible bias in the selection and allocation of patients arising from the
predictability of treatment assignments.
Although unrestricted randomisation is an acceptable approach, some
advantages can generally be gained by randomising patients in blocks. This
helps to increase the comparability of the treatment groups, particularly when
patient characteristics may change over time, as a result, for example, of
changes in recruitment policy.
In multicentre trials the randomisation procedures should be organised centrally. It is advisable to have a separate random scheme for each centre, that is,
to stratify by centre or to allocate several whole blocks to each centre. More
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
generally, stratification by important prognostic factors measured at baseline
(e. g., severity of disease, age, or sex) may sometimes be valuable in order to
promote balanced allocation within strata; this has greater potential benefit in
small trials. The use of more than two or three stratification factors is rarely
necessary, is less successful at achieving balance, and is logistically troublesome.
The next patient to be randomised into a study should always receive the
treatment corresponding to the next free number in the appropriate randomisation schedule (in the respective stratum, if randomisation is stratified).
The appropriate number and associated treatment for the next patient should
only be allocated when entry of that patient to the randomised part of the trial
has been confirmed.
Study Design Considerations
Study Configuration
Parallel Group Design. The most common clinical trial design for confirmatory
trials is the parallel group design, in which patients are randomised to one of
two or more arms, each arm being allocated a different treatment. These treatments will include the investigational product at one or more doses and one or
more control treatments, such as a placebo and/or an active comparator. The
assumptions underlying this design are less complex than for most other
designs. However, there may be additional features of the design which complicate the analysis and interpretation (e. g., covariates, repeated measurements
over time, interactions between design factors, protocol violations, dropouts,
and withdrawals).
Cross-Over Design. In the cross-over design, each patient is randomised to a
sequence of two or more treatments and hence acts as his/her own control for
treatment comparisons. This simple manoeuvre is attractive primarily because
it reduces the number of patients and usually the number of assessments required to achieve a specific power, sometimes to a marked extent. In the
simplest 2 x 2 cross-over design, each patient receives each of two treatments in
randomised order in two successive treatment periods, often separated by a
washout period.
Cross-over designs have a number of problems which can invalidate their
results. The chief difficulty concerns carryover, that is, the residual influence of
treatments in subsequent treatment periods. In an additive model, the effect of
unequal carryover will be to bias direct treatment comparisons.
Factorial Designs. In a factorial design two or more factors, such as different
dosages of contrast media and flow velocity are evaluated simultaneously in the
same set of patients through the use of varying combinations. The simplest
example is the 2 x 2 factorial design in which patients are randomly allocated to
one of the four possible combinations of two dosages, for example, 50 and 70 ml
contrast media, and two flow velocities, for example, 2 and 4 mlls. In many cases
47
48
CHAPTER 1
General Fundamentals
this design is used for the specific purpose of examining the interaction of
dosage and velocity.
Another important use of the factorial design is to establish the doseresponse characteristics of a combination product, for example, one combining
treatments C and D, especially when the efficacy of each monotherapy has been
established at some dose in prior studies. A number, m, of doses of C is selected,
usually including a zero dose (placebo), and a similar number, n, of doses of D.
The full design then consists of m . n treatment groups, each receiving a different combination of doses C and D. The resulting estimate of the response
surface may then be used to help to identify an appropriate combination of
doses of C and D for clinical use.
Uncontrolled Design. When no approved comparator exists, for example, when
an imaging agent under development or the modality itself is novel to the indication being sought, the accuracy of the diagnosis afforded by the test agent
should be verified whenever possible by comparison to a "gold standard" such
as an independent assessment of the disease via tissue examination, and/or
another diagnostic modality which has been previously established as being
safe and effective for the indication under study. When a suitable gold standard
does not exist, comparisons may be made to an assessment of all available
clinical information, excluding information obtained with a test agent, that is, a
final diagnosis or clinical impression.
Blinded Reader Design. Clinically blinded reader (BR) studies are used to
evaluate efficacy data (content information in the image alone) in a "worst-case
scenario". This evaluation is conducted in a controlled setting with minimal
clinical information provided to the reader. This environment is not representative of the conditions under which the test agent will ultimately be used clinically, but may provide inportant performance information and reduce study
bias. The specific information provided may depend on the modality under
study, type of agent, and/or proposed indication. The BR should be provided
with sufficient information to provide a diagnosis without leading the reader to
a specific determination.
The current state of the art requires that multiple readers (at least two) be
used for each clinical study. With multiple readers, there may be points of
disagreement between or among readers. Each reader provides a valid set of
reading; information on accuracy, sensitivity, and specificity (if appropriate) is
valid for each reader. Methods to minimise inter-reader variability should be
incorporated into the study design.
Multicentre Trials
Multicentre trials are carried out for two main reasons. Firstly, a multicentre
trial is an accepted way of evaluating a new medication more efficiently; under
some circumstances, it may present the only practical means of recruiting sufficient patients to satisfy the trial objective within a reasonable time-frame.
Multicentre trials of this nature may, in principle, be carried out at any stage of
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
clinical development. They may have several centres with a large number of
patients or centres with very few patients.
Secondly, a trial may be designed as a multicentre (and multi-investigator)
trial, primarily to provide a better basis for the subsequent generalisation of its
findings. This arises from the possibility of recruiting the patients from a wider
population and of administering the medication in a broader range of clinical
settings, thus presenting an experimental situation which is more typical of
future use. In this case the involvement of a number of investigators also gives
the potential for a wider range of clinical judgement concerning the value of the
medication. Such a trial, for example, would be a confirmatory trial in the later
phases of drug development and would be likely to involve a large number of
investigators and centres. It might sometimes be conducted in a number of different countries in order to facilitate generalisation even further.
The statistical model to be adopted for the comparison of treatments should
be described in the protocol. The main treatment effect may first be investigated
using a model which allows for centre differences. In the absence of a true
centre-by-treatment interaction, the routine inclusion of interaction terms in
the model reduces the efficiency of the test for the main effects. In the presence
of a true centre-by-treatment interaction, the interpretation of the main treatment effect is controversial.
Type of Comparison
Trials to Show Superiority. Scientifically, efficacy is most convincingly established by demonstrating superiority to a placebo, for example a native scan in
an imaging study, by showing superiority to an active control treatment or by
demonstrating a dose-response relationship. This type of trial is referred to as
a "superiority" trial. The appropriateness of placebo control versus active control must be considered on a study-by-study basis.
Trials to Show Equivalence or Non-Inferiority. In some cases, an investigational
product is compared to a reference treatment without the objective of showing
superiority. This type of trial is divided into two major categories according to its
objective; one is an "equivalence" trial and the other is a "non-inferiority" trial.
Active control equivalence or non-inferiority trials may also incorporate a placebo, thus pursuing multiple goals in one trial, for example, establishing superiority to a placebo and hence validating the study design and evaluating the degree
of similarity of efficacy and safety to the active comparator. There are wellknown limitations associated with the use of the active control equivalence (or
non-inferiority) trials that do not incorporate a placebo. The equivalence (or noninferiority) trial is not conservative in nature, so that many flaws in the design or
conduct of the trial will tend to bias the results towards a conclusion of equivalence. For these reasons the design features of such trials need special attention.
Sample Size
The number of patients in a clinical trial should always be large enough to
provide a reliable answer to the questions addressed. This number is usually
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CHAPTER 1
General Fundamentals
determined by the primary objective of the trial. If the sample size is determined on some other basis, then this should be made clear and justified. For
example, a trial sized on the basis of safety questions or requirements may need
larger numbers of patients than one sized on the basis of efficacy questions.
The usual method for determining the appropriate sample size requires that
the following items should be specified: a primary variable, the test statistic, the
null hypothesis, the alternative ("working") hypothesis at the chosen dose(s)
(embodying consideration of the treatment difference to be detected or rejected
in the dose and in the patient population selected), the probability of
erroneously rejecting the null hypothesis (the type-I error), and the probability
of erroneously failing to reject the null hypothesis (the type-II error), as well as
the approach to dealing with treatment withdrawals and protocol violations. In
some instances, the event rate is of primary interest for evaluating power, and
assumptions should be made to extrapolate from the required number of events
to the eventual sample size for the trial.
In confirmatory studies, assumptions should normally be based on published data or on the results of earlier studies. The treatment difference to be
detected may be based on a judgement concerning the minimal effect that has
clinical relevance in the management of patients or on a judgement concerning
the anticipated effect of the new treatment, where this is larger. Conventionally,
the probability of type-I error is set at 5 % or less or as dictated by any adjustments made necessary for multiplicity considerations; the precise choice is
influenced by the prior plausibility of the hypothesis under test and the desired
impact of the results. The probability of type-II error is conventionally set at
20 % or less; it is in the sponsor's interest to keep this figure as low as feasible,
especially in the case of studies which are difficult or impossible to repeat.
The sample size in a group sequential trial cannot be fixed in advance
because it depends upon the play of chance in combination with the chosen
stopping rule and the true treatment difference. The design of the stopping rule
should take into account the consequent distribution of the sample size, usually embodied in the expected and maximum sample sizes.
When event rates are lower than anticipated or variability is larger than
expected, methods for sample size re-estimation are available without unblinding data or making treatment comparisons.
Data Capture and Processing
The collection of data and transfer of data from the investigator to the sponsor
can take place through a variety of media, including paper case record forms,
remote site monitoring systems, medical computer systems, and electronic
transfer. Whatever data capture instrument is used, the form and content of the
information collected should be in full accordance with the protocol and should
be established in advance of the conduct of the clinical trial. It should focus on
the data necessary to implement the analysis plan, including the context information (such as timing assessments relative to dosing) necessary to confirm protocol compliance or identify important protocol deviations. "Missing values"
should be distinguishable from the "value zero" or "characteristic absent".
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
The process of data capture through to database finalisation should be
carried out in accordance with GCP.
Interim Analysis and Early Stopping
Any analysis intended to compare treatment arms with respect to efficacy or
safety at any time prior to formal completion of a trial is an interim analysis.
Because the number, methods, and consequences of these comparisons affect
the interpretation of the trial, all interim analyses should be carefully planned
in advance and described in the protocol, but otherwise in amendments prior
to unblinded access to treatment comparison data. When an interim analysis is
planned with the intention of deciding whether or not to terminate a trial, this
is usually accomplished by the use of a group sequential design which employs
statistical monitoring schemes as guidelines. The goal of such an interim
analysis is to stop the trial early if the superiority of the treatment under study
is clearly established, if the demonstration of a relevant treatment difference
has become unlikely, or if unacceptable adverse effects are apparent. Generally,
boundaries for monitoring efficacy require more evidence to terminate a trial
early (i.e., are more conservative) than do boundaries to terminate a trial for
safety reasons. When the trial design and monitoring objective involve multiple
endpoints, then this aspect of multiplicity may also need be taken into acoount.
The execution of an interim analysis must be a completely confidential
process, because unblinded data and results are potentially involved. All staff
involved in the conduct of the trial should remain blind to the results of such
analyses, because of the possibility that their attitudes to the trial will be modified and cause changes in recruitment patterns or biases in treatment comparisons. This principle applies to the investigators and their staff and to staff
employed by the sponsor who come into contact with clinic staff or patients.
Investigators should only be informed about the decision to continue or to discontinue the trial or to implement modifications to trial procedures.
Data Analysis
Prespecified Analysis Plan
When designing a clinical trial the principal features of the eventual statistical
analysis of the data should be described in the statistical section of the protocol. This section should include all features of the proposed confirmatory
analysis of the primary variable(s) and the way in which anticipated analysis
problems will be handled. In case of exploratory trials this section could describe more general principles and directions.
Analysis Set
The set of patients whose data are to be included in the main analyses should
be defined in the statistical section of the protocol.
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General Fundamentals
If all patients randomised into a clinical trial satisfied all entry criteria, followed all trial procedures perfectly with no losses to follow-up, and provided
complete data records, then the set of patients to be included in the analysis
would be self-evident. The design and conduct of a trial should aim to approach
this ideal as closely as possible, but, in practice, it is doubtful if it can ever be
fully achieved. The blind review of data to identify possible amendments to the
analysis plan due to the protocol violations should be carried out before unblinding. It is desirable to identify any important protocol violation with respect
to the time when it occurred, plus its cause and influence on the trial result.
All Randomised Patients. The intention-to-treat principle implies that the
primary analysis should include all randomised patients. In practice, this ideal
may be difficult to achieve, for reasons to be described. Hence, analysis sets
referred to as "all randomised patients" may not, in fact, include every patient.
There are two types of major protocol violations. One is violation of entry
criteria. The second is violation of the protocol after randomisation. Patients
who fail to satisfy an objective entry criterion measured prior to randomisation
but who enter the trial may be excluded from analysis without introducing bias
into the treatment comparison, assuming all patients receive equal scrutiny for
eligibility violations.
Other problems occur after randomisation (error in treatment assignment,
use of excluded medications, poor compliance, loss to follow-up, missing data,
and other protocol violations). These problems are especially difficult when
their occurrence is related to treatment assignment. It is good practice to assess
the pattern of such problems with respect to frequency and time to occurrence
among treatment groups. Patients withdrawn from treatment may introduce
serious bias, and, if they have provided no data after withdrawal, there is no
obvious solution.
Per Protocol Patients. The "per protocol" set of patients, sometimes described
as the "valid cases;' the "efficacy" sample or the "evaluate patients" sample,
defines a subset of the data used in all randomised patients' analyses and is
characterised by the following criteria:
The completion of a certain pre-specified minimal exposure to the treatment
regimen.
2. The availability of measurements of the primary variable(s).
3. The absence of any major protocol violations, including the violation of
entry criteria, where the nature of and reasons for these protocol violations
should be defined and documented before breaking the blind.
1.
This set may maximise the opportunity for a new treatment to show additional
efficacy in the analysis, and most closely reflects the scientific model underlying
the protocol. However, it mayor may not be conservative, depending on the
study, and may be patient biased (possibly severely) because the patients
adhering most diligently to the study protocol may not be representative of the
entire study population.
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
Missing Values and Outliers
Missing values represent a potential source of bias in a clinical trial. Hence,
every effort should be undertaken to fulfIl all the requirements of the protocol
concerning the collection and management of data. However, in reality there
will almost always be some missing data. A study may be regarded as valid,
nonetheless, provided the methods of dealing with missing values are sensible,
and particularly if those methods are pre-defIned in the analysis plan of the
protocol. Pre-definition of methods may be facilitated by updating this aspect
of the analysis plan during the blind review. Unfortunately, no universally applicable methods of handling missing values can be recommended. An investigation should be made concerning the sensitivity of the results of analysis to the
method of handling missing values, especially if the number of missing values
is substantial.
A similar approach should be adopted to exploring the influence of outliers,
the statistical defInition of which is, to some extent, arbitary. Clear identification of a particular value as an outlier is most convincing when justified medically as well as statistically, and the medical context will then often defIne the
appropriate action. Any outlier procedure set out in the protocol should be such
as not to favour any treatment group a priori. Once again, this aspect of the
analysis plan can be usefully updated during blind review. If no procedure for
dealing with outlier was foreseen in the study protocol, one analysis with the
actual values and at least one other analysis eliminating or reducing the outlier
effect should be performed and differences between their results discussed.
Data Transformation/Modification
The decision to transform key variables prior to analysis is best made during
the design of the trial on the basis of similar data from earlier clinical trials.
Transformations (e. g. square root, logarithm) should be specified in the protocol and a rationale provided, especially for the primary variable(s). The general
principles guiding the use of transformations to ensure that the assumptions
underlying the statistical methods are met are to be found in standard texts;
conventions for particular variables have been developed in a number of
specific clinical areas. The decision on whether and how to transform a variable
should be influenced by the preference for a scale which facilitates clinical interpretation.
Similar considerations apply to other data modifications sometimes used to
create a variable for analysis, such as the use of change from baseline, percentage change from baseline, the "area under the curve" of repeated measures, or
the ratio of two different variables. Subsequent clinical interpretation should be
carefully considered, and the modifIcation should be justified in the protocol.
Estimation, Confidence Intervals and Hypothesis Testing
The statistical section of the protocol should specify the hypotheses which are
to be tested and/or the treatment effects which are to be estimated in order to
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CHAPTER 1
General Fundamentals
satisfy the objectives of the trial. The statistical methods to be used to accomplish these tasks should be described for the primary (and preferably the
secondary) variables, and the underlying statistical model should be made
clear. Estimates of treatment effects should be accompanied by confidence
intervals, whenever possible, and the way in which these will be calculated
should be identified. The plan should also describe any intentions to use baseline data to improve precision and to adjust estimates for potential baseline differences, for example, by means of analysis of covariance. The reporting of precise p-values (e.g. "p = 0.034") should be envisaged in the plan rather than
exclusive reference to critical values (e. g. "p < 0.05"). It is important to clarify
whether one- or two-sided tests of statistical significance will be used, and in
particular to justify prospectively the use of one-sided tests. If formal hypothesis tests are not considered appropriate, then the alternative process for
arriving at statistical conclusions should be given.
The particular statistical model chosen should reflect the current state of
medical and statistical knowledge about the variables to be analysed. All effects
to be fitted in the analysis (for example, in analysis of variance models) should
be fully specified, and the manner, if any, in which this set of effects might be
modified in response to preliminary results should be explained. The same
considerations apply to set of covariates fitted in an analysis of covariance. In
the choice of statistical methods, due attention should be paid to the statistical
distribution of both primary and secondary variables. When making this choice
it is important to bear in mind the need to provide statistical estimates of the
size of treatment effects together with confidence intervals (in addition to
significance tests), as this may influence the choice when there is any doubt
about the appropriateness of the method.
The primary analysis of the primary variable should be clearly distinguished
from supporting analyses of the primary or secondary variables. Within the
statistical section of the protocol there should also be an outline of the way in
which data other than the primary and secondary variables will be summarised
and reported. This should include a reference to any approaches adopted for the
purpose of achieving consistency of analysis across a range of studies, for
example, for safety data.
Subgroups, Interactions and Covariates
The primary variable(s) is/are often systematically related to other influences
apart from treatment. For example, there may be relationships to covariates
such as age and sex, or there may be differences between specific subgroups of
patients such as those treated at the different centres of a multicentre trial. In
some instances an adjustment for the influence of covariates or for subgroup
effects is an integral part of the analysis plan and hence should be set out in the
protocol. Pre-study deliberations should identify those covariates and factors
expected to have an important influence on the primary variable(s) and should
consider how to account for these in the analysis in order to improve precision
and to compensate for any lack of balance between treatment groups. When the
potential value of an adjustment is in doubt, it is often advisable to nominate
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
the unadjusted analysis as the one for primary attention, the adjusted analysis
being supportive. Special attention should be paid to centre effects and to role
of baseline measurements of the primary variable. It is not advisable to adjust
the main analyses for covariates measured after randomisation because they
may be affected by the treatments.
The treatment effect itself may also vary with subgroup or covariate - for
example, the effect may decrease with age or be larger in a particular diagnostic
category of patients. In some cases such interactions are anticipated, and hence
a subgroup analysis, or a statistical model including interactions, is part of the
confirmatory analysis plan. In most cases, however, subgroup or interaction
analyses are exploratory and should be clearly identified as such; they should
explore the uniformity of any treatment effects found overall. In general, such
analyses should proceed first through the addition of interaction terms to the
statistical model in question, complemented by additional exploratory analysis
within relevant subgroups of patients, or within strata defined by the covariates.
When exploratory, these analyses should be interpreted cautiously; any conclusion of treatment efficacy (or lack thereof) or safety based solely on exploratory subgroup analyses are unlikely to be accepted.
Evaluation of Safety and Tolerability
Choice of Variables and Data Collection
In any clinical trial the methods and measurements chosen to evaluate the
safety and tolerability of a drug will depend on a number of factors, including
knowledge of the adverse effects of closely related drugs, information from
non-clinical and earlier clinical studies, and possible consequences of the
pharmacodynamic/pharmacokinetic properties of the particular drug, the
mode of administration, the type of patients to be studied, and the duration of
the study. Laboratory tests concerning clinical chemistry and hematology, vital
signs, and clinical adverse events (diseases, signs and symptoms) usually form
the main body of the safety and tolerability data. The occurrence of serious
adverse events and treatment discontinuations due to adverse events are particularly important to register.
Furthermore, it is recommended that a consistent methodology be used for
the data collection and evaluation throughout a clinical trial programme in
order to facilitate the combining of data from different trials. The use of a common adverse-event dictionary is particularly important. This dictionary has a
structure which makes it possible to summarise the adverse-event data on three
different levels: system-organ class, preferred term, or included term. The
preferred term is the level on which adverse events usually are summarised, and
preferred terms belonging to the same system-organ class could then be
brought together in the descriptive presentation of data.
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General Fundamentals
Statistical Evaluation
The investigation of safety and tolerability is a multidimensional problem.
Although some specific adverse events can usually be anticipated and specifically monitored for any drug, the range of possible adverse events is very large,
and new and unforeseeable effects are always possible. Further, an adverse event
experienced after a protocol violation, such as use of an excluded medication,
may introduce a bias. This background underlies the statistical difficulties associated with the analytical evaluation of safety and tolerability of drugs, and
means that confirmatory information from phase-III clinical trials is the exception rather than the rule.
In most trials the safety and tolerability implications are best addressed by
applying descriptive statistical methods to the data, supplemented by calculation of confidence intervals wherever this aids interpretation. It is also valuable
to make use of graphical presentations, for example boxplots and histograms,
in which patterns of adverse events are displayed both within treatment groups
and within patients.
If hypothesis tests are used, statistical adjustments for multiplicity to quantitative type-I error are appropriate, but the type-II error is usually of more concern. Care must be taken when interpreting putative statisticallly significant
findings when there is no multiplicity adjustment.
Reporting
The primary goal of the analysis of a clinical trial should be to answer the
questions posed by its main objectives; new questions based on the observed
data may well emerge during the unblinded analysis. Additional and perhaps
complex statistical analysis may be the consequence. This additional work
should be strictly distinguished in the report from work which was planned in
the protocol.
The change of plan may lead to unforeseen imbalances between the treatment groups in terms of baseline measurements not pre-defined as covariates
in the analysis plan but having some prognostic importance nevertheless. This
is best dealt with by showing that a subsidiary analysis which accounts for these
imbalances reaches essentially the same conclusion as the planned analysis. If
this is not the case, the effect of the imbalances on the conclusions should be
discussed.
In general, sparing use should be made of unplanned subsidiary analyses.
Subsidiary analyses are often carried out when it is thought that the treatment
effect may vary according to some other factor or factors. An attempt may then
be made to identify subgroups of subjects for whom the effect is particularly
beneficial. The potential dangers of over-interpretation of unplanned subgroup
analyses are well known, and should be carefully avoided. Although similar
problems of interpretation arise if a treatment appears to have no benefit or an
adverse effect in a subgroup of subjects, such possibilities must be properly
assessed and should therefore be reported.
1.8 Statistical Considerations in the Design and Analysis of Clinical Trials
Finally, statistical judgement should be brought to bear on the analysis, interpretation and presentation of the results of a clinical trial. To this end, the trial
statistician should be a member of the team responsible for the study report
and should approve the final report.
References
1. The European Agency for the Evaluation of Medical Products (erna) (1997) Note for
guidance on statistical principles for clinical trials ICH E9. CPMP/ICH/363/96 : 1- 37
57
CHAPTER 2
Pharmaceutical Quality and Stability
of Iodinated X-Ray Contrast Media
2.1
What Are the Steps in the Production
of X-Ray Contrast Media?
D.HERRMANN
Because X-ray contrast media (CM) are normally injected or infused in fairly
large volumes of highly concentrated solutions, the greatest possible chemical,
physical and microbiological purity including freedom from particles and
pyrogens is of paramount importance. Accordingly, the standards of purity of
the starting materials and of the finished product are in the ppm range or even
lower in some cases. As part of the development of the manufacturing procedures for modern CM, researchers have been successful in substantially reducing the content of iodide ions. The manufacture of CM absolutely free from
iodide is, however, impossible and, in any case, would be futile because iodide is
produced again on prolonged storage and because deiodination with the release
of iodide ions - albeit minimal - takes place endogenously in the organism.
In contrast to the conventional ionic CM substances, the newer non-ionic
substances cannot be purified by precipitation through the addition of an acid
and they are also highly susceptible to microbial contamination. Because of
this, an initial ultrafiltration is performed - usually immediately after the
synthesis - which can also remove pyrogens. The CM substance can be obtained
from aqueous solution by freeze-drying or spray-drying.
After dissolution of the CM compound in water for injection and addition of
the stabiliser and buffer (see 2.3), the pH is adjusted to the "before sterilisation"
value, which - in accordance with the tests performed to validate the manufacturing procedure - must be somewhat different to the pH of the CM
preparation "after sterilisation" (about pH 7) ready for delivery. The solution
is subjected to fIltration involving multiple steps. 0.22 J.lm membrane fIlters
separate subvisual particles and also bacterial contamination; ultrafiltration serves to separate pyrogens and any contamination inducing subvisual
particles.
2.2
Which Chemical Degradation Products Are Formed?
The virtually aseptic solution is filled into ampoules, infusion bottles, injection cartridges or flexible plastic containers, sealed with stoppers of synthetic
elastomer (preferably chlorobutyl or bromobutyl rubber) and immediately
sterilised by autoclaving at 121°C. In view of the susceptibility of non-ionic CM
solutions to microbial contamination, this autoclaving is regarded as indispensable for safety reasons, and a reduction of the germ count of at least 1 : 106
is required.
This is followed by optical inspection for particulate matter and for leakage.
Both checks can be performed fully automatically using state-of-the art technology, e.g. the "television" picture of the bottle contents is scanned electronoptically, and leaks are detected by spark ionisation in the high-tension field;
defective individual containers are automatically discarded.
Parallel to these final checks, samples drawn according to a statistical sample
plan are analysed chemically for identity and purity and microbiologically for
sterility and pyrogenicity (see 2.6 and 2.7). Because of the high standard of the
in-process controls, these release tests are primarily of a formal character but
are still regarded as indispensable.
This is followed by labelling and packaging of the preparations in folding
boxes and despatch cartons. These working steps are verified by automatic code
readers (bar codes); important conventional identity features are the shape and
colour of the flanged caps.
2.2
Which Chemical Degradation Products Are Formed?
D.HERRMANN
Because of the identical nature of the functional groups contained equally in
the older ionic and the newer non-ionic CM, no significant differences exist
between the two groups. The only thing is that the reaction rates depend on the
molecular structure of the respective CM compound and the remaining composition of the CM solution - in particular on the pH setting and the choice of
buffer and stabiliser.
For example, the release of iodide ions can be observed with all CM whose
common structural feature is a triiodinated aromatic ring system. Thus, the
release of colourless iodide ions occurs in ionic and in non-ionic CM, e. g. in the
sodium and meglumine salts of diatrizoic acid and ioglycamic acid as well as in
the non-ionic compounds such as iohexol, iopromide, iopamidol etc.; Fig. 2.2.1
shows diatrizoate as an example. "Under-iodinated" compounds arise which are
equivalent to iodide cleavage, whereby a phenolic OH group may be found on
the aromate instead of the iodine atom. This decomposition is promoted by
high temperatures and, in particular, exposure to light. Iodide release is accelerated catalytically by heavy metal ions (see 2.3).
59
60
CHAPTER
2
Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
Fig. 2.2.1.
Release of iodide and
formation of an aromatic amine
from amidotrizoic acid
O~ /OH
'. ~C
•
,"
~ I /~
\
I "
, --1
~:
H C-C--'-'
1
II:
o
j
H
I
W
N-C-CH ,
H I
II
, 0
Elementary iodine, on the other hand, is not usually released. The yellow discoloration observed to varying degrees in CM solutions is, therefore, attributable not to free iodine, but to organic secondary compounds (see 2.8).
Another degradation reaction is the formation of primary aromatic amine
compounds as a result of saponification of the amide bond. This reaction can
occur only in the case of suitably structured CM compounds which display a
primary amide function of an aromatic carbonic acid (i. e., not with Isovist, for
example). Fig. 2.2.1 shows diatrizoate as an example. This reaction also depends
very much on the pH value of the CM solution and on the temperature. In contrast to iodide release, exposure to light has no effect.
Decreases and also increases of the pH value are observed to varying degrees
in CM solutions as a consequence of degradation reactions, i. e. they are
secondary reactions. Shifts in the pH can then provoke further changes if they
are outside the optimal range for stability.
2.3
What Additives Do X-Ray Contrast Media Solutions
Contain?
D.HERRMANN
CM solutions contain buffers (esp. the nonionic CM), complexing agents and, in
some cases, electrolytes as well. The purpose of the individual additives is as
follows:
Buffers are used to adjust the pH to the optimum range for stability, which
should be as close as possible to the physiological pH range of 7-2-7-4. The
higher the pH value, the faster iodide release and amide saponification are likely to be. During storage, a slight release of acid must be expected on onset of
degradation of the CM molecule (hydroiodic acid/phenolic OR' groups etc.),
while the release of alkali from the bottle glass must be anticipated. The pH
range normally specified for CM solutions is 6.5 - 8.0.
Commonly used buffers are: Trometamol (trishydroxymethyl aminomethane), citrate, phosphate and bicarbonate.
2.4 What Is the Importance of Additives in Contrast Medium Formulations?
Complexing agents should bind ubiquitously present heavy metal traces
which can catalyse the release of iodide. Preferably copper ions but also iron
ions promote the degradation of unprotected CM molecules (see 2.2). A possible source of such heavy metal traces is the equipment used for the chemical
synthesis of the CM compounds.
The use of ethylene diamine tetraacetic acid (EDTA) in the form of
Na2EDTA.2H20 or CaNa2EDTA is common. Usual concentrations are 0.1 mg/
ml or 0.05 mg/ml. Stoichiometrically, the two complexing agents are almost
equivalent (considering that the dosage is specified as dihydrate or as anhydrous substance).
Electrolytes: Ionic contrast media consist of the salts of diatrizoic acid, ioglycarnic acid, iotroxic acid, adipiodone etc. The cations are usually sodium and Nmethyl glucamine. An excess content of alkaline earth ions can lead to precipitation as, for example, almost unsoluble calcium salt.
In the case of non-ionic contrast media, account must be taken of the opposed ions of the above mentioned excipients, particularly Na+, Ca++ (if they are
not complex-bound) and also CI, if trometamol is dosed on the form of its
hydrochloride or neutralised with hydrochloric acid.
With the aim of increasing the tolerance, some non-ionic preparations contain additional electrolytes, preferably calcium, magnesium and potassium salts
(opinions vary as regards their clinical significance, see also 2-4). Because the
osmolality of the solution should, if possible lie within the isotonic range, there
is only a small margin for such additives.
2.4
What Is the Importance of Additives in Contrast Medium
Formulations?
P.DAWSON
Some of the conventional CM contain sodium citrate or sodium edetate. Both
these materials are capable of binding calcium and undoubtedly playa role in the
various manifestations of cardiotoxicity seen with these agents. Indeed, the addition of a little calcium to the formulation may largely eliminate the cardiotoxic
effects in these compounds. It is important to note, also, that the anion in the ionic
CM is itself also capable of binding calcium without the presence of additives.
The nonionic solutions contain no citrate and a different preparation of EDTA,
namely calcium disodium edetate CaNa2-EDTA. Neither this additive nor the
nonionic molecule itself is capable of significant calcium binding, and this
undoubtedly is an important element in their significantly lower cardiotoxicity.
Recently, animal experiments have been performed which indicate that the
absence of sodium ions in the nonionic CM formulations may lead to an increased incidence of ventricular fibrillation. It is important to understand that
61
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CHAPTER 2 Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
this appears only to be the case in experimental situations, which do not reflect
at all well clinical practice in real coronary angiography. Indeed, after widespread use for some years in clinical coronary angiography worldwide, there
has been no impression of any increase in ventricular fibrillation. However,these animal experiments have led to suggestions that sodium ions should be
added to nonionic formulations in some way and some commercial companies
are at least experimenting with the idea. The addition of sodium in the form of
sodium chloride is one simple possibility. An alternative would be the addition
of sodium citrate. This would not only supply the sodium ions deemed necessary to minimize the incidence of ventricular fibrillation but would also restore
a calcium binding potential to the formulations. In so far as this would restore
the strong anticoagulant effects which are routinely found in the ionic agents,
but have been largely lost in the nonionic agents, this is thought by some authorities to be desirable. However, there appear to be at least two problems.
First, the calcium binding not only mediates an anticoagulant effect but also, as
indicated above, is largely responsible for cardiotoxicity. Such formulations
might therefore be expected to be more cardiotoxic as regards effects on pump
function and various aspects of electrophysiology, not withstanding the original aim of reducing the incidence of ventricular fibrillation! The second problem is that the addition of significant amounts of sodium citrate in our laboratory studies appeared to markedly raise the osmolality of the solutions.
In short, the philosophy in the development of the nonionics has been to try
to attain something close to the ideal of total inertness of eM formulations, and
the addition of more active additives, or new additives, to achieve doubtful
ends, while at the same time risking loss of the very inertness desired, seems a
rather undesirable course on which to embark.
2.5
How Is the Sterility of X-Ray Contrast Media Assured?
D.HERRMANN
Sterility is defined as the absence of micro-organismus capable of reproduction.
While this is an absolute definition, sterility of a product cannot be quaranteed
by testing, it has to be assured by the application of a suitable validated production process (Pharmeuropa 6, 2. June 1994). Important elements are membrane
fIltration of the solution immediately before filling into ampoules, bottles etc.,
scrupulous cleansing of these containes as well as of the infusion/injection bottle
stoppers, the avoidance of unreasonably long standing times between manufacture of the solution, its fIltration and fIlling up to autoclaving of the filled containers and, finally, demonstration of adequate heat penetration of the entire
sterilisation batch in the autoclaves used. The latter are fitted with thermosensors which permit continuous documentation of the temperature and pressure
2.6 How Is the Chemical Stability of Contrast Media Checked?
pattern. The autoclaves themselves are checked at regular intervals for faultless
function by means of test sterilisation. Another aspect is the subsequent inspection for intactness of all containers, since micro-organisms can invade
through hairline cracks, for example. Hairline cracks caused by infusion bottles
being knocked together are also critical.
The following methods are suitable for checking the sterility or microbial
burden of the solution:
In the direct loading method (culture tube method), samples of the CM
solution are mixed with selected culture media and incubated. Increasing
turbidity indicates unsterility, and the nature of the turbidity is checked under
the microscope. Only a plus/minus statement is possible, but the advantage of
this method is that larger amounts of individual samples per production batch
can be examined.
In the membrane filtration method, the solution is filtered through membrane filters with a maximum pore width of 0.45 p.m. After the solution to be
examined has been washed out, the membrane filter discs are placed on culture
media or saturated with them. After incubation, the number of colonies in the
surface of the filters is counted. Contrary to the direct loading method, this
procedure therefore permits a statement about the contamination rate, the
number of colony-forming units. The advantage of this method is that a potential inhibitory effect of the solution under examination is eliminated because
the filter is rinsed out before incubation; the filtration of larger volumes of an
individual sample also leads to an accumulation of vegetative micro-organisms
and spores on the membrane filter.
2.6
How Is the Chemical Stability of Contrast Media Checked?
D.HERRMANN
Stability means the maintenance of quality over time. Quality in the sense of the
Medicines Act means efficacy, safety and pharmaceutical quality. The latter, in
turn, is determined by identity, concentration and chemical, physical and
microbiological purity. Account must be taken of the physical status of the formulation. In the case of X-ray contrast medium solutions, this means inspection
of the solution for clarity and freedom from deposits. Changes to the identity
due to storage appear remote, but when it is considered that CM solutions often
contain mixtures of isomers and also physicochemical association complexes,
then a check on the identity as part of stability testing can also be seen to be
important.
As with any drug, loading tests with acid, alkali, oxygen and light are performed in the developmental phase of a CM as well in order to determine the
degradation profile of the CM substance (see also 2.2) and to establish a testing
63
64
CHAPTER
2
Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
Table: Routine test criteria for X-ray contrast medium solutions
Additional test criteria may also be examined, e.g. volume/container (evaporation loss),
UV /VIS spectrum and sterility
Test criteria
Method
Remarks
Visual status
pH
Visual comparison of colour
and turbidity
Optical inspection for
particle
Potentiometric measurement
Iodide
(degradation product)
Aromatic amine
(degradation product)
Assay (CM substance)
Titration with Ag 0, under
potentiometric indication
Diazotisation, coupling,
photometric measurement
HPLC
Organoleptic tests with strict
regard to environmental
conditions
See also 2.9
Regard to defined temperature
essential
ee al 02.2
Complexing agent excess Complexometric titration
with Cu" ions under
(stabiliser)
potentiometric indication
Membrane filtration with
Particle count
micro copic count or use of
light obscuration technique
See also 2.2
Content selectively against
degradation product /i orner
distribution
Optionally also titration with
alkaline earth ions,
see al 0 2.3,2.4
Instrumental counting methods
See also 2.9
standard indicative of the stability. Chromatographic separating procedures
have become established, popular among which is high-pressure liquid chromatography (HPLC), which permits determination of both the total concentration and the isomer ratios and the quantitative development of degradation
products. Any decrease of the content registered in the course of storage should
correspond to an equivalent increase of demonstrable degradation products.
In the 2nd stage of development a stability prognosis is desirable. CM solutions
usually permit reaction-kinetic derivations using the Arrhenius equation: Storage tests are conducted at increased temperatures. The anticipated stability at
room temperature can be determined from the reaction rates of degradation.
Long-term storage tests at least 25°C (upper limit for room temperature
according to the European Pharmacopoeia) and at 40 °C with 3 production lots
which must have been manufactured with regard to the equipment of the
pharmaceutical production unit and whose chosen container material and filling volumes must correspond to the later commercial preparation. Depending
on the region in which the product is to be marketed, 30°C storage tests are also
provided for. Testing of the samples of the 25 °C and, where applicable, 30°C
storage must be conducted up to the end of the proposed period of stability, if
necessary up to 5 years. Interim tests are performed after 3, 6, 9, 12, 18, 24, 36 and
48 months; the final test then after 60 months.
2.8 To What Are Colour Changes of Contrast Media Attributable?
2.7
How Are X-Ray Contrast Media Checked for Freedom
from Pyrogens?
D.HERRMANN
The following testing methods are used:
The rabbit test is the conventional test, it is nowadays mostly used only for
basic testing or routinely in the case of the older CM preparations. When a
pyrogen-containing solution is administered intravenously (preferably into an
ear vein) to a rabbit, an increase of temperature (preferably measured rectally)
occurs within 3 hours. The squares of the temperature increases are formed and
must not exceed a threshold value specified by the pharmacopoeia.
The limulus test (LAL test) has now become widely established. When a
pyrogen-containing solution is mixed and incubated with a lysate from the
blood of limulus polyphemus (horseshoe crab), characteristic gelatinisation
occurs which is visually recognisable in dilution series. This test is usually more
sensitive and also offers the possibility of better quantitative evaluation. A further, special advantage is that it can be performed within the pharmaceutical
production itself in the sense of a process control, which is impossible in the
case of the rabbit test because of the need to keep animals. It is, however, essential that the test be validated with reference to the rabbit test.
2.8
To What Are Colour Changes of Contrast Media Attributable?
D.HERRMANN
There are two possible reasons for a faint yellow or brown-yellowish discoloration of contrast media solutions:
1.
2.
The presence of by-products from the synthesis of the active substance.
Chemical decomposition of the active substance or of the by-products;
further decomposition beyond deiodination or hydrolysis of the amide
structure under the influence of temperature and light.
The yellowish or brown-yellowish discoloration is attributable to organic
molecules. As a rule, free inorganic iodide is not detectable within these
solutions.
65
66
CHAPTER
2
Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
2.9
Does Particulate Contamination Occur
in X-Ray Contrast Media, and How Important Is It?
D.HERRMANN
Particulate matter consist of mobile, randomly-sourced, extraneous substances,
other than gas bubbles. This definition demarcates these impurities from
droplets, pharmaceutical suspensions and gas bubbles (of importance, for
example, in the case of echocontrast agents). Given the present state of technology, particulate contamination of parenteral products (not only CM) cannot
be completely avoided, but every effort should be made to reduce the number
and size of the particles in order to minimise the load on the patient. No
threshold value can, however, be given for the tolerance from a toxicological
point of view. The risk of occlusion of blood vessels always exists, and histological studies have shown that cell proliferation around foreign bodies can lead
to the development of granulomas. Asbestos fibres are carcinogenic, apparently
because they can pierce cell membranes.
Visual, microscopic and instrumental examination procedures are described
in the various pharmacopoeias (German Pharmacopoeia/Drug Code, European
Pharmacopoeia, US American Pharmacopoeia etc.).
Good pharmaceutical practice demands that every individual container be
subjected to visual inspection immediately after its production. A similar check
is recommended immediately before use of parenteral preparations, and it
should be borne in mind here as well that the typical application aids such as
disposable syringes and infusion kits can likewise be contaminated by foreign
particles. The container is illuminated from the side with a white light source of
at least 1000 Lux and inspected against a matt black background and a white
background. Almost 100 % of particles 55 }lm in size are recognisable, while the
probability of detecting 25 }lm particles is about 50%. Under almost observation conditions 10 }lm particles are discenable. This is far below the limit of
resolution of the human eye, since any particulate matter present is perceived through its brightness contrast (scattered light) with the background and
not because of its contours or colour. The use of a magnifying glass is common
(e. g. 3 dioptres), but does not significantly increase the detection of particulate
matter.
For counting on membrane filters, the solution being examined is swirled
around in its container at least 20 times and then passed through filters which
have been rinsed beforehand with particle-free water. The solution is rinsed off
with an excess of particle-free water, the membrane ftlter is stuck on suitable
glass slides (e. g. so-called Petri slides) and, after drying, examined under a
microscope. Filtration and the preparation of the ftlters up to drying must be
performed in a dust-free environment; the use of laminar flow (low-turbulence
displacement flow) is preferred. The count is done under oblique lateral illumination in the classes: All particles> 10 }lm and all particles> 25 }lm; the classes
2.10
Which Factors Reduce the Stability of X-Ray Contrast Media
> 50 JIm and fibres> 100 JIm are also common. The presence of asbestos fibres
can, however, only be determined by electron microscopy.
The light obscuration method has become generally established as an
instrumental counting procedure. The solution (again after being swirled
around at least 20 times) is pumped at a defined rate through a special cell
through which a strong light (preferably laser light) is passed from the side. The
shadows thrown by individual particles lead to attenuation of the brightness of
the light and, hence, to a reduction in the current or voltage of a photoelectric
cell. The magnitude of this decrease in the photoelectric current is measured
individually for every single particle and, provided the equipment is calibrated,
the size and number of the particles can be calculated mathematically. The previously used examination method, preferably in saline solutions, of measuring
the electrical conductivity, which is reduced by particles as the solution flows
through a capillary (Coulter counter) is virtually impracticable in the case of
CM solutions because electrolysis takes place.
2.10
Which Factors Reduce the Stability
of X-Ray Contrast Media and What Are the Implications
of Storage Recommendations?
D.HERRMANN
In general, a distinction should be made between long-term storage in the sense
of stocking and short-term provision. The latter has no significant influence
from the point of view of kinetics. In contrast, excessive warming should be
avoided over the long term, meaning that X-ray contrast media should be stored at room temperature (15 - 25°C) and protected from light.
CM solutions are allowed be placed in a warming cupboard for a short time,
for example to warm up the solution to 37°C body temperature before injection
or infusion. Figure 2.10.1 shows as an example the release of iodide from Ultravist observed within the framework of long-term stability tests with exposure
to elevated temperature. This shows clearly that no objections exist to storage in
heating cabinets or in water baths heated to about 40°C for one or even several
days.
CM solutions may also safely be placed in hot water for a short time, e. g.
heating to about 60 - 80°C can be used to redissolve crystallised CM solution.
This brings us to another way in which CM solutions can change during
storage, i.e. purely physical crystallisation during winter-time transport, for
example. It must be borne in mind that highly concentrated CM solutions are
normally used. The concentration is usually related to the iodine content; an
Ultravist 370 solution containing 370 mg iodine/ml has a concentration of
0.769 g iopromide/ml, i. e. it is a 76.9 % solution (m/v).
67
68
CHAPTER 2 Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
20
1S
~
.:;
c:
o
.~
~ 10
Q)
o
c
o
o
.if{•...•
(I)
~
"0
~
S
.....
,/
" "
~;'
...•....
....
(!)
0.l....t-0----S----r10----1-S----r20----2...
S----raO----:3...
S-
Storage time (months)
Fig.2.1O.1. Iodide release from Ultravist 370 (50-ml vials) stored at 20°C (\7 -) and 30°C
(L'> ••• )
Finally, aqueous solutions can freeze on being cooled too much. However,
experience shows that not all the bottle contents of a pack crystallise on undercooling, since seed crystals are required and the formation of ice begins
mainly on simultaneous mechanical agitation. In the case of frozen bottle
contents, however, the solutions can be restored again by heating, whether by
placing them in hot water or by leaving them to stand at room temperature for
a while and swirling the solution occasionally. In general, the contents should
be checked before use for freedom from particles and, particularly, from
crystals.
Sustained exposure to light has a much more critical effect on the stability of
CM than does exposure to heat. Typical light-induced changes are increases of
the iodide content and pH decreases, which can ultimately lead to the separation of CM acid in the case of ionic CM, e. g. Urografin. As an example, Figure
2.10.2 shows the cleavage of iodide from Ultravist solution in relation to the
duration of exposure to an average of 600 Lux.
No definite shelf lives of CM solutions exposed to light can be given for daily
practice. The stability data on the CM packs refer to storage protected from
light. This is because the rate and extent of light-induced degradation depend
very much on the brightness and the spectral composition of the light. The
short-wave spectral range of visible light and the near-UV range - which is contained not only in sunlight but also in daylight (450-290 nm) - are photochemically active. These factors are, in turn, dependent on the kind of illumination
2.10
Which Factors Reduce the Stability of X-Ray Contrast Media
800
PH 5 ....2
700
800
t
a
c:
!l00
.Q
PH 8.95
"§
'E ... 00
g
Ql
o
<.>
Ql
300
"0
~
200
100
0"-:;:":-:....:.:...."'-'-""'--..."",
50
Fig. 2.10.2. Iodide release from
600 lux light
50
-."...,.-
..."",
100
150
Days at 600 lux
ml Ultravist
370
--.-
200
-.-
250
soo
as a function of duration of exposure to
(daylightlfluorescent tube light/electric bulb light); in the case of daylight, they
are determined by the degree of cloudiness and even by the geographicallocation. As a general rule of thumb, about a day's exposure to an average workplace
brightness of 600 Lux can be regarded as uncritical. Exposure to sunlight,
however, must be avoided under all circumstances, even brief exposure, since,
apart from the brightness of sunlight (e. g. 70 000 Lux), the latter also has a considerable UV component with particularly high photochemical efficacy.
In principle, the stability of CM solutions with regard to exposure to light
could be improved by using amber glass. Since, however, the provision of CM
solutions filled even in colourless bottles and also the use of CM under normal
workplace brightness are justifiable with appropriate restriction on the standing times, amber glass must not be employed. The latter is permissible only for
extremely light-sensitive drug formulations for parenteral use. And because, on
the other hand, brown glass is not completely impermeable to part of the photochemically active spectral range, degradation of the CM solutions would still be
possible even in amber glass bottles or ampoules in the case of prolonged exposure to light and particularly when exposure to sunlight cannot be ruled out. A
warning about light protection would also be necessary.
An elegant solution to the problem is possible on use of a special foil for
attaching the bottle bracket in the case of infusion bottles. If a UV-absorbing
foil is used, the ruggedness towards light exposure increases substantially, but
no claim to light-excluding packaging in the sense of the pharmacopoeia can be
69
70
CHAPTER
2
Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
made because the colourless transparent jacket allows the short-wave range and
thus photochemically active pant of the visible spectrum to pass.
CM can be damaged not only by short-wave light, but also by X-rays. Consequently, CM may not be stored for prolonged periods within the range of the
scattered radiation from X-ray units. On the other hand, there are no objections
to their brief exposure for diagnostic purposes or to their provision for the
examination session.
2.11
What Precautions Are Necessary in Drawing Up X-Ray
Contrast Media into Syringes and in Administering Them
Using Infusion Devices and High Pressure Injectors?
D.HERRMANN
Highly concentrated CM solutions in particular can be drawn up into syringes
much more easily if the solution is warmed to body temperature, since this
decreases the viscosity by almost a half.
In principle, the stopper of a CM bottle should be pierced only with a cannula with the narrowest possible lumen and with a long ground point or with
the spike of an infusion kit. Large-calibre cannulas, e. g. 2.0 mm, and cannulas
with a short ground point such as those used for venous puncture are burdened
with the risk of fragmentation, i. e. they can punch out particles of rubber.
Multiple piercing, particularly at the same place on the rubber stopper, must
always be avoided because of the increased associated risk of fragmentation
and also leakage The use of aspiration spikes, e. g. SterifIx spikes (Braun) is
recommended. So-called Nokor cannulas (Becton-Dickinson) are also suitable.
These are special cannulas with a scalpel-shaped point and a lateral opening.
When these articles are used, no air should be pressed into the CM bottle from
the disposable syringe.
Infusion kits fItted with fIlters should always be used so that particles can
be fIltered out. The mesh fIlters (usually 15 }lm) permit an adequate flow of liquid.
On the other hand, the use of special fIlter cannulas or aspiration spikes with integrated fluid fIlters is unfortunately impracticable because of the high viscosity of
the CM solutions. Furthermore, such fIlter cannulas (e.g. 0.2 }lm) are intended
more for the separation of bacterial contamination than of particles.
CM are usually compatible with the customary and standardised singleapplication devices, e. g. disposable syringes of polypropylene or infusion kits
including their delivery tubes, which are usually made of soft Pvc. When
running through them, the CM solutions are not contaminated by the softener
normally employed, diethylhexylphthalat. The CM manufacturers subject the
syringes and infusion kits supplied together with the CM to appropriate type
testing, so they can be regarded as safe.
2.12
How Long Do X-Ray Contrast Media Remain
Possible materials for administration equipment for multiple use are, preferably, glass, stainless steel and chemically inert plastics which can also be cleaned and sterilised before use, e. g. polysulfone or polycarbonate as material for
cylinder cartridges for high-pressure injectors. Objections exist to the use of
aspiration aids and cannula couplings made of brass, since they can provoke
interactions, e. g. the release of iodide secondary to the release of copper ions.
Discoloration of CM solutions after contact with parts made of brass have also
been observed on occasions. Where such equipment is not made of stainless
steel, care must be taken that they are perfectly and completely chrome-plated
throughout, internally as well.
CM bottles are usually closed with stoppers made of synthetic elastomer
which are not burdened with the frequently asked-about risk of latex allergy.
But, the piston stoppers of commercially available disposable syringes and the
elastic connecting pieces in infusion kits can be a problem in this respect. Such
parts are usually made of natural rubber. Relevant information can be obtained
from the manufacturer of the medical devices.
2.12
How Long Do X-Ray Contrast Media Remain Usable After
the Original Container Has Been Opened?
D.HERRMANN
Once a container has been opened, the CM solution should be drawn from it
only on the same day. The risk of microbial growth and of a resultant pyrogenic
reaction increases considerably the longer the solution is allowed to stand
beyond the day of the examination. Crystallisation as a result of evaporation
can also occur under these circumstances, since seed crystals can form at the
surface of the exposed liquid which accelerate crystallisation of the entire
contents of the bottle. The risk of light-induced degradation also increases the
longer the solution is allowed to stand.
According to the laws governing drug use, the collection of unused remains
of CM bottles and the repeated extraction from a container over several days
must be regarded as multiple extraction. This is inadmissible, since injectables
intended for multiple extraction must be protected against microbial growth by
a preservative and both the German and European pharmacopoeia state that
the preservation of parenteral formulations is not permitted for volumes
greater than 15 ml, which are typical of CM.
But there are special constructions where the container is pierced only once
for the contents to be delivered via special roller pumps (e. g. an Ulrich Injector)
or drawn up into cartridges (e.g. MedRad) and it is then possible for the contents of several CM bottles to be delivered sequentially. Modern injectors can
also be programmed in advance to deliver a particular amount at a particular
71
72
CHAPTER 2 Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
rate of flow, and also allow the flow rate to be slowed down and even automatic
dilution with, for example, NaCI solution and a flush. 500 ml or even 1000 ml
CM bottles are available and can be used for more than 1 patient under the supposition that the sufficient long patient tube is changed regularly. It is obvious
that the use of such systems requires careful checks on the responsiveness of the
safety components; for example, reflux should be prevented by means of nonreturn valves. Bubble detectors are incorporated to prevent the infusion of air.
Attention must also be paid to the exact dose per patient and the maxinlUm
permissible flow rate. The repeated attachment of part-empty bottles to these
delivery systems is generally inadmissible. Any remaining solution at the end of
the working day must be discarded together with the transfer and pump tubes
designed as disposable articles.
2.13
May X-Ray Contrast Media Be Resterilised, Diluted
or Mixed with Other Drugs?
D.HERMANN
Resterilisation of unused CM remainders by autoclaving must be avoided in any
case. Although CM solutions are sterilised immediately after their manufacture
in pressurised, saturated steam at 121°C, this is done in the original sealed
vessels and under the strictly controlled conditions of good manufacturing
practice (GMP). Any further sterilisation would not only mean an additive
thermal burden, but would also critically affect the pharmaceutical quality
because of the no longer surveyable framework conditions after opening of the
container in the meantime or even refilling into other containers. Possible consequences are excessive iodide content, pH shifts, the occurrence of primary
aromatic amines and contamination with foreign particles.
From the point of view of the drug laws, dilution or mixing with other
preparations constitutes the manufacture of a new drug for which the hospital
pharmacists, for example, must accept responsibility. Possible diluting media
are, preferably, physiological saline solution or water for injection.
Mixtures with other drugs are permissible only after suitable compatibility
tests and only if they are made up immediately before administration. Mixtures
with solutions containing chemically reducing substances or containing heavy
metals should be avoided because of the possible induction of iodide release.
Compatibility with other solutions can be assessed on the basis of colour,
turbidity and the pH value. The pH range of the quality specification of the xray contrast medium, e. g. pH 6.5 - 8.0 for Ultravist, should never be left. The US
American pharmacopoeia USP, among others, contains special chemical testing
methods for analysing various CM.
2.14 Can the Re-Use of Disposable Catheters for Angiography be Justified?
2.14
Can the Re-Use of Disposable Catheters for Angiography
be Justified?
M. THELEN
Catheter Processing
Problem
Can the re-use of disposable catheters for angiography be justified after
processing and, if so, can conditions for the processing be specified in detail?
Definition, Legal Situation
The reprocessing and resterilisation of disposable material have long been the subject of controversial discussion. For some time now, the number of users beginning
to reprocess expensive disposable materials such as intravascular catheters and
measuring probes has been increasing for reasons of economy. These articles,
which were previously subject to the Medicines Act in Germany, were made subject
to the Medical Products Act (MPA) - based on an european guideline in 1994.
At least in Germany, the legal situation remains unclear even after the new
legal regulations, since no express rules governing reprocessing exist even in
the MPA.
Opponents of the re-use of disposable articles quote Articles 22, 23 of the
MPA: ''Active medical products may be installed, operated and used only in
accordance with their intended purpose, with the stipulations of this Act and
decrees issued in this regard, with the generally accepted rules of technology
and the regulations governing safety at work and accident prevention. They
may not be operated and used if they display defects as a result of which
patients, employees or third-persons may be put at risk." Article 4 of the MPA is
also quoted in connection with the legality of re-use: "The marketing, installation, operation and use of medical products is prohibited if a reasonable
suspicion exists that, on proper use, maintenance and use for their intended
purpose, they jeopardise the safety and health of the patients, the users or third
persons beyond a degree justifiable by the knowledge of medical sciences ..."
Those opposing the re-use of disposable products maintain that a risk to
patients must be assumed through the re-processing and re-sterilisation.
Accordingly, the advocates of re-use are duty-bound to refute this assumption, i.e. they must prove that the safety and health of the patient is not
jeopardised through the process of reprocessing and resterilisation. The
reprocessor must, therefore, guarantee that, in particular, the materials
(physical, chemical properties, interaction of the materials with blood, thrombogenicity) and the hygienic properties of the reprocessed product satisfy the
requirements of existing norms and guidelines.
73
74
CHAPTER
2
Pharmaceutical Quality and Stability of Iodinated X-Ray Contrast Media
Reprocessing of Disposable Angiography Catheters
A precondition for any processing procedure is the validation of each individual
step, with cleaning, rinsing, material safety and sterilisation needing to be
validated individually. Detailed quality criteria must be established for each of
these steps. Apart from the question of sterility and the physical and functional
properties of the catheters, attention must be paid in particular to the toxicological safety including interactions between catheter materials and cleaning
agents and disinfectants. At present, no validated quality criteria of this kind
exist.
Given the plethora of materials, material combinations, diameters and
shapes used in catheter technology and in view of the difficulties involved in the
technical performance and validation of the individual processing steps, it is
doubtful whether reprocessing and resterilisation in individual institutions
(hospitals, practices) can be economically worthwhile.
There are no laws which explicitly exclude the reprocessing of angiography
catheters. However, in view of the numerous problems particularly with regard
to quality control , such a procedure must remain the sole domain of central
processing institutions if it is to be practised at all. As long as such institutions
(internal facilities of large hospitals or external industrial companies) guarantee adherence to the quality criteria laid down by norms and guidelines, there
can be a case for the reprocessing of selected catheters (particularly those with
a high initial purchase price such as balloon catheters or catheters for electrophysiological diagnostics and therapy).
Outside of Germany, however, national laws and regulations relating to the
reprocessing of catheters must also be taken into account.
CHAPTER
3
Influence of Contrast Media on Organs and Vessels
3.1
What Are the Mechanisms of Toxicity Associated
with Contrast Media?
P.DAWSON
Three factors are usually cited as involved in CM toxicity, namely hyperosmolality, chemotoxicity and charge, although strictly speaking charge should be
incorporated under the heading "chemotoxicity" since it forms part of that
phenomenon.
Hyperosmolality effects are quite easily understood in general terms. They
include acute expansion of the plasma volume, generalized vasodilatation
resulting from an effect on smooth muscle, rigidification of red cells, histamine
release from basophils and mast cells and endothelial injury, which may lead to
thrombophlebitis or frank thrombosis following venous injection. These
hyperosmolality phenomena are all due to the nonspecific effects of the highly
concentrated solutions of the formulations in clinical use.
Chemotoxic effects arise from the properties of the CM molecules themselves. These are less easy to understand and have only been unravelled in the
last decade or so. A stimulus and a help in elucidating the processes was the
arrival of the newer generation of nonionic CM since having molecules with
different detailed structures and different magnitudes of chemotoxicity
provided an experimental test bed for investigation.
In summary, it seems that chemotoxic effects are mediated by nonspecific
interactions between CM molecules and biological macromolecules. While
some hydrophilic interactions are undoubtedly possible, it seems likely, since
the hydrophilic portions of the CM molecules are solvated in water solution,
that most of the interactions are between hydrophobic groups. The hydrophobic
groups of any CM molecule are, most importantly, the benzene ring and iodine
central core of the molecule. These hydrophobic interactions are augmented by
Coulomb interactions when charged ions are involved, as in the case of the
conventional agents.
76
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
The route to minimizing chemotoxic interactions therefore lies in eliminating charge and in masking the hydrophobic core of such molecules by an array
of hydrophilic moieties. This prescription is essentially a description of the
current nonionic agents. These, by definition, lack charge and all have an
extensive array of hydrophilic groups around the hydrophobic core. It is true
that these hydrophilic groups were designed to restore high water solubility lost
when the carboxyl-group of the ionic CM was eliminated, but they have had the
serendipitous effect of also meeting the design specification now understood in
general terms for an agent low chemotoxicity. The current generation of nonionic agents differ, of course, in detailed structure and have been shown to
differ in degree of toxicity in laboratory studies, though there is no evidence of
significant differences between them in manifest clinical toxicity.
Insights of this kind may lead to the rational design of better contrast agents
using computer design techniques.
References
1.
2.
Dawson P (1984) Chemotoxicity of contrast media and clinical adverse effects: a review.
Invest Radiol 20: 583 - 591
Howell MJ, Dawson P (1985) Contrast agents and enzyme inhibition. II Mechanisms. Br J
Radiol 58 : 845 - 848
3.2
Do Contrast Media Affect the Viscosity of Blood?
N. H. STRICKLAND
The viscosity of any cell system, including blood (a plasma-red cell system), is
affected by four major factors: the suspending phase viscosity, the cellular size,
the cellular deformability and the presence of aggregates, which in the case of
blood are red cell rouleaux, that is, red cell aggregates induced by plasma
proteins. CM alter blood viscosity by affecting these four parameters to a
greater or lesser degree.
The viscosity of liquids may be simply and reliably calculated from their
shear rate using a bob-in-cup viscometer apparatus. All neat CM behave as true
Newtonian fluids since their viscosity does not vary with shear rate [4]. Experiments examining how various concentrations of CM affect the viscosity of
the suspending phase of blood (i. e. plasma) show that the viscosities of all
plasma-CM mixtures are very high in comparison with plasma. Mixtures with
the ionic monomer ioxaglate showed lower viscosities than mixtures with corresponding concentrations of ionic or nonionic monomeric CM. Mixtures of
CM with isotonic phosphate-buffered saline behaved similarly to the plasma-
3.2 Do Contrast Media Affect the Viscosity of Blood?
CM mixtures [5]. This is important because it demonstrates that CM do not
significantly affect the plasma proteins and in particular they do not cause
appreciable plasma protein aggregation or precipitation.
Numerous studies have demonstrated that the hyperosmolality of CM
reduces cellular size. This is reflected in the reduction in blood haematocrit
engendered by CM and can be explained solely by the hypertonicity of the
suspending phase of the mixture [5].
In addition, different CM alter red cell morphology to varying degrees,
causing some erythrocytes to lose their normal biconcave shape and form
echinocytes. Light microscopy and scanning electron microscopy [1] have
shown that the ionic dimer ioxaglate results in only slight changes in red cell
morphology compared with equivalent concentrations of ionic and nonionic
monomeric CM. This phenomenon cannot be attributed merely to the osmolality of the solution since it has been shown that changes in red cell morphology engendered by the highest concentrations of ioxaglate studied (75%) were
less than those produced by hyperosmolar saline [1].
The viscosity characteristics of red cell suspensions in the presence of different concentrations of CM are largely influenced by the additional effects of
the CM upon cellular deformability and the presence of red cell rouleaux. The
experimental situation is simpler at high shear rates (~128.S S-I) because the
effects of the small cellular aggregation forces then become negligible, so rouleaux can be ignored.
At low shear rates cellular aggregation forces become significant, so rouleaux
will significantly affect viscosity measurements. At low shear rates (~0.277 S-I)
viscosity falls rapidly with increasing concentration for all types of CM. This fall
in viscosity at low shear is due to cellular aggregation decreasing at higher CM
concentrations, so the suspension becomes less viscous. CM can inhibit cellular
aggregation in at least two ways. First, a direct effect on the red cell inhibits
rouleaux formation. Second, the viscosity of the suspending phase increases as
the CM concentration increases and this produces higher local shear forces in
the red cells, tending to pull the cellular aggregates apart.
It has been shown that at both high and low shear rates, the rate of change of
viscosity with CM concentration differs markedly between the various types of
CM [2,5]. The conventional ionic monomers caused most disturbance to blood
viscosity. The monoacid dimer ioxaglate was least disturbing to the viscometric
characteristics of blood and the newer, nonionic monomers were intermediate
in their effects. This is surprising because, in contradistinction to the accepted
hierarchy for the effects of CM at the molecular level [3], ioxaglate is closest to
the ideal of total inertness with respect to changes in viscometric properties of
red cell suspensions. The explanation for this observation must at present be
speculative, but it seems likely that what matters most in determining low viscometric disturbance for a CM is low osmolality, low density and low inherent
viscosity, rather than its ionic or nonionic status.
77
78
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
Clinical Significance of Changes in Viscosity
Once uniform distribution of, for example, a 50-ml bolus of CM has taken place
in the whole circulation, the final low plasma concentration of about 2 % will
have very little effect on blood viscosity. However, during in vivo angiographic
procedures there are a number of situations in which very high concentrations
of CM are present. These high concentrations can be expected to have
significant effects on blood rheology because of the resulting high density,
osmolality and viscosity.
Early after bolus injection of CM into large vessels, mixing between it and
blood is incomplete. Blood cells at the CM-blood interface will be in contact
with very high concentrations of CM and this may cause marked rheological
effects; results predict that where shear rate is high, along the walls of vessels
and at the origin of side branches, viscosity will be increased [4].
After selective injection into any organ, there will be high local CM concentration in its microcirculation and this may be expected to alter the normal
rheology of the organ's microvasculature. In small vessels where shear rate
is high the increased viscosity of blood exposed to high CM concentrations
could lead to increased sludging and occlusion of these small vessels. In
other small vessels where shear rate is low, the decreased viscosity of blood in
contact with high CM concentrations may increase the flow through these
vessels. Differential perfusion of the microvascular bed may thus result and this
would not be an accurate representation of the normal pattern of blood flow
through those vessels in the absence of CM. Such effects could be accentuated
by the initial nonuniform distribution of the injected CM within the vascular
bed.
A final important clinical situation is created during an angioplasty procedure. Blood flow around the angioplasty site may be reduced almost to zero
in the presence of atheromatous plaque and an intraluminal balloon catheter or
laser. This will accentuate the rheological effects of high bolus concentrations of
CM delivered locally, with repercussions on haemodynamics. The nature of
such changes will depend upon whether the prevailing local shear forces are
high or low. During a balloon or laser angioplasty procedure the stasis itself
would be expected to produce conditions favouring low shear forces, which
should lower blood viscosity in the presence of high eM concentrations, and
this might, if anything, be beneficial. However, local shear forces are more likely
to be high if a rotary atherectomy device is used, or in the immediate postangioplasty situation where high flow conditions are reinstated and in addition
a local contrast bolus is injected at the angioplasty site to document the radiographic result. The increase in viscosity under such circumstances might favour
thrombus formation on a freshly cracked plaque or in the distal run-off vessels.
References
1.
Aspelin P (1978) Effect of ionic and non-ionic contrast media on morphology of human
erythrocytes. Acta Radiol Diagn 19: 675 - 687
3.3 Are There any Differences Between Ionic and Nonionic Contrast Media
2. Hardeman NR, Goedhart P, Koeni Y (1991) The effect of low-osmolar ionic and non-ionic
contrast media on human blood viscosity, erythrocyte morphology, and aggregation
behaviour. Invest Radiol 26: 810 - 818
3. Howell L, Dawson P (1986) Contrast agents and enzyme inhibition. II Mechanisms. Br J
Radiol 59 : 987 - 991
4. Strickland NH, Rampling MW, Dawson P, Martin G (1992) Contrast media-induced effects
on blood rheology and their importance in angiography. Clin Radiol (in press)
5. Strickland NH, Rarnpling MW, Dawson P, Martin G (1992) The effects of radiocontrast
media on the rheological properties of blood. Eur J Haemorheol (in press)
3.3
Are There any Differences Between Ionic and Nonionic
Contrast Media in Their Effect on Coagulation?
P.DAWSON
All the available evidence supports the idea that all iodinated intravascular
CM are qualitatively similar in their effects on coagulation and differ only in
the magnitude of these effects [2]. Thus, both nonionics and ionics interfere with the coagulation cascade at a number of levels, in particular inhibiting
fibrin polymerization and inhibiting platelet aggregation. The nonionics, however, have significantly weaker effects, particularly at higher concentrations,
than do the ionic agents of conventional or low osmolality. The occasional
formation in syringes or catheters of clots during angiographic procedures
carried out with the less anticoagulant nonionic agents [4] has been misinterpreted in some quarters as evidence for some "procoagulant" property of these
materials. Indeed, the adjective "thrombogenic" has been applied to them.
There is, however, absolutely no evidence on which to base such an idea. Some
statements, made in good faith and intended to be helpful, to the effect that
prolonged contact between nonionic agents and blood should be avoided,
are also misleading. Certainly, angiographic procedures should be carried
out as quickly as is compatible with other aspects of safety, but there is no
question but that nonionic agents are also anticoagulant and are therefore
entirely helpful in preventing coagulation and subsequent thromboembolic
events [3]. They are simply somewhat less helpful in this sense than the ionic
agents.
It is also important to realize that the lesser anticoagulant properties of the
nonionic agents are part and parcel of their generally greater inertness and
biocompatibility [1]. More anticoagulant CM are more toxic.
The role played by catheter and syringe materials in promoting coagulation
by contact activation is just as important as the role of contrast agents in inhibiting it. There are significant differences between materials: for instance,
glass is a much more powerful activator than any plastic and polyurethane
tends to be a more powerful activator than polyethylene [3].
79
80
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
In principle, a more careful angiographic technique might arguably be
necessary in clinical angiography with nonionic agents than with ionic agents
but, on the basis of extensive experience over several years in Europe, there
appears to be no significant difference in the incidence of problems in practice
with the new, and in other regards better and safer, agents.
References
Dawson P (1985) Chemotoxicity of contrast agents and clinical adverse effects. Invest
Radiol 20: 584 - 591
2. Dawson P et al. (1986) Contrast, coagulation and fibrinolysis. Invest Radiol21: 248 - 252
3. Dawson P, Strickland NS (1991) Thromboembolic phenomena in clinical angiography: role
of materials and technique. JVIR 2: 125-132
4. Robertson MJF (1987) Blood clot formation in angiographic syringes containing non-ionic
contrast media. Radiology 162: 621- 622
1.
3.4
Do Contrast Media Affect Cardiovascular Function?
P.DAWSON
CM have a variety of adverse effects on the cardiovascular system [5]. They have
primary central effects on the heart (myocardial contractility, electrophysiology and coronary blood flow are all affected) and primary effects on the peripheral vasculature. They also expand plasma volume [6], adversely affect blood
rheology [3] and have anticoagulant properties [4]. Homeostatic responses are
invoked and, although at first sight entirely physiologically appropriate, these
may not in some patients be entirely desirable.
One of the most stressful events when a large bolus of CM is delivered into
the intravascular space by any route is the generalized vasodilatation engendered, which results in systemic hypotension with a reflex tachycardia [5]. This
is largely a hyperosmolality-mediated effect on smooth muscle, but inhibition
of acetylcholine in blood and tissues [2] and histamine release [1] have also
been invoked as mediators.
The effects on the heart itself are obviously greatest when injection is directly
into the coronary arteries, as during coronary arteriography. There are marked
depressant effects on cardiac pump function, however assessed, which are dosedependent and most persistent in the ischaemic heart. They are also cumulative, hence the need for rest intervals between injections in clinical work.
Osmolality, chemotoxicity, oxygen displacement and ionic content all contribute to these effects [5].
There are also striking changes in electrophysiology following coronary
artery injection [5]. These are due to a combination of direct and indirect
3.5 Do Contrast Media Affect Pulmonary Function?
neurally mediated effects on sinus rate, intracardiac conduction velocity,
duration of ventricular depolarization-repolarization processes and a consequent liability to tachyarrhythmias. The ventricular fibrillation threshold is
reduced in a dose-dependent fashion.
Coronary blood flow is also increased by CM [5]. This is not, as would first
appear, a necessarily desirable consequence of their injection in that the
hyperaemic response occurs in more normal areas of vascularity but not in
areas of abnormal vascularity. There may, therefore, be a steal phenomenon
rendering the ischaemic areas even more ischaemic.
The nonionic agents are also associated with all these effects, but to a
markedly lesser degree. Indeed, in some animal studies they have, rather than a
negative inotropic effect, a small positive inotropic effect. The differences are
based on their lower osmolality, their lower chemotoxicity and their almost
insignificant capacity for binding calcium [5].
References
1.
2.
3.
4.
5.
6.
Assem ESK, Bray K, Dawson P (1983) The release of histamine from human basophils by
radiological contrast agents. Br J Radiol56: 647-652
Dawson P, Edgerton D (1983) Contrast media and enzyme inhibition. I Acetylcholinesterase. Br J Radiol 56: 653 - 656
Dawson P, Harrison MJG, Weisblat E (1983) Effect of contrast media on red cell flltrability
and morphology. Br J Radiol56: 707-710
Dawson P et al. (1986) Contrast, coagulation and fibrinolysis. Invest Radiol 21: 248 - 252
Dawson P (1989) Cardiovascular effects of contrast agents. Am J Cardiol64: 2E-9E
Hine AL, Lui D, Dawson P (1985) Contrast media osmolality and plasma volume changes.
Acta Radiol 26: 753 -756
3.5
Do Contrast Media Affect Pulmonary Function?
P.DAWSON
There is no doubt that in a number of ways various contrast procedures may
affect pulmonary function, though it must be said that this is an area in which
detailed study has been lacking.
When hyperosmolar CM are delivered directly into the bronchial tree,
osmotic effects may produce acute pulmonary oedema.
When Lipiodol is used for lymphography the CM finds it way through the
thoracic duct into the subclavian vein and hence through the right side of the
heart and into the lungs. Globules of CM are trapped in the capillaries and may
be seen on chest radiographs. In the period the lungs are dealing with this oil
there is impairment of lung function, with a reduction in pulmonary com-
81
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CHAPTER 3 Influence of Contrast Media on Organs and Vessels
pliance and decreases in pulmonary capillary blood volume and pulmonary
diffusion capacity [4].
In bronchography, as might be expected, the introduction of CM into the
tracheobronchial tree causes some degree of breathlessness. Measurements of
vital capacity and maximum breathing capacity show an average reduction of
20 % immediately following unilateral bronchography and 30 % in the case of
bilateral bronchography [8]. Diffusion scans with macro-aggregates of albumin
carried out an hour or so after bronchography may show localized diffusion
defects in the lungs [8], presumably in response to partial bronchial obstruction
by CM. Ventilation scans also show areas of deficit [8]. There is a significant
reduction in diffusion capacity, which may not return to normal for 72 hours.
Not surprisingly, direct introduction of CM of the bronchial tree may also precipitate bronchospasm, particularly in asthmatic patients [1].
As regards intravascular contrast agents, Littner et al. demonstrated that subclinical bronchospasm could be routinely detected in patients receiving
peripheral venous boluses of CM in urography-type doses [5]. Dawson et al.
confirmed this observation and noted that there were smaller changes when a
nonionic CM was used [3]. It seems reasonable to suggest, though relevant convincing clinical studies have not been carried out, that nonionic CM should be
used in all patients at risk for bronchospasm. This would include not only
asthmatics per se but also those with chronic obstructive airways disease with
an element of bronchospasm.
Another observation of interest is that occasional cases of noncardiogenic,
acute pulmonary oedema based on increased capillary permeability may occasionally be seen following intravenous CM administration [2]. The increased
permeability may be based on vascular injury by the CM and/or the release of
histamine in the histamine-rich pulmonary bed. Interestingly, intravenous
injection of ionic CM has been shown to increase pulmonary capillary permeability routinely and to cause a marked, if transitory, elevation for extravascular
lung water [6]. A nonionic CM has been demonstrated to engender much less
marked effects and pretreatment with methylprednisolone [7] significantly
reduces this experimental subclinical pulmonary oedema. Detailed studies have
not been made, but these changes probably affect diffusion and compliance.
References
1. Beales JSM, Saxton HM (1968) The radiographic demonstration of bronchospasm and its
relief by aminophylline. Br J Radiol 41: 899 - 901
2. Chambalin WH, Stockman GD, Wray WP (1979) Shock and non cardiogenic pulmonary
oedema following meglumine diatrizoate for intravenous urography. Am J Med 67: 684686
3. Dawson P, Pitfield J, Britton J (1983) Contrast media and bronchospasm: a study with
iopamidol. Clin Radiol 34: 227 - 230
4. Gold WH (1965) Pulmonary function abnormalities after lymphangiography. N Engl J Med
273: 519 - 524
5. Littner MR, Rosenfield AT, Ulreich S, Putman CE (1977) Evaluation of bronchospasm
during excretion urography. Radiology 124: 17 - 21
3.6 Do Contrast Media Affect Hepatic Function?
6. Mare K, Violante M, Zack A (1984) Contrast media induced pulmonary oedema. Comparison of ionic and non-ionic agents in an animal model. Invest Radiol19 : 566 - 569
7. Mare K, Violante M, Zack A (1985) Pulmonary oedema following high intravenous doses of
diatrizoate in the rat. Effects of corticosteroid pretreatment. Acta Radiol 26: 477 - 482
8. Suprenant E, Wilson A, Bennett L, O'Reilly R, Webber M (1968) Changes in regional
pulmonary function following bronchography. Radiology 91 : 736 -741
3.6
Do Contrast Media Affect Hepatic Function?
V. TAENZER
There are scarcely any reports on the effects of the administration of intravascular CM on hepatic function. In studies of pigs, only slight statistically nonsignificant changes in the hepatic enzymes were observed after administration
of both ionic (metrizoate 370) and nonionic substances (iohexol 370) in relatively high doses for selective coeliac angiography with a balloon occlusion of
the coeliac trunk.
Further experimental studies of the tolerability of uroangiographic X-ray
CM in Wistar rats with cirrhosis of the liver showed that marked worsening
of cirrhosis occurred after administration of both ionic and nonionic X-ray
CM.
Even in patients with healthy livers, the use of ionic and nonionic substances
for visceral angiography results in slight temporary increases in hepatic
enzymes. The maximum increase in liver enzymes (alkaline phosphatase,
glutamate pyruvate transaminase, glutamate oxaloacetate transaminase) is seen
between 48 and 72 h after CM administration.
By contrast, in double-blind studies of intravenous ionic and nonionic renal
CM for both urography and digital subtraction angiography, no significant
changes in the liver enzymes were demonstrated. These liver-specific parameters were also not affected in patients with healthy livers when intravenous
cholangiographic CM were administered and measurements made prior to and
up to 3 days after CM administration.
Combined with the intravenous administration of former used cholangiographic CM (Biligrafin®, Bilivistan®, Biligram®) necrosis of liver cells was
reported in single cases. Pathomechanisms and clinical relevance were not
finally proven.
83
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CHAPTER 3 Influence of Contrast Media on Organs and Vessels
3.7
Do Contrast Media Lead to Impaired Kidney Function?
J.E. SCHERBERICH
Water-soluble parenteral contrast media (CM) are counted as very widely used
and very safe drugs. All of them, however, can impair kidney function (the
glomerular filtration rate, GFR) to some degree or another. A CM-induced effect
is designated "nephrotoxic" if the serum creatinine concentration increases by
0.5 -1.0 mgldl in the follow-up phase or if creatinine clearance falls by at least 25 %
from the baseline value (normal range: 80-120 mlJmin). CM-induced renal failure is usually reversible. The maximum degree of acutely impaired kidney function is reached about 4-7 days after CM administration, and is followed by a
repair phase of 1- 4 weeks, after which serum creatinine has returned to normal.
The incidence of CM-induced acute renal failure is about 0.6 % (i. v. urography) in the case of out-patients with primarily healthy kidneys and 4-5%
(i. v. urography) and 8.2 % (angiography) in in-patients with healthy kidneys.
Reversible renal failure following CM injection (i. v., i. a.) can occur more
frequently and with greater severity in: diabetic nephropathy (> 70 %), patients
with a history of kidney disease (about 22 %) and CM injections repeated at
short intervals. The most important risk factor is hypohydration of the patient
[6,7]. Most cases of CM-induced renal failure are transient and asymptomatic,
although acute oligoanuric cases with oedema (hydrops anasarca), severe
dyspnoea (pulmonary oedema) and electrolyte imbalance are also possible.
CM-induced renal failure is reported to account for approx. 12 % of all cases of
acute renal failure treated in hospitals, although possible nephrotoxic concurrent medication (e.g. antibiotics, non-steroidal antirheumatics) must also be
considered. Some predisposing factors are described in Chapters 4.8 - 4.12. The
prognosis of the oligoanuric forms is worse than that of the polyuric.
The pathogenesis of CM-induced nephrotoxicity is not yet fully understood.
The following are possible important factors [1-6]:
Disturbances of Glomerular Microcirculation
- pH, charge, osmolality and chemotoxicity of the CM: Damage to glomerular
endothelia and podocyte pedicles,
- erythrocyte sludge formation,
- pseudoagglutination (CM and para/cryoglobulinaemia),
- negative effect on the glomerular ultrafiltration coefficient.
"Biphasic" Change of Renal Haemodynamics
- in animal experiments, the injection of CM provokes vasodilatation initially
and then vasoconstriction; reduced corticomedullary perfusion (intrarenal
shunting),
3.7 Do Contrast Media Lead to Impaired Kidney Function?
- reduction of the glomerular ultrafiltration coefficient in the presence of a
virtually unchanged renal plasma flow,
- intrarenal activation of the renin-angiotensin II system,
- stimulation of endothelin release.
Direct Tubulotoxic Effects
- intracytoplasmic vacuole formation,
- in the proximal tubule: Shedding of the microvillous cuticular border
towards the lumen with formation of so-called "obstructive domed blisters",
which aggregate and block the tubular lumen,
- inhibition of energy-rich compounds, inhibition of renal sodium, potassium
ATPase (CM chemotoxicity),
- disturbed or reduced absorption of sodium in the proximal tubule, induction
of the so-called "Thurau mechanism", high end-distal sodium concentration
(macula densa): intrarenal renin-angiotensin II release, reduction of the GFR
- intracellular accumulation of calcium,
- instability of the cytoskeleton (lysis of the microtubules and microfilaments)
- increased formation of free (cytotoxic) oxygen radicals,
- aggregation of CM with Bence-Jones proteins (free monoclonal light chains)
or with Tamm-Horsfall uromucoid.
Possible Parameters for Measuring CM-Induced Nephrotoxicity
- serum creatinine concentration (normally below 1.3 mg/dl). N. B.: So called
"creatinine-blind" range of kidney function (GFR),
- creatinine clearance (normally 80 -120 mllmin),
- import-export balance (caution: increasingly positive balance after CM
administration),
- weight behaviour (caution: increase of 500 g/day),
- tubular marker enzymes (aminopeptidase M, gamma-GT, alkaline phosphatase, N-acetyl-p-D-glucosaminidase, p-NAG) or immunoreactive microvillous membrane proteins of the proximal tubule in urine,
- alpha-l-microglobulin in urine (normally up to about 12 mg/l).
Prophylaxis of CM-Induced Renal Failure [6, 7]
- adequate fluid intake (at least 2.51 fluid/day), if necessary parenteral administration of 0.45 % NaCl solution (possibly with the addition of 20 ml
bicarbonate per 500 ml NaCl). Continuous NaCl infusion: start 2 hours
before CM injection (80-100 mllhour),
- if there is a risk of a positive fluid balance (heart failure): dopamine (5 mg
per kg/min); loop diuretics with maintenance of isovolaemia (continuous
fluid replacement!), e.g. furosemide 20 mg Lv.; dopamine is not primarily
indicated in patients with diabetes mellitus and secondary complications,
85
86
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
- addition of a small amount of mannitol 10 % 100 ml (in animal experiments,
prevents tubular obstruction by cellular detritus in the initial phase after CM
injection; in addition, oxygen radical interceptors),
- not proven is the cytoprotective and prophylactic administration of calcium
antagonists or adenosine antagonists such as theophyllin. Latest data on this
have not, however, been able to confirm individual earlier positive clinical
findings. Under experimental conditions, endothelin A receptor antagonists
reduced the severity of CM-induced nephropathy.
References
1. Barrett BJ (1994) Contrast nephrotoxicity. J Am Soc Nephrol 5 : 125 -137
2. Dobrota M, Powell q, Holtz E, Wallin A, Vik H (1995) Biochemical and morphological
effects of contrast media on the kidney. Acta Radiol36, Suppl. 399 : 196 - 203
3. Scherberich JE, Wolf G, Schoeppe W (1993) Shedding and repair of renal cell membranes
following drug induced nephrotoxicity in humans. Eur J. Clin Pharmacol44 (SUppl1): 33 - 38
4. Scherberich JE, Wolf G (1994) Disintegration and recovery of kidney cell membrane
proteins: Consequence of acute and chronic renal failure. Kidney Int 46 (SuPpI47): 52- 57
5. Scherberich JE, Rautschka E, Fischer A et al. (1990) Tubular histuria: Clinical evaluation of
the different nephrotoxic potential of X-ray contrast media. Contr Nephrol 83: 229 - 236
6. Scherberich JE (1996) Rontgenkontrastmittel und Nierenfunktion. In: Lins M, Heller M,
Simon R (eds) (?) Kardiologische Diagnostik heute. Hartmann, Hessdorf-Klebheim,
pp 20-26
7. Solomon R, Werner C, Mann D et al. (1994) Effects of saline, mannitol and furosemide on
acute decrease in renal function induced by radiocontrast agents. N Engl J Med
331: 1416 -1420
8. Weisberg LS, Kurnik PB, Kurnik BR (1994) Risk of radiocontrast nephropathy in patients
with and without diabetes mellitus. Kidney Int 45: 259 - 265
3.8
Do Iodinated X-Ray Contrast Media
Affect Thyroid Function?
B. GLOBEL
Iodinated X-ray CM do not have any direct influence on thyroid function.
Nevertheless, the preparations do contain small amounts of free iodide. Moreover, after the CM is introduced into the living organism, iodide splits off from
the molecule. Both free and separated-off iodide take part in iodine metabolism
and can influence thyroid function in this way. Iodide in amounts exceeding the
normal daily intake can lead to a decrease in hormone synthesis (Plummer's
treatment, Wolff-Chaikoff effect). In latent hyperthyroidism, where an iodine
deficiency has prevented the condition from becoming clinically manifest, the
iodide can be sufficient to trigger manifest hyperthyroidism.
3.9 What is the Relationship Between Iodinated Contrast Media
The engendering of hypofunction is primarily a risk in newborns and small
children, where relatively high iodide concentrations are reached because of the
comparatively small volume of distribution in these patients. The effects of
iodinated X-ray CM are generally reversible, however, and subside once the
iodide has been excreted. Hyperthyroidism is mainly a risk for older individuals. The real risk here is in fact that a hyperthyroid metabolic condition could
progress into a so-called thyrotoxic crisis. With present knowledge, there is no
screening test enabling recognition of the risk of thyrotoxic crisis in advance.
The incidence of thyrotoxic crisis is estimated to be about 1: 50,000 in Germany, independent of the source of the increased iodine supply.
3.9
What is the Relationship Between Iodinated Contrast
Media and the Blood-Brain Barrier?
M.R.
SAGE
The unique anatomical and molecular features of the endothelium of small
cerebral vessels, particularly the very tight interendothelial junctions and the
lack of transendothelial vesicular transport, constitute the so-called "bloodbrain barrier" (BBB) [1]. This results in the cerebral endothelium having the
permeability properties of a continuous plasma membrane, with the virtual
elimination of passive diffusion across the endothelium. Whether or not a
particular blood-borne solute is able to cross the endothelial cell from the
blood into the extracellular fluid of the brain (CNS) depends on its relative
affinity for the four major molecular groups present at the membrane interface
between the blood and the endothelium, namely, plasma water, plasma proteins,
membrane lipids and membrane proteins [2]. The relative affinity of a solute for
lipid versus water is expressed by its oil:water partition coefficient, and a clear
relationship between the oil:water partition coefficient that is, the lipophilicty
of a particular solute and its BBB permeability has been demonstrated [3].
Therefore, highly lipophilic solutes such as caffeine, ethanol and heroin have a
high permeability, whereas less lipophilic solutes, that is, hydrophilic solutes
have lower permeability.
The current iodinated contrast media (CM) all have high affinities for
plasma water that is, high hydrophilicity, low affinities for plasma proteins and
extremely low partition coefficients [4], and thus they do not penetrate the
intact BBB. Therefore, in the presence of an intact BBB, intravascular iodinated
CM, whether injected intra-arterially or intravenously, remain within the lumen
of blood vessels and do not penetrate into the CNS. On the other hand, the
intravascular contrast medium itself may have a direct affect on the BBB,
altering its permeability and allowing the CM to cross the BBB. This affect is
87
88
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
determined by both the osmolality and the molecular structure of a particular
CM, and thus it is not surprising that ionic CM are more likely to affect the
integrity of the BBB than non-ionic CM [1].
Not all cerebral capillaries have a BBB. Fenestrated capillaries are located in
a number of small specialised areas of the brain known as the circumventricular organs, which include the median eminence, area postrema, the
subfornical organ, the pineal gland and the organ vasculosum of the lamina
terminalis [1]. Unlike the rest of the brain, these areas are highly vascularised
and lack a BBB, and therefore intravascular iodinated CM can potentially pass
across these vessels into the tissue of the CNS. As a result, these areas have the
potential to enhance normally during contrast-enhanced computerised tomography. The role of such areas in the acute allergic reactions or anaphylactic
reactions that may result from intravascular CM has not been determined. Following large intravenous injections of iodinated CM, a CSF concentration of an
ionic CM of less than 1 % of the corresponding blood concentration has been
demonstrated one hour after intravenous injection [5]. This indicates that only
a small amount of injected CM does penetrate into the CNS, but because of the
great sensitivity of neural tissue to any insult, in a particular individual this may
be sufficient to result in systemic adverse reaction. Acute hypertension is known
to open the BBB reversibly [6], and this suggests that acute hypertension may
be a risk factor for BBB damage from intravascular CM. Pre-treatment with
steroids has been considered to have a protective affect in reducing the neurotoxicity of intravascular CM. Although the affect of steroids in reducing cerebral
oedema is thought to be multifactorial, they are thought to reduce the permeability of the BBB, and this increase in the integrity of the BBB has been
postulated as at least one basis for the neuroprotective affects of steroids.
References
1.
2.
3.
4.
5.
6.
Sage MR, Wilson AJ (1994) The blood-brain barrier: An important concept in neuroimaging. AJNR 15 : 601- 622
Oldendorf WH (1984) The blood-brain barrier. In: Lajtha A (ed) Handbook of Neurochemistry, 2nd ed, Vol 7: Structural elements of the nervous system. New York, Plenum,
PP·485-499
Oldendorf WH (1974) Lipid solubility and drug penetration of the blood-brain barrier.
Proc Soc Exp BioI Med 147: 813 - 816
Morris TW (1989) Intravascular contrast media and their properties. In: Skucas J (ed)
Radiographic contrast agents, 2nd ed. Rockville, Aspen, pp 199 - 228
Sage MR, Wilcox J (1983) Transfer of intravenous CM to the cerebrospinal fluid. Aust Rad
27: 3: 230-232
Rapoport SI (1976) Opening of the blood-brain barrier by acute hypertension. Exp Neurol
52 :467-479
3.10 Do Contrast Media Affect the Central Nervous System?
3.10
Do Contrast Media Affect the Central Nervous System?
M.R.SAGE
Introduction
Depending on the nature of the examination, intraarterial, intravenous or
intrathecal injections of water-soluble CM are made during certain neuroimaging procedures. As a result, CM comes into contact with at least one of the
three interfaces of the CNS, namely the blood-brain interface (BBB), the bloodcerebrospinal fluid (CSF) interface or the brain-CSF interface [5]. Potentially
this could result in neurotoxicity. In general the overall toxicity of nonionic CM
is less than that of equivalent iodine concentrations of ionic CM [6].
Neuroangiography
Neurotoxicity is a recognized complication of cerebral and spinal angiography
[6]. Many of the neurological complications of cerebral angiography are probably related to the catheterization procedure rather than the CM [3]. Other
complications may result from the haemodynamic effects of CM such as hypotension, bradycardia, vasodilation or vasospasm, alterations in regional cerebral
blood flow and an increase in blood viscosity and aggregation and clumping of
red blood cells [2,6,9].
In general, these haemodynamic effects are less marked with nonionic CM.
The actual role of CM itself in neurological complications is not clear. During
neuroangiography, CM comes in contact with the endothelium of the cerebral
or spinal cord capillaries. The morphological characteristics of neural endothelium differ from those of non-neural capillaries. The neural endothelium
behaves like a plasma membrane [1], controlling the passage of many substances, including water-soluble molecules, between blood and brain and hence
maintaining the homeostasis of the neurons ls]. This constitutes the so-called
blood-brain barrier (BBB) [6,7]. An intact BBB therefore prevents the CM from
coming into direct contact with the nervous tissue itself by preventing the passage of the CM from the blood into the extracellular fluid of the brain or spine.
The integrity of the BBB is therefore probably the_major factor in preventing
neurotoxicity of intravascular CM. When the BBB·is deliberately broken down
with hypertonic mannitol, seizures have been observed [6] and seizures may be
provoked during neuroangiography if thereis a pathological breakdown in the
BBB [6]. The pathological loss of the integrity of the BBB allows the CM to cross
into the external fluid of the brain, resulting in a direct chemotoxic effect.
Similarly, hypertonic CM injected intra-arterially may themselves increase the
permeability of the BBB [5, 6, 10] and therefore allow the passage of such CM
into the extracellular fluid of the brain. As ionic CM are more hypertonic than
89
90
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
corresponding iodine concentrations of nonionic CM, it is not surprising that
they are more neurotoxic.
It has been shown that the BBB may take between 5 min and 3 h to be reconstituted after a carotid infusion of hypertonic solutions, depending on the condition of the infusion [6] and so repeated injections of ionic CM within several
minutes of each other may increase the risk of neurotoxic effects. Sodium salts
of ionic CM have been shown to be more neurotoxic than equivalent concentrations of meglumine/methylglucamine salts. Once having crossed the BBB,
neurotoxicity of an ionic CM is therefore due to its chemotoxic effect, which is
related to its molecular structure, rather than to an osmotic effect [6].
A number of substances have been studied to see if they have a protective
role against potential neurotoxicity of CM. Experimentally, both low molecular
weight dextran and steroids have been shown to have protective effects [9], but
their routine use has not been justified clinically.
In general, although the above effects on the BBB may occur during neuroangiography, particularly with hypertonic ionic CM, most neurological deficits
associated with neuroangiography are probably related to ischaemic complications of catheter technique rather than the result of the toxic effects of the CM [3,
6]. On the other hand, the seizures that have been reported in 0.2 % of cerebral
angiograms and 0-4 % of arch aortograms [3] are probably related to the CM
crossing the BBB because of pre-existing pathology or osmotic breakdown.
Transient cortical blindness occasionally occurs during or following an
uncomplicated vertebral angiogram, and this complication may be a direct
effect of the CM on the occipital lobe. Patients with ischaemic cerebrovascular
disease or subarachnoid haemorrhage have a great incidence of neurological
complications from neuroangiography [3, 6]. This may be related to an increased risk of arterial embolism or haemodynamic effects such as spasm, but
there may be greater sensitivity to the CM itself, perhaps due to increased BBB
permeability [6].
Spinal cord injury as a result of uncomplicated aortography or, more specifically, spinal angiography, is well recognized and, although such injury may be
the result of catheter technique, many feel that permanent spinal cord injury
may be due to the direct neurotoxic effect of the CM l3].
Intrathecal Contrast Media
The interface between the CSF and the brain is at the pia mater overlying the
brain surface and the ependyma lining the ventricular system. Unlike the
physiological barrier of the BBB between the blood and brain parenchyma,
there appears to be no barrier between the CSF and the extracellular fluid of the
brain [5,6], and water-soluble molecules such as CM appear to enter the brain
parenchyma by simple diffusion into the extracellular space. Brain penetration
by water-soluble CM after intrathecal injection has been well documented
experimentally [5,6] and clinically [5] and so therefore such CM comes into
direct contact with the neuronal cells. Such penetration occurs with both ionic
and nonionic CM to a similar degree.
3-10 Do Contrast Media Affect the Central Nervous System?
Intrathecal nonionic CM have been shown to cause electroencephalographic
(EEG) changes, presumably due to this brain penetration, and such changes
appear to result from the chemotoxic rather than the osmotic action of the CM
[5,6]. Seizures have been reported [6] even with the latest nonionic CM and
therefore a history of seizures or medication known to reduce the seizure
threshold are relative contraindications to intrathecal CM.
Neuropsychological reactions such as behavioural disturbances, confusion,
amnesia, agitation and hallucinations have been reported after intrathecal
nonionic CM [5,6], a frequency of 13 % - 38 % being reported with metrizamide,
and they have not been completely eliminated with the later nonionic CM. Such
reactions are presumably due to the passage of the intrathecal CM into the
extracellular fluid of the brain.
Headache frequently follows the injection of intrathecal CM. An incidence of
38% has been reported [8], the highest frequency following cervical myelography with lumbar puncture and the lowest frequency occurring with a Cl- 2
puncture [8]. Overall, leakage of CSF following thecal puncture is probably the
most important factor in provoking headache, not CM toxicity, as the frequency
of headache after myelography using lumbar puncture has been reported as
approximately the same as that following diagnostic lumbar puncture [8].
Adhesive arachnoiditis has been reported following lumbar myelography
using ionic water-soluble CM [8], but this does not appear to be a problem with
the latest generation of nonionic CM.
There is a continuing debate regarding the efficacy of epidural and intrathecal
steroids and their possible promotion of arachnoiditis. Therefore, for medicolegal reasons alone, the injection of intraspinal steroids is currently inadvisable.
References
1. Bradbury MW (1988) Transport across the blood-brain barrier. In: Neuwelt EA (ed)
Implications of the blood-brain barrier and its manipulation. Plenum, New York, pp 119 -134
2. Hilal SK (1966) Haemodynamic responses in the cerebral vessels to angiographic contrast
media. Acta Radiol 5: 211- 231
3. Junck J, Marshall WH (1983) Neurotoxicity of radiological contrast agents. Ann Neurol
13: 469-484
4. Murphy DJ (1973) Cerebrovascular permeability after meglumine iothalamate administration. Neurology 23: 926 - 936
5. Sage MR (1983) Kinetics of water-soluble contrast media in the central nervous system.
AJNR 4: 897 - 906
6. Sage MR (1989) Neuroangiography. In: Skucas J (ed) Radiographic contrast agents, 2nd
edn. Aspen, Rockville, pp 170 -188
7. Sage MR, Wilson AJ (1994) The blood-brain barrier: an important concept in neuroimaging. AJNR 15 : 601- 622
8. Skalpe 10, Nakstad P (1988) Myelography with iohexol (Omnipaque): a clinical report
with special reference to the adverse effects. Neuroradiology 30 : 169 -174
9. Sovak M (1984) Contrast media for imaging of the central nervous system. In: Sovak M
(ed) Radio Contrast Agents. Springer, Berlin Heidelberg New York, pp 295-340 (Handbook of experimental pharmacology, vol 73)
10. Wilson AJ, Sage MR (1994) Cytochemical studies on contrast medium induced BBB
damage. Invest Radiol29 (supp 2): 105-107
91
92
CHAPTER 3
Influence of Contrast Media on Organs and Vessels
3.11
Do Contrast Media Affect Blood Vessel Walls?
F. LAERuM
It is generally accepted that hyperosmolar ionic CM may cause peripheral
artery injection pain and may have neurotoxic effects after cerebral angiography or engender deep venous thrombosis and phlebitis following phlebography. Over the years, various in vitro and in vivo models have been employed
to demonstrate that such effects are often due to vessel wall injury. Damage to
the intima caused by CM exposure has been demonstrated by several authors by
means of silver staining of the vascular endothelium of aorta or vena cava in
rats. Activation of coagulation factors by underlying tissue after denuding subendothelial structures may then cause thrombosis. Grabowski [4] employed a
microvessel system and found that, at a concentration of CM in culture medium
of 20 % by volume, monolayer endothelial cell morphology was less altered by
the nonionic low-osmolar CM iohexol than by the ionic CM diatrizoate or
ioxaglate and that monolayer production of prostacyclin was enhanced by the
low-osmolar ioxaglate compared to saline controls.
Schneider et al. examined the effects of diatrizoate, iohexol and ioxilan on
the endothelium of rabbit aortic rings and on endothelial-derived relaxing
factor (dilator response) [14]. Hyperosmolar diatrizoate produced intercellular
gaps and vesicles containing myelin figures as seen on electron microscopy and
after 15 minutes of incubation, the dilator response was irreversibly reduced to
49 %. In contrast, iohexol and ioxilan produced just some irregularities in cell
and vesicle borders, and the contact time for iohexol had to be raised to 60 min
to produce a dilator response similar to that with diatrizoate, even after this
period; the similarly nonionic low-osmolar CM ioxilan still did not produce
such a response. The role of CM in addition to effects of manipulation of
catheters, guidewires and other intravascular devices or pharmaceuticals
remains to be clarified. Occlusions or reocclusions of arterial stenoses or
recanalized segmental obstructions may be seen in connection with angioplasty. In such cases, injury to the vessel wall by mechanical manipulation of
catheters or guidewires may also be involved.
In the veins, there is clear evidence of deep venous thrombosis in the lower
limbs following phlebography with hyperosmolar CM. The reported incidence
varies from 6 % - 26 %, probably due to differences in contact time, CM volume
and wash-out procedures. This iatrogenic problem may be avoided by using
low-osmolar compounds. Lowering the CM concentration or prophylactic anticoagulant treatment may also decrease the incidence. Studies on venous endothelium in vivo and in vitro have revealed injurious effects of hyperosmolar
CM. We performed a lethality test on human endothelial cells in culture. The
cells were derived from umbilical cord veins. When the cell cultures were in
confluence, they were labelled with 51Cr and then exposed to various CM and
concentrations for 10 min or 24 h.
3.11 Do Contrast Media Affect Blood Vessel Walls?
The lO-min exposure was performed with ordinary 300 mg IIml contrast
media solutions added to the cell cultures after removal of the cell culture
medium. This model should mimic the local effects of a pulsed CM injection
into a small vein. The 51 Cr release from these cultures was up to six times higher
following exposure to hyperosmolar CM (diatrizoate, metrizoate) than to the
least toxic agent, iopamidol. The other low-osmolar CM tested (ioxaglate,
metrizamide, iohexol) had about the same effects as 0.9% saline.
In the 24-h test, the CM were added in decreasing concentrations of 21.32.1 vol% to the cell culture medium, thus testing general biocompatibility of
the agents. The cell toxicity was (in decreasing order): diatrizoate, metrizoate,
ioxaglate, iopamidol, metrizamide, iohexol. Diatrizoate led to 99 % cell death in
this model, iohexol 40 % at the same concentration. The strongest osmolalityindependent toxic effect was caused by the dimeric CM ioxaglate. In both the
designs, the results revealed significant differences among the various CM as to
endothelial damage. Hyperosmolality was the most important noxious factor,
but we also noted that ionic CM had more chemotoxic effects than nonionic CM
media, apart from osmolality. Thiesen and Muetzel infused CM or sorbitol for
2 min into mesenteric veins of rabbits [15]: they concluded that hyperosmolality is the causal factor in endothelial damage, since electron microscopy revealed shrinkage of cell cytoplasm and in nuclear material. Inflammatory
processes in the venous wall may also be enhanced by the exposure to contrast
media [13].
In conclusion, CM may damage the vessel wall, in particular the endothelium. The injury is primarily linked to the CM osmolality, but chemotoxicity
also plays a role. Low-osmolar CM are better and the nonionic solutions seem
preferable to the ionic.
References
1.
2.
3.
4.
5.
Albrechtsson U, Olsson C-G (1979) Thrombosis after phlebography: a comparison of two
contrast media. Cardiovasc Radiol 2: 9 -14
Bettmann MA, Salzman EW, Rosenthal D et al. (1980) Reduction of venous thrombosis
complicating phlebography. AJR 134: 1169 -1172
Bromann T, Olsson 0 (1949) Experimental study of contrast media for cerebral angiography with reference to possible injurious effects on the cerebral blood vessels. Acta
Radiol 31 : 321- 334
Grabowski EF (1989) Effects of contrast media on endothelial cell monolayers under controlled flow conditions. In: Enge I, Edgren P (eds) Patient safety and adverse events in contrast medium examinations. No. 816 Elsevier/Excerpta Medica, Amsterdam, pp 85 - 95
(International Congress series, no 816)
Hoi R, Skjerven 0 (1954) Spinal cord damage in abdominal angiography. Acta Radiol
42:276-284
6. H5rup A, Eliassen B, Reimer-Jensen A, Praestholm J (1982) Comparison of Hexabrix and
Urografin in the study of post-phlebographic thrombotic side effects. In: Amiel M (ed)
Contrast media in Radiology. Springer, Berlin Heidelberg New York, pp 231- 232
7. Laerum F (1987) Cytotoxic effects of six angiographic contrast media on human endothelium in culture. Acta Radiol 28: 99 -105
8. Laerum F (1983) Acute damage to human endothelial cells by brief exposure to contrast
media in vitro. Radiology 147: 681- 684
93
94
CHAPTER 3 Influence of Contrast Media on Organs and Vessels
9. Laerum F, Holm HA (1981) PostpWebographic thrombosis. A double blind study with
methylglucanIine metrizoate and metrizamide. Radiology 140 : 651- 654
10. Mersereau WA, Robertson HR (1961) Observations on venous endothelial injury following
the injection of various radiographic contrast media in the rat. J Neurosurg 18 : 289 - 294
11. Nyman U,Almen T (1980) Effects of contrast media on aortic endothelium. Experiments
in the rat with non-ionic monomeric and mono-acidic dimeric contrast media. Acta
Radiol Suppl 362: 65 -71
12. Raininko R (1979) Role of hypertonicity in the endothelial injury caused by angiographic
contrast media. Acta Radiol 20: 410 - 416
13. Ritchie WGM, Lynch PR, Stewart GJ (1974) The effect of contrast media on normal and
inflamed canine veins. Invest Radiol9: 444-455
14. Schneider KM, Ham KN, Friedhuber A, Rand MJ (1988) Functional and morphologic
effects of ioxilan, iohexol and diatrizoate on endothelial cells. Invest Radiol 23 (SUppll):
S147- 149
15. Thiesen B, Muetzel W (1990) Effects of contrast media on venous endothelium of rabbits.
Invest Radiol25 : 121-126
16. Zinner G, Gottlob R (1959) Die gefaBschadigende Wirkung verschiedener Rontgenkontrastmittel, vergleichende Untersuchungen. Fortschr Roentgenstr 91 : 507 - 511
3.12
Can X-Ray Contrast Media
Affect the Results of Laboratory Tests?
W.JUNGE
Although laboratory tests for diagnostic purposes are very rarely performed in
patients who have just undergone a contrast medium examination, they may be
necessary in individual cases of contrast medium reactions or of complications
not connected with contrast medium administration. On the other hand,
laboratory tests are a crucial parameter in the determination of the safety of
new contrast media in clinical studies. In order then to obtain diagnostically
valid results, it must be ensured that the contrast medium (CM) does not interfere with the analytical procedures employed, i. e. that it does not act as an interfering factor which only simulates an in-vivo deviation of a variable from the
norm. Surprisingly little attention has been paid in the literature to the basic
problem underlying this reflection, that is whether and to what extent a substance administered to man - in this case CM - falsifies laboratory tests in vitro,
simulating a situation which does not actually exist in vivo.
There is, in fact, a very simple solution to this problem: Before it is used in
man for the first time, a new CM is always tested on control material for its "side
effects" so as to avoid any unpleasant surprises in the later phase VII clinical
studies, for example. It would obviously be ideal if the manufacturer would then
state in his package insert whether the substance interferes with important
routine methods. A laboratory head must otherwise conduct relevant studies
himself with the CM employed in his institute.
3.12 Can X-Ray Contrast Media Affect the Results of Laboratory Tests?
As far as I can discover, no published systematic studies exist in this regard.
Some effects are well-documented for certain variables, e. g. the falsely high
values in the determination of PBI (plasma-bound iodine), a now obsolete parameter. Interference with precipitation methods used to determine urinary
proteins is also well-documented.
A few years ago, this unsatisfactory data situation prompted us in collaboration with Schering AG to perform a systematic study of the influence of various
ionic and non-ionic CM on clinico-chemical testing procedures in urine and
serum, albeit using only the procedures then employed in our laboratory. To
this end, control material was loaded with up to 20 vol. % contrast material urine with up to 50 %.
In summary, the results of this study demonstrate that CM do not interfere
with the determination of any of the enzyme reactions - 12 serum enzymes
were examined - relevant to emergency situations. Ioxaglate exerted a
moderate inhibitory effect only on ALAT (GPT). The measurements were also
correct in the presence of various X-ray contrast media for important substrates
(glucose, urea, creatinine) and electrolytes (sodium, potassium, calcium,
chloride) studied as part of the acute diagnostic work-up.
In contrast, a certain degree of interference was found with regard to
variables such as iron, copper, total protein and phosphate, which are determined with complexometric procedures. These variables play no role in acute
diagnosis, however, and can be correctly determined 12 to 24 hours after CM
administration, i.e. at a time when the CM is present in the circulation only in
traces.
A slight curiosity might be mentioned in conclusion: Non-ionic CM such as
iohexol and iopromide are used for precise determination of the glomerular
filtration rate, since - unlike creatinine - they are subject only to glomerular filtration and not to tubular secretion.
95
CHAPTER
4
Determination of Risk Factors Regarding
the Administration of Contrast Media
4.1
In Which Patients is the Administration of X-Ray Contrast
Media Associated with an Increased Risk?
W.CLAUSS
Prospective clinical studies with large numbers of cases have demonstrated
that, after i. v. contrast medium (CM) administration, the tolerance of the nonionic, low-osmolar agents is far superior to that of ionic, hyperosmolar CM. This
is true not only for mild to moderate reactions, but also for severe reactions, the
rate of which is clearly reduced particularly in the examination of high-risk
patients (Table 4.1.1).
Table 4.1.1 Adverse events after i. v. injection of high-osmolar ionic and low-osmolar nonionic X-ray contrast media
Source
Patients [n]
Ionic
Schrott
et al. 1986
Palmer, 1988
Wolf, 1989
Katayama
et aI., 1990
onionic
Side effects rate [%1
Total
Severe
reactions
High-risk patients
Ionic Nonionic
Ionic
Ionic Nonionic
2.1
50642 -
onionic
0.01
79278
30268
3.8
1.2
0.10
0.01
10.3
6006
7170
4.1
0.7
3.1
0.4
0.22
0.0
0.04
44.0
169284 168363 12.7
23.4
4.1 (in known CM
hypersensitivity)
3.3 (in known allergy)
1.3 (with various risk
factors)
11.2 (in known eM
hypersensitivity)
6.9 (in known allergy)
4.1 Administration of X-Ray Contrast Media
Although the number and intensity of CM reactions after administration of
non-ionic CM are reduced, clinical experience to date shows that the side effect
profile and the risks still apply to the use of non-ionic agents as well.
As regards all the main risks mentioned in the following, the examination
with non-ionic CM should be performed after careful consideration of the
benefits and risks in association with appropriate prophylactic measures. This
means that the examining doctor must carefully elicit any risks in the case
history, consider the pathogenetic associations - where known -, initiate the
prophylactic measures and, if necessary, arrange for follow-up of the patient.
The main risks which can lead to an increased rate of side effects or to
further deterioration of organ function are:
hypersensitivity to CM,
allergy,
manifest and latent hyperthyroidism,
non-toxic nodular goitre,
dehydration,
severe cardiovascular insufficiency,
high-grade pulmonary insufficiency,
asthma,
renal failure,
diabetes mellitus in nephropathy,
paraproteinosis,
phaeochromocytoma,
autoimmune diseases,
high patient age,
excessive fear of the examination.
If, despite existing risks, it is decided to administer an X-ray contrast medium
because of the benefits, the following precautionary measures, among others,
must be considered:
Use of non-ionic CM,
as Iowa CM concentration as possible,
hydration,
mental stabilisation,
premedication,
speedy use of the examination equipment by experienced examiners,
- in case of side-effects: early start of therapeutic measurements.
References
Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K (1990)
Adverse reactions to ionic and non-ionic contrast media. Radiology 175: 621- 628
2. Palmer FJ (1989) The RACR survey of intravenous contrast media reactions. Australas
Radiol 32 : 426 - 428
3. Schrott KM, Behrends B, Clauss W, Kaufmann J, Lehnert J (1986) Iohexol in der Ausscheidungsurographie. Fortschr Med 7: 153 -156
1.
97
98
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
4. Wolf GL, Arenson RL, Cross AP (1989) A prospective trial of ionic versus non-ionic contrast agents in routine clinical practice. AJR 152: 939 - 944
5. Elke M (1992) Kontrastmittel in der radiologischen Diagnostik. 3. Auflage, Georg Thieme
Verlag Stuttgart New York
4.2
How Big is the Risk of an Examination with X-Ray
Contrast Media of Patients with Known
Hypersensitivity to CM and for Allergic Patients?
W.CLAUSS
Like local anaesthetics, i. v. anaesthetics, colloidal volume substitutes and acetyl
salicylic acid, X-ray contrast media (CM) can lead to pseudoallergic reactions.
Clinically, these reactions are the same as the classical IgE-mediated anaphylactoid reactions, although they are not generally of immunological origin and,
consequently are also known as anaphylactoid or pseudoallergic reactions. The
underlying pathomechanism is still unknown, although complement activation, the direct release of mediators such as histamine and serotonin, interaction with the clotting system, the fibrinolytic system and the kallikreinkinine system and the involvement of neuropsychogenic reflexes are all under
discussion.
As the large statistical survey by Katayama [1] shows, the side effect rate after
intravascular administration of low-osmolar, non-ionic CM (3.1 %) can be
reduced by a factor of about 4 compared to hyperosmolar ionic CM (12.7%). In
the group of patients with a known history of hypersensitivity reactions to the
CM used, the risk of renewed side effects at the repeat examination compared
to the group with no history of reactions increased about 5 times from 2.2 % to
11.3 % after administration of non-ionic CM and from 9.0 % to 44.0 % on administration of ionic hyperosmolar CM.
Patients with a history of allergy likewise display an increased risk on administration of CM. In the Katayama study, the side effects rate compared to the group
of non-allergics increased 2.5 and 2 times, respectively, from 2.8 % to 6.9 % after
i. v. administration of non-ionic CM and from 11.7% to 23-4 % after ionic CM.
Other studies with large numbers of patients confirm Katayama's results
[2-5] and show that non-ionic CM have a much lower potential for inducing
pseudoallergic reactions. A residual risk always remains, however, although it
can be reduced further by appropriate prophylactic measures, particularly in
patients with defined risks.
Pseudoallergic reactions are more frequent after intravenous than after
intraarterial administration, a phenomenon attributable to the increased
release of histamines from the mast cells of the lung in response to the still
relatively undiluted contrast material.
4.3 Does an Existing Allergy to Iodine Mean
The occurrence of pseudoallergic reactions cannot be completely avoided
even by intracavitary and retrograde CM administration. However, they are
observed very rarely and are attributable to the small amounts of contrast
material absorbed or introduced directly into the blood stream.
References
1.
2.
3.
4.
5.
Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K (1990) Adverse
reactions to ionic and non-ionic contrast media. Radiology 175 : 621- 628
Palmer FJ (1989) The RACR survey of intravenous contrast media reactions final report.
Australas Radiol 4
Schrott KM, Behrends B, Clauss W, Kaufmann J, Lehnert J (1986) Iohexol in der Ausscheidungsurographie. Ergebnisse des Drug-monitorings. Fortschr Med 7: 153/51-156/54
Wolf GL, Arenson RL, Cross AP (1989) A prospective trial of ionic versus non-ionic contrast agents in routine clinical practice: Comparison of adverse effects. AJR 152: 939
Gerstmann BB (1991) Epidemiologic critique of the report of adverse reactions to ionic
and non ionic media by the Japanese Committee on the Safety of Contrast Media.
Radiology 178 : 787
4.3
Does an Existing Allergy to Iodine Mean an Increased Risk
for an X-Ray Contrast Medium Examination?
W.CLAUSS
The allergic reaction to iodine is a type IV reaction in the sense of allergic
contact dermatitis. Consequently, the intravascular administration of iodinated
contrast material does not automatically lead to an anaphylactoid reaction in
patients with an iodine allergy. The occurrence of hemotogenous contact
eczema cannot, however, be ruled out, since CM contain a very small amount of
iodine in the form of iodide as a contaminant and another small amount is
released in the organism from the contrast medium molecule.
A known allergy to iodine does not, therefore, constitute a contraindication
to the administration of X-ray contrast media. The risk to the allergic patient of
suffering a pseudoallergic reaction is not higher than to the group of all other
allergic patients.
References
1.
Ring J (1988) Pseudoallergische Arzneimittel-Reaktionen. Angewandte Allergologie,
2. Aufl., MMV Medizin, Miinchen, 223 - 234
99
100
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
4.4
Why Does the Administration of Iodinated Contrast Media
to Patients with Manifest or Latent Hyperthyroidism
Represent a Risk?
B. GLOBEL
Hyperfunction of the thyroid gland only leads to a hyperthyroid metabolic
condition if the thyroid has enough iodide at its disposal to be able to produce excessive amounts of iodinated thyroid hormones. In a geographical area
of iodine deficiency, (e.g. Germany), cases of hyperthyroidism only then appear if the quantity of iodide supplied is increased. This occurs, for example,
in the administration of iodinated X-ray CM. Here, a possible exacerbation
of the symptoms of hyperthyroidism can occur with the real risk of lapse into
a thyrotoxic crisis. For this reason, hyperthyroidism should be treated and
under control prior to an examination of such patients with iodinated X-ray
CM. Emergency cases of untreated hyperthyroidism or autonomy of the
thyroid gland can be treated with thyroid depressants. However, a physician
experienced in the diagnosis and therapy of diseases of the thyroid gland
should be consulted as soon as possible after the CM examination. The period
of intensive observation of the patient should run at least 8 weeks. The following table provides an introductory guide to the dosage of antithyroid agents
(Table 441).
Table 4.4.1. Comparative dosing of thyroid depressants in relation to carbimazole 1
Generic name Carbimazole
Chemic
term
Commercial
preparations
3-methyl-2-thioxo4-imidazoline-}carbon dioxideethylester
Carbimazol
10 mg"Henning"
eo-Morphazole
eo-Thyreostat
I
Comparable
doses
Initial doses, 15-80 mg/day
month 1
Subsequent
5-15 mg/day
dose • month 2
Methimazole
Tbiamazol
Propylthiouracil
(PTU)
Perchlorate
l-methyl-2mercaptoimidazole
4-propyl2-thiouracil
Favistan
Propycil
Thyreostat II
Sodium
perchlorate
Potassium
perchlorate
lrenat
I 1/2
ca.8-12
19
60-120 mg/day 150-600 mg/day 600-1200 mg/day
(week I)
5-20 mg/day
25-100 mg/day
150-300 mg/day
(weeks 2-8)
4.5 Why Does the Administration of Iodinated Contrast Media Represent a Risk
4.5
Why Does the Administration of Iodinated Contrast Media
Represent a Risk to Patients with Non-Toxic
Nodular Goitre?
B.GLOBEL
Almost all non-toxic nodular goitres are the result of a longer-term iodine
deficiency. In iodine deficiency, the thyroid is constantly stimulated via the
regulatory organs of the hypothalamus and the pituitary gland to absorb more
iodine and to produce more thyroid hormone. It appears that in this situation
autonomous thyroid cells increasingly arise that are no longer subject to regulation. If such patients are suddenly supplied with an increased amount of
iodide, there is a danger that the autonomous thyroid regions will produce too
much thyroid hormone and thereby create a hyperthyroid metabolic condition.
The hyperthyroid metabolic condition is limited by the excretion of the additional iodide. The amount of iodide supplied by more modern iodinated
X-ray CM is usually only sufficient to temporarily remedy the existing iodine
deficiency.
Considerations for Diagnostically Necessary Examinations
with Iodinated X-Ray Contrast Media
A hyperthyroid metabolic condition is most likely to be triggered in newborns
and small children because of the relatively small volume of distribution. High
iodide concentrations in the plasma can result, which in turn leads to an inhibition of thyroid hormone synthesis. Transient hypothyroidism is involved
here, which as a rule does not last longer than 4 days. As a precautionary
measure, a test of thyroid function can be performed after ca. 8 days. Should a
hypothyroid metabolic condition still exist at this time, then thyroid hormone
substitution therapy can be implemented. The risk to newborns following the
examination of their mothers with iodinated X-ray CM should be clinically
insignificant. The passage of iodide into the mother's milk ranges from a few
percent to a maximum of ten percent. The second group at risk through the
increased supply of iodide is represented by those patients known to have latent
or manifest hyperthyroidism. In these patients, for different reasons, autonomous tissue sections exist in the thyroid that increase production of thyroid
hormones when the supply of iodide is increased. Here, too, transient hyperthyroidism is involved in most cases; after excretion of the iodide supplied, it
recedes and does not require treatment.
The risk of a thyrotoxic crisis cannot presently be predicted with certainty.
In Germany it can be assumed that this risk is at maximum 1: 50,000. It is
probably much smaller since the more recent iodinated X-ray CM used intra-
101
102
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
venously are extremely biologically stable and are only contaminated with
small amounts of free iodide in production. The additional amount of iodide
supplied ranges as a rule between 0.1 and 10 mg per examination. Such amounts
of iodide are felt to be completely acceptable in iodized salt and they are, for
example, much smaller than are contained in the so-called "iodine" tablets that
are recommended for use in the reduction of internal radiation exposure after
nuclear catastrophes.
4.6
How do I Recognise Hyperthyroidism or the Presence
of Non-Toxic Nodular Goitre?
B. GLOEBEL
The individual risk to the patient of developing iodine-induced hyperthyroidism must always be estimated before an iodinated X-ray contrast medium is
injected. Thorough documentation of the case history is essential here, and the
Table 4.5.1. Recommended examinations before administration of iodinated X-raycontrast
media with and without emergency indication
Emergency indication
Recommendation:
o emergency indication
Recommendation:
Recommendation:
Recommendation:
Before contrast medium admini tration: Blood sample for
later determination of TSH and thyroid hormones
Hi tory of hyperthyroidism
and/or
positive thyroid palpation finding (enlargement or nodular
change)
Prophylactic therapy with perchlorate and/or thiamazol
Determination of the peripheral thyroid function parameter TSH baseline, the thyroid hormone parameters T), Tl
and f- T), f-T.
Is baseline TSH <0.3 mUll and/or
is there a history of hyperthyroidism and/or
a positive thyroid palpation finding?
Performance of thyroid sonography
Is thyroid volume greatly increa ed (>50 ml)
or
can thyroid nodes be demonstrated?
Performance of quantitative scintigraphy
I the volume of an autonomous node> 10 mJ or
is Tc99m uptake under uppre sion conditions >3%?
Definitive therapy of the thyroid disease before iodine
admini tration
4.7 Does Underlying Cardiovascular Disease Constitute an Increased Risk
patient should be asked specifically about previous exposure to iodine and any
thyroid diseases. Palpation of the thyroid is likewise essential.
Indicators of an increased risk can be gathered from the tests and examinations summarised in Table 4.6.l.
The following should be borne in mind as regards the situation in Germany
and other countries which must be regarded as iodine deficiency regions:
The administration of additional iodine whether as iodide or in connection
with the administration of a drug or diagnostic agent to a patient in an iodine
deficiency region usually leads to changes of thyroid function which can be
detected by laboratory tests and phases of which can also be interpreted as a
hyperthyroid metabolic state. In most cases, however, these changes regress
after a short time usually within days to return to the level of normal function.
4.7
Does Underlying Cardiovascular Disease Constitute
an Increased Risk in Contrast Media Administration?
P.DAWSON
Severe Cardiovascular Insufficiency
CM are able to produce marked peripheral vasodilatation with a sometimes profound fall in systemic blood pressure [1]. Patients with normal cardiac function
can raise a reflex tachycardia without difficulty; patients with poor cardiac reserve, however, may undergo what amounts to a cardiac function stress test on
administration of a contrast agent and may be at risk. Attacks of angina are not
infrequently observed in patients with ischaemic heart disease undergoing contrast examinations. CM injected directly into the coronary arteries actually may
increase coronary blood flow for a short time but this appears to occur only in
areas of relatively normal vascularity and not in areas of abnormal vascularity
b]. There appears, as a consequence, to be a steal phenomenon which renders
ischaemic areas even more ischaemic and the effect is entirely undesirable. Patients with ischaemic heart disease are therefore at risk in this regard. Intracoronary and left ventricular contrast agents also have adverse effects on pump
function and on cardiac electrophysiology [1]. In patients with pre-existing
ischaemic heart disease the effects may be more marked and more prolonged
with a greater propensity to ventricular fibrillation [3].
As regards peripheral injection of contrast agents, as in intravenous urography and CT enhancement, it may be possible to exaggerate the importance
of cardiac disease. Katayama [2] in his recent large-scale study of adverse effects
of ionic and nonionic CM did not observe any significantly increased risk of
problems in the older age groups as would be expected on the basis of an anticipated increasing incidence of cardiac disease in an aging population.
103
104
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
References
1. Dawson P (1989) Cardiovascular effects of contrast agents. Am J Cardiol 64: 2E- 9E
2. Katayama H et al. (1990) Adverse reactions to ionic and non-ionic contrast media. A report
from the Japanese Committee on the Safety of Contrast Media. Radiology 175 : 621- 628
3. Wolf GL, Kraft L, Kilzer K (1978) Contrast agents lower ventricular fibrillation threshold.
Radiology 129: 215 - 217
4.8
Why Is Pre-existing Lung Disease a Risk
for the Administration of Contrast Media?
P.DAWSON
As discussed elsewhere, CM administered directly into the bronchopulmonary
tree or into the lymphatics or peripheral veins are capable of producing a
number of adverse effects in the lungs, including an increase in interstitial
pulmonary water [2] with impairment of both compliance and diffusion [I], the
production of a routine subclinical bronchospasm and an occasional more
dramatic bronchospasm. Patients with pre-existing lung function disturbances
may therefore be at increased risk. These include those with already impaired
compliance and diffusion and those with a tendency to bronchospasm, not only
asthmatics, but also those with chronic obstructive airways disease with an
element of bronchospasm.
References
Dawson P, Pitfield J, Britton J (1983) Contrast media and bronchospasm: a study with
iopamidol. Clin Radiol 34: 227 - 230
2. Slutsky RA, Mackney DB, Peck WN, Higgins CB (1983) Extravascular lung water: effects of
ionic and non-ionic contrast media. Radiology 149 : 375 - 381
1.
4.9
Why does Previous Renal Failure Represent a Risk?
J. E. SCHERB ERiCH
The greater the severity of previous renal failure, the greater also the risk that
CM-induced further impairment of kidney function will no longer be transient
and asymptomatic. The assumption here is that hypermetabolic and haemody-
4.9 Why does Previous Renal Failure Represent a Risk?
namically"stressed", hyperfIltering (residual) nephrons are more vulnerable to
toxic influences than the nephrons of primarily healthy patients. The endogenous energy reserves (ATP-ases) are smaller in previously damaged renal
cells and, apart from this, CM inhibit certain transport enzymes. The histological picture of the kidneys in chronic renal failure reveals many typical features
which help explain poor cellular regeneration under, for example, acute toxic
influences [4]. Many years ago, acute renal failure was observed in particular
after high-osmolar CM in high-risk patients (diabetic nephropathy, chronic
renal failure and hypertension) with concurrent relative volume depletion (high
doses of loop diuretics, simultaneous hypoproteinaemia, low circulating blood
volume) [1, 5]. The first clinical signs of acute renal failure are polyuria or
oligoanuria (urinary volume < 200 mllday) and, radiologically, a persistent
nephrogram. The risk of deterioration of renal function is reported to be about
4 times higher after intraarterial CM injection than after intravenous administration (of the same amount of CM) [2]. In patients with a history of renal
failure, the rate of acute renal failure requiring dialysis increases substantially
after CM administration [7]. In contrast, a double-blind study of 16 patients
with chronic preterminal renal failure did not show any signs of increased
proteinuria or enzymuria or of deterioration of renal function after angiographic injection of low-osmolar CM (iodixanol, iohexol) [3]. Adequate hydration of the patient is demonstrably a crucial factor in stable renal function even
in patients with a chronically low glomerular fIltration rate [4].
References
1.
2.
3.
4.
5.
6.
Porter GA (1994) Contrast-associated nephropathy: Presentation, pathophysiology and
management. Min Electrolyt Metab 20 : 232 - 243
Rudnick MR et al. (1994) Nephrotoxic risk of renal angiography: Contrast media associated nephrotoxicity and atheroembolism - a critical review. Am J Kidney Dis 24: 713 -727
Jakobsen JA (1995) Renal effects of iodixanol in healthy volunteers and patients with severe
renal failure. Acta radiol (Suppl. 399): 191-195
Scherberich JE, Wolf G, Albers C, Nowack A, Stuckhardt S, Schoeppe W (1989) Glomerular
and tubular membrane antigens reflecting cellular adaptation in human renal failure.
Kidney Int 36 (suppl. 27): 38-51
Scherberich JE (1990) Nephrotoxizitat von Rontgenkontrastmitteln: Diagnose- und Therapiestrategie bei Risikopatienten. In: Riemann H, Kollath J, Rienhoff 0 (1990) Digitale
Radiographie. Schatzor, Konstanz, pp 280 - 288
Solomon R, Werner C, Mann D et al. (1994) Effect of saline, mannitol and furosemide on
acute decreases in renal function induced by radio contrast agents. N. Engl J Med
331 : 1415 -1420
7. Vlietstra RE, Nunn CM, Navarte J, Browne KF (1996) Contrast nephropathy after coronary
angioplasty in chronic renal insufficiency. Am Heart J 132: 1049 -1050
105
106
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
4.10
Why Does Previous Diabetes Mellitus Represent a Risk?
J. E. SCHERBERICH
Diabetes mellitus is a systemic disease associated with angiopathic and neuropathic changes which do not, however, become clinically manifest until later.
Some factors involved in the generalised angiopathy are circulating glycotoxins
(or advanced glycated end-products, AGE), which ultimately lead to pathologically increased vascular permeability (leakage) and simultaneous vascular
rigidity (ageing). The significance of this as regards the kidneys is the relatively
early development of functional and structural lesions, which are further
exacerbated by the administration of CM. A further frequent complication is
vascular damage in the sense of intimal/medial hypertrophy, sclerosis of the
media and obliterative arteriosclerosis due to arterial hypertension and hyperlipidaemia. The risk of "ischaemic nephropathy" after CM administration is
then particularly high and can be observed even in patients who do not yet display elevated serum creatinine [1,2]. Patients with diabetes mellitus and normal
kidney function excrete significantly more tubule-specific renal antigens in the
urine after administration of hyperosmolar than after injection oflow-osmolar
CM (intravenous DSA) [3, 4]. After glomerular fIltration, moreover, the CM
passes through tubular epithelia which have undergone "nephrotic" alteration
(Armani-Epstein cells) due to the increased accumulation of glucose and
secondary glycogen deposits and which, consequently, display lower tolerance
to toxins. After coronary angiography and after the administration of CM for
other diagnostic X-ray procedures, the incidence of renal failure requiring
dialysis is many times higher in diabetics than in patients without diabetes mellitus [1,2,5].
References
1.
2.
3.
4.
5.
McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW (1997) Acute renal failure after
coronary intervention: Incidence, risk factors and relationship to mortality. Am I Med
103: 368 - 375
Parfey PS, Griffiths SM, Barrett BI et al. (1989) Contrast material induced renal failure in
patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study.
N Engl I Med 320 : 143 -149
Scherberich I, Fischer A, Rautschka E, Kollath I, Riemann H (1989) Nephrotoxicity of high
and low osmolar contrast media: Case control studies following digital subtraction angiography in potential risk patients. In: Taenzer V, Wende S (1989) Recent developm. nonionic
contrast media. Thieme, Stuttgart N.Y. pp 91-94
Scherberich Ie, Rautschka E, Fischer A, Kollath I, Riemann HE (1990) Tubular histuria:
Clinical evaluation of the different nephrotoxic potential of X-ray contrast media. Contr
Nephrol83: 229 - 236
Weisberg LS, Kurnik PB, Kurnik BR (1994) Risk of radiocontrast nephropathy in patients
with and without diabetes mellitus. Kidney Int 45: 259 - 265
4.11 Why Does Previous Paraproteinaemia Represent a Risk?
4.11
Why Does Previous Paraproteinaemia Represent a Risk?
J. E. SCHERBERICH
In the '60S and '70S, acute renal failure in patients with malignant myeloma
(plasma cytoma, monoclonal gammopathy) was a remarkably frequent occurrence after CM administration. In such cases, the primary diagnosis of
monoclonal malignant paraproteinaemia, particularly the form with free
monoclonal light chains, tended to be made only after the occurrence of renal
failure, i. e. it was not usually known at the time of the CM injection. The
repeatedly mentioned association between acute renal failure and X-ray CM
administration was, however, due largely to: I) ignorance of the underlying
disease and, consequently, 2) unsatisfactory preparation such as adequate
hydration and balancing of the patient before and after CM injection. According
to some studies, the aggregation of CM tends to increase under in-vitro conditions after the administration of alkaline Bence-Jones protein bodies or of
high-molecular Tamm-Horsfall uromucoid (of the distal tubule). The complex
of CM and protein precipitated in the tubules induced intrarenal obstructive
nephropathy as a result (similar to "cast nephropathy"), with consequent renal
failure. Recent retrospective studies in myeloma patients failed to confirm an
increased risk similar to that in patients with diabetes mellitus, for example.
Plasmacytoma is no longer regarded as a contraindication to diagnostic
imaging with iodinated, low-osmolar, water-soluble X-ray CM, although the
precautions mentioned above must be taken [1-31.As usual, the CM dose must
be kept as low as possible and all potentially nephrotoxic drugs (non-steroidal
antirheumatics, aminoglycoside antibiotics, amphotericin B etc.) must be withdrawn beforehand.
References
1.
McCathy CS, Becker JA (1992) Multiple myeloma and contrast media. Radiology
183: 519 - 521
2. Liebl R, Dramer BK (1996) Komplikationen nach Applikation von Rontgen-Kontrastmitteln bei Risikopatienten 121: 1475 -1479
3. Scherberich JE, Kollath J, Riemann H, Schoeppe W (1990) Nephrotoxizitat von Rontgenkontrastmitteln. Nieren- u. Hochdruckkrankh 19: 449 - 452
107
108
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
4.12
How Can the Risk of Provoking a Hypertensive Crisis
in Patients with Phaeochromocytoma Be Reduced?
P.DAwSON
Evidence that intravascular CM may be associated with hypertensive crises in
patients with phaeochromocytoma is anecdotal and no large studies have been
performed. Small series with a proportion of hypertensive responses have been
observed in arteriography [1], in adrenal phlebography b] and in enhanced CT
[5] in patients with these tumours. In so far as the phenomenon is documented,
a-adrenergic blockade appears to be helpful in preventing a life-threatening
crisis. However, occasional deaths ascribed to the phenomenon have been
reported even relatively recently [4]. No evidence is available concerning the
status of low osmolality agents, ionic or nonionic, in this regard. Only the
argument from first principles may be called in aid, namely that nonionic CM
are more biocompatible in general terms and it seems reasonable to use these
agents in such patients.
Dawson has suggested a possible mechanism [2]. The cells of the adrenal
medulla are histologically closely related to autonomic ganglion cells and are
innervated by preganglionic sympathetic fibres. Stimulation of these fibres
raises blood pressure by release of adrenalin and noradrenalin into the circulation. Before the rise of blood pressure there is sometimes a fall which is increased after administration of physostigmine and abolished by atropine evidence that acetylcholine as first liberated at stimulated nerve endings is the
transmitter involved. Indeed, acetylcholine has been identified in the adrenal
vein following sympathetic stimulation. Perhaps the mechanisms involved are,
therefore, cholinergic.
Prophylaxis consists of adequate a-adrenergic blockade and the drug of
choice was phentolamine, but some authorities prefer combined a and ~
blockade because phaeochromocytomas secrete both adrenaline and noradrenaline (and other mediators). This may be achieved by a labetalol infusion
during the procedure titrated against the blood pressure.
Hypertensive crises, if they nevertheless occur, may be treated with intravenous phentolamine, 5 -10 mg, with 0.5 mg/min infusion if required. The effect
is rapid but short-lived.
References
1.
2.
Christenson R, Smith CW, Burko M (1976) Arteriographic manifestation of phaeochromocytoma. AJR 126: 567 - 575
Dawson P (1987) Cholinergic mechanisms in contrast media induced adverse reactions. In:
Parvez Z, Moncada S, Sovak M (eds) Contrast media: biologic effects and clinical application. CRC Press, Boca Raton
4.13 Does the Examination of Dehydrated Patients Represent an Increased Risk?
3. Fisch HP, Reutter FW (1976) Paralytic ileus in phaeochromocytoma. Possible correlation
with an attempt at adrenal phlebography. Schweiz Med Wochenschr 106: 1187-1191
4. Kashimura S, Umetsu K, Suzuki T (1979) A sudden death from phaeochromocytoma following arteriography. Jpn Legal Med 33: 7-12
5. Raisanen J, Shapiro B, Glazer GM (1984) Plasma catacholamines in phaeochromocytoma:
effect of urographic contrast media. AJR 143: 43 - 46
4.13
Does the Examination of Dehydrated Patients Represent
an Increased Risk?
J.E. SCHERBERICH
In the '70S and '80S, most side effects associated with multiple complications,
particularly acute impairment of kidney function, occurring after the injection
of CM were attributable to inadequate fluid intake by the patients concerned.
After this was realised and attention was paid to adequate "hydration" in highrisk patients, the administration of contrast media in the patient group with
plasmacytoma, for example, was no longer contraindicated.
In heart failure patients, import and export must be balanced when giving
fluids, and the baseline weight must be known. Adequate volume administration suppresses the vasoconstrictive renin-angiotensin system, inhibits the
release of vasopressin (which, in the activated state, further reduces glomerular
perfusion in volume contraction) and promotes the secretion of atrial natriuretic hormone. In one study, the administration of 0.45 % NaCI solution alone
prior to CM administration proved to be the best precautionary measure as
regards maintaining the glomerular filtration rate [1]. If the volume contraction
of the blood observed via polyuria under loop diuretics were to be continuously compensated for by a correspondingly increased fluid intake, a favourable
synergistic effect could also be expected, since the free water clearance increases overall under these conditions. Moreover, high intratubular urinary
flow rates reduce the contact time between CM and tubular epithelia.
References
1.
Solomon R, Werner C, Mann D et al. (1994) Effect of saline, mannitol and furosemide on
acute decrease in renal function induced by radio contrast agents. N Engl J Med 331 : 141614 20
109
110
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
4.14
Are Patients with Autoimmune Disorders at Any Particular
Risk on Contrast Media Administration?
P.DAWSON
There have been a number of case reports over the last 15 years or so of adverse
reactions to a variety of iodinated CM in patients known to be suffering from
autoimmune disorders [16]. It is always difficult to be certain about cause and
effect and patients with such disorders may have exacerbations of their symptoms from time to time. However, the exceptionally dramatic episodes and
florid symptomatology displayed by some of those patients shortly following
administration of CM suggests the possibility of a link. Some cases involved a
nonionic agent, others an ionic agent. Variously, intra-arterial, intravenous and
intrathecal routes of administration were involved. If the circumstantial
evidence of a link is accepted, we might speculate that the ability of CM to
activate complement might be involved in the aetiology.
Caution is indicated. As always the need for a contrast examination in these
patients should be carefully assessed and alternatives considered. If a decision
is made to perform the contrast examination, it is suggested on purely empirical
grounds that corticosteroid prophylaxis for 24 - 48 h before the examination be
used.
References
1.
Gelmers HJ (1984) Exacerbation of systemic lupus erythematosus, aseptic meningitis and
acute mental symptoms, following metrizamide lumbar myelography. Neuroradiology
26:65-66
2. Goodfellow T et al. (1986) Fatal acute vasculitis after high-dose urography with iohexol. Br
J Radiol 59 : 620 - 621
3. Kaur JS et al. (1982) Acute renal failure following arteriography in a patient with polyarteritis nodosa. JAMA 6: 833 - 834
4. Reuter FW, Eugster C (1985) Akuter Jodismus mit Sialadenitis, allergischer Vaskulitis und
Konjunktivitis nach Verabreichung iodhaltiger Kontrastmittel. Schweiz Med Wochenschr
115: 1646 -1651
5. Savill JS et al. (1988) Fatal Stevens-Johnson syndrome following urography with iopamidol
in systemic lupus erythematosus. Postgrad Med J 64: 392 - 394
6. Vaillant L et al. (1990) Iododerma and acute respiratory distress with leucocytoc1astic
vasculitis following the intravenous injection of contrast medium. Clin Dermat 15: 232- 233
4.15 Does the Administration of Iodinated Contrast Media
4.15
Does the Administration of Iodinated Contrast Media
to Patients with Sickle Cell Anaemia Result in Further
Change in Erythrocytic Shape?
R. DICKERHOFF
Sickle cell disease is an inherited disorder resulting from a point mutation in
the P-globin gene of chromosome 11. It is found in individuals of African, Asian,
Mediterranean and Middle Eastern descent [1,2]. The abnormal hemoglobin S
(HbS) polymerizes under certain conditions (hypoxia, dehydration, hypertonicity) and forces the red cell to take on the sickle shape. Abnormal shape and an
abnormal tendency of the red cell membrane to adhere to endothelium [4] lead
to recurrent vaso-occlusive events anywhere in the vascular system, including
the CNS b]. Of sickle cell patients, 7-15% suffer cerebral infarcts or hemorrhage [6], and another 15% have clinically silent CNS vascular disease [5].
Besides bone marrow transplantation, chronic transfusion for many years is the
only way to prevent recurrence of CNS infarcts [8, 9]. Infarcts or major vascular
changes can be documented by non-invasive methods (CT, MRI, MRA) in most
instances. However, cerebral angiography is needed in cerebral hemorrhage and
in patients with transient ischemic attacks (TIA) who have an inconclusive
MRIIMRA in order to determine the need for a chronic transfusion program.
Conventional, hypertonic ionic CM (osmolality 0.9-2.5 osm/kg H 20) when
used intra-arterially in sickle cell patients causes increased sickling [7]. To
prevent disastrous complications, a partial exchange transfusion to reduce the
HbS level to < 30 % needs to precede cerebral angiography. Intravenous
pyelography, however, can safely be performed without prior transfusion. The
newer non-ionic CM with lower osmolality (0.29-0.6 sm/kg H 20) should be
safer, but there are still no recommendations for their intra-arterial use in sickle
cell patients without first lowering the HbS level [5]. Cerebral angiography in
sickle cell patients should be done with non-ionic CM, but not without prior
partial exchange transfusion.
References
Bunn HF (1997) Pathogenesis and treatment of sickle cell disease. N Engl J Med
337: 762 -769
2. Dickerhoff R et al. (1990) Sichelzellerkrankungen in West-Deutschland. Dtsch Arztebl
87: 1466 -14711
3. French JA et al. (1997) Mechanisms of stroke in sickle cell disease: sickle erythrocytes
1.
decrease cerebral blood flow in rats after nitric oxyde synthase inhibition. Blood
89: 4591- 4599
4. Kaul DK, Fabry ME, Nagel RL (1996) The pathophysiology of vascular obstruction in the
sickle syndromes. Blood Review 10 : 29 - 44
111
112
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
5. Moran q, Siegel MJ, DeBaun MR (1998) Sickle cell disease: imaging of cerebrovascular
complications. Radiology 206 : 311- 321
6. Powars DR (1990) Sickle cell anemia and major organ failure, Hemoglobin 14: 573 - 598
7. Rao VM et al. (1982) The effect of ionic and nonionic contrast media on the sickling
phenomenon. Radiology 144: 291- 293
8. Wang WC et al. (1991) High risk of recurrent stroke after discontinuation of five to twelve
years of transfusion therapy in patients with sickle cell disease. J Pediatr 118: 377 - 382
9. Walters MC et al. (1996) Bone marrow transplantation for sickle cell diseas. N Engl J Med
335: 369 - 37 6
4.16
Are Contrast Media-Induced Side Effects Dependent
on Age?
H.KATAYAMA
Among several risk factors for CM reactions, the age of the patient is thought to
be one of the principal ones. As far as overall reactions are concerned, Shehadi
reported that they were more prevalent in the third and fourth decades.
Incidence was lowest at either end of the age spectrum [5, 7]. According to
Ansell [2], the incidence rates of minor reactions were highest in the 20- to
29-year age group and tended to be lower in younger and older patients. Intermediate reactions showed a similar trend. The severe reactions showed a more
uniform distribution, with perhaps a slight predominance in the older age
group. These data are based on patients administered conventional high
osmolar ionic CM.
Katayama [3] has reported on a large survey of adverse reactions to ionic and
nonionic CM. It showed the highest incidence of overall reactions in the third
and fourth decades. There was no definite trend for severe reactions but with a
slight predominance in the third to fifth decade. This was true both with ionic
and nonionic CM though with an indistinct trend in severe reactions with
nonionic CM (Table 4.16.1).
Parameters estimated for the selected logistic regression model for severe
adverse reactions show the odds ratios to be: under 9 years 0.58; 10-49 years
1.0; and over 50 years 0.68 [4]. As far as fatal reactions were concerned, Shehadi
reported that the peak incidence of fatal reactions was observed in the sixth to
seventh decade [6]. The cause of death is thought to be mainly due to cardiovascular collapse secondary to administration of high osmolar CM. Ansell's [1]
results agreed with this trend.
In conclusion, overall adverse reactions are more common in the early
middle age group. Fatal reactions are thought to be more common in the group
over 50 years of age.
4.17 Can Contrast Media Procedures Be Carried Out Despite Defined Risks?
Table 4.16.1. Prevalence of ADRs by age Distribution (from [3])
Age
of
patients
(years)
<1
1-9
10-19
20-29
30-39
40-49
50-59
60-69
70-79
~80
No entry
Cases with non-ionic
contrast media
Cases with ionic
contrast media
Tota!
(n)
With
ADR
(n) (%)
With
severe
ADR
(n) (%)
Total
(n)
With
ADR
(n) (%)
With
severe
ADR
(n) (%)
272
2701
6359
8842
16428
25352
40311
38807
24807
4681
724
2 (0.74)
338(12.51)
1068(16.80)
1615 (I 8.27)
2806 (I 7.08)
3825(15.09)
5025(12.47)
4087(10.53)
2185(8.81)
371 (7.93)
0(0)
2(0.07)
26(0.41)
21 (0.24)
49(0.30)
69(0.27)
69(0.17)
82(0.21)
41(0.17)
6(0.13)
916
5479
7066
8009
14569
23386
38014
38220
26201
5562
941
4(0.44)
138(2.52)
319(4.51 )
372(4.64)
661 (4.54)
962(4.11)
1200(3.16)
996(2.61)
507 (1.94)
81 (1.46)
0(0)
4(0.07)
5(0.07)
5(0.06)
6(0.04)
13 (0.06)
15 (0.04)
10(0.03)
8(0.03)
4(0.07)
References
1. Ansell G et al. (1980) The current status of reactions to i. v. CM. Invest Radiol [Suppl]:
32-39
2. Ansell G (1970) Adverse reactions to CA. Invest Radiol 6: 374- 384
3. Katayama H et al. (1990) Adverse reaction to ionic and non-ionic CM. Radiology
175 : 621- 628
4. Katayama H et al. (1991) Full-scale investigation into adverse reaction in Japan, risk factor
analysis. Invest Radiol26 [Suppl]: Sl-S4
5. Shehadi WH (1975) Adverse reactions to intravasculary administered CM. AJR 124: 115 -152
6. Shehadi WH et al. (1980) Adverse reactions to CM. Radiology 137: 299 - 302
7. Shehadi WH (1985) Acta Radiol Diagn 26: 457 - 461
4.17
Can Contrast Media Procedures Be Carried Out
Despite Defined Risks?
P.DAWSON
In the author's opinion there are no absolute contraindications to contrastenhanced studies. Risk and contraindication in medicine, as elsewhere, are
always relative terms. Clearly, if there is a definable factor increasing the risk of
113
114
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
the procedure, thought must be given to whether it is really necessary and to
whether an alternative and possibly safer procedure not requiring CM might
give the same or similar information. In the patient in whom, in spite of
definable risk factors, a contrast examination is still thought necessary, several
precautions may be taken: nonionic CM should be used since these are associated with a reduced incidence of reactions, particularly in high risk patients
[2] and are associated with reduced toxicity in higher doses [1]; the smallest
dose compatible with obtaining the essential information should be used;
prophylaxis with corticosteroids or antihistamines may be given to patients
who have reacted on a previous occasion, are atopic or asthmatic, or are
generally allergic to other drugs or agents. An anaesthesist might be asked to
present in case of the need for skilled resuscitation.
Only the clinician in charge of the case with full knowledge of the individual patient's clinical history and current state of health can properly assess the
situation and no precise rules of conduct can reasonably be laid down. If the
radiologist has sensibly considered the need for the examination, excluded the
possibility that alternative methods might provide the information needed, has
assessed the likely risk as far as is possible and has taken some of the precautions listed above, then he will have acted reasonably both ethically and medicolegally speaking.
References
Dawson P, Hemingway A (1987) Contrast doses in interventionaI radiology. J Intervent
Radiol 2: 145 -146
2. Katayama H et aI. (1990) Report of the Japanese committee on the safety of contrast media.
Radiology 175 : 621- 628
1.
4.18
What Interactions Are Known Between Contrast Media
and Other Medications?
P.DAWSON
A number of drugs are known to be physically incompatible with some CM [3].
These incompatibilities include persistent or transient precipitation with conventional and low osmolality ionic CM of papaverine, protamine, cimetidine,
diphenhydramine-HCl and garamycin. No such incompatibilities are known
with the nonionic agents but great caution should be exercised in the physical
mixing of any drugs prior to injection into patients.
A number of drugs have been tested in animals in clinical range doses to
investigate the possibility of synergism with radiocontrast agents. Among the
4.18 What Interactions Are Known Between Contrast Media and Other Medications?
commonly used drugs, only the cardiac glycosides have been found to act
synergistically [1]. Another observation was that Strophanthin-K in the near
lethal dose range produced a greater mortality if low or clinical doses if
Diatrizoate were given with it [1]. Fischer and colleagues [1] also noted
synergism between nonionic metrizamide and cardiac glycosides with cardiopulmonary death. Since many of the toxic effects of the glycosides are on the
heart with arrythmias and ventricular fibrillation in high doses, it is not surprising that CM, which have their own cardiotoxic effects may act synergistically with these. However, there is some evidence that the effects are centrally
mediated rather than directly on the heart [1].
Hamilton has reported two patients taking fJ-blockers who suffered hypotensive reactions while undergoing excretory urography [2]. Perhaps the
fJ-adrenergic blocking agents may interfere with the body's ability to counteract hypotension-inducing events such as those associated with CM. It might
also be thought, though there is no clinical evidence, that there may be a possibility of a synergistic effect as regards bronchospasm in susceptible patients
between fJ-blockers and CM.
A synergistic effect between the calcium antagonist verapamil and ionic CM
has been observed in experimental coronary angiography as an enhanced inhibition of atrioventricular conduction [6]. No such effects have been observed
following peripheral injection of CM experimentally or clinically.
The possibility that angiotensin-converting enzyme (ACE) inhibitors might
act synergistically with CM has been raised [4]. Both inhibit ACE and could,
theoretically, lead to high levels of bradykinin in association with contrast
administration. This remains entirely speculative.
One well-established synergy is between the first generation nonionic agent
metrizamide administered intrathecally and concomitant systemic chlorpromazine [5]. No such significant interactions have been established involving the
second generation nonionic agents.
References
1.
2.
3.
4.
5.
6.
Fischer MW, Morris TW, King AN, Harnish PP (1978) Deleterious synergism of a cardiac
glycoside and sodium diatrizoate. Investigative Radiology 1978, 13: 340 - 346
Hamilton G (1985) Severe adverse reactions to urography in patients taking b-adrenergic
blocking agents. Canadian Medical Association Journal 133 : 122
Irving MD, Burbridge BE (1989) Incompatibility of contrast agents with intravascular
medications. Radiology 173 :91- 92
Lasser EC (1987) A general and personal perspective on contrast material research. Invest
Radiol 23: S71- S74
Maly P, Olivecrona M, Almen T, Golman K (1984) Interaction between chlorpromazine and
intrathecally injected non-ionics contrast media in non-anaesthetised rabbits. Neuroradiology 26 : 235 - 240
Peck WW, Slutsky RA, Mancini J, Higgins CB. Combined actions of verapamil and contrast
media on atrio-ventricular conduction. Invest Radiol19: 202-207
115
116
CHAPTER 4 Determination of Risk Factors Regarding the Administration of Contrast Media
4.19
What Effects do Iodinated Contrast Media Have When
Administered During Pregnancy or Lactation?
K.A. WANDL-VERGESSLICH and H. IMHOF
The incidence and severity of adverse events have decreased substantially since
the introduction of non-ionic contrast media (CM), allowing them to be used in
paediatric imaging, and even in neonates. The question of whether their use
during pregnancy or lactation poses a risk is particularly important in clinical
practice.
Pregnancy
Several experimental studies of the placental passage of CM have shown that
both the foetal plasma concentration and the concentration in the amniotic
fluid is below the limit of detection [1, 2, 5]. A toxic effect on the foetus and
particularly on thyroid function is, therefore, unlikely.
Lactation
In theory, contrast media entering the breast milk can exert their toxicity via
two mechanisms:
1.
2.
in the development of hyperosmolar conditions or
through an anaphylactic reaction.
The amounts excreted with the breast milk after a single dose of an i. v. bolus
are minimal owing to the only slight solubility of water-soluble CM in fat [4]. In
the first 24 hours, the baby absorbs about 0.2 % of the dose which would be
administered to a baby for an X-ray examination with contrast material [1].
Adverse effects on kidney or liver function can, therefore, be ignored. Moreover,
the low hyperosmolarity of non-ionic CM prevents any serious disturbance of
the osmolarity equilibrium of the sensitive neonate. The risk of induction of a
hyperthyroid metabolic state can be virtually ignored. The iodine levels in the
maternal plasma can no longer be detected 6-24 hours after CM administration [3], and only about 10 % of the iodine enters the breast milk.
Consequently, the following conclusions can be drawn:
No injurious effect of non-ionic contrast media on the foetus is likely on use
of such CM during pregnancy. With the exception of vital indications, however, X-ray examinations should not be performed during pregnancy.
The performance of a contrast medium X-ray examination of the mother
during lactation is not associated with any risk of toxicity to the baby (with
the exception of the theoretical risk of an anaphylactoid reaction). There is,
therefore, no need to discontinue breast-feeding.
4.19 What Effects do Iodinated Contrast Media
References
1. Bourinet P, Dencausse A, Havard P et al. (1995) Transplacental passage and milk excretion
of iobitrido!. Invest Radiol30 (3): 156 -158
2. Dencausse A, Violas X, Feldman H et al. (1996) Pharmacokinetic profile of iobitridol Acta
Radiologica (Supp!.) 400: 25 - 34
3. Lorusso V, Luzzani F, Bertani F et al. (1994) Pharmacokinetics and tissue distribution of
iomeprol in animals. Eur J Radiol18 (SUpp!.I): 13-20
4. Nielsen S, Matheson I, Rasmussen I et al. (1987) Excretion of iohexol and metrizoate in
human breast milk. Acta Radiologica 28 (Fasc 5): 523 - 526
5. Tauber U, Mutel W, Schulze PE (1989) Whole Body Autoradiographic Distribution Studies
on Nonionic X-Ray Contrast Agents in Pregnant Rats. In: Taenzer V, Wende S (eds) (1989)
Recent Developments in Nonionic Media. Thieme, Stuttgart New York, pp 215 -219
117
CHAPTER
5
Prophylactic Measures
5.1
What Is the Place of Fasting and Dehydration
Before Contrast Media Administration?
W.
CLAUSS
Since risk patients tolerate nonionic X-ray CM and effective premedications are
available, previously frequent side effects of CM examinations, such as nausea
and vomiting, now occur rarely. Moreover, patients who have not had anything
to eat or drink for longer periods of time are less calm and cooperative and
more susceptible to side effects during an examination. In view of this, in 1992
a German group of radiological experts took up the question of optimal patient
hospitals
12
10
8
e
4
2
o
o
1
2
3
4
5
8
8
12 hours
Fig. 5.1.1 a-d. Intra-arterial (a), intravenous (b), intrathecal (c), and intra-articular (d) CM
administration: abstinence from solid food and liquids. • , abstinence from solid food;
0, abstinence from liquids
hospitals
18
14
12
10
8
8
4
2
0
0,5
0
1
3
4
5
e
8
12 hours
Fig. p.lb
hospitals
14
12
---,.,...-
10
8
6
4
2
o
Fig·5·I.IC
hospitals
18
14
12
10
8
8
4
2
0
Fig.5.1.1d
14
-----------------------------------_._-----;
120
CHAPTER 5 Prophylactic Measures
preparation, in the interests of both physician and patient and for the safety of
the latter. A survey of the participating experts showed great discrepancies in
the recommended periods of abstinence from solid food and liquids prior to
intraarterial, intravenous, intrathecal, and intraarticular X-ray CM administration (Fig. 5-1.1 a - d); standardization therefore seemed desirable. After intensive,
as well as controversial discussions, a recommendation was made to hydrate
patients adequately both before and after X-ray CM administration, i. e. to urge
the patient to drink. Moreover, for the administration of nonionic X-ray CM,
sufficient reasons could no longer be found for maintaining the previously held
recommendation of at least a 4-h absolute abstinence from food.
A small meal (the size of which, however, should be agreed upon in consultation with the anaesthetist) taken approximately 2 h before the intravascular administration of nonionic X-ray CM often decreases the strain of the
examination for both physician and patient [1]. Such examinations conducted
without any restrictions on the intake of food or liquids do not lead to an
increased rate of side effects [2].
References
Expertengesprach Kontrastmittel (1992) Radiologe 9 (Suppl)
2. Wagner HJ et al. (1997) MuB der Patient vor intravasaler Applikation eines nichtionischen
Kontrastmittels niichtern sein? Fortschr R6ntgenstr 166/5: 370 - 375
1.
5.2
Can Hypersensitivity Reactions to Contrast Media
Be Predicted Through Preliminary Testing?
W. CLAUSS and V. TAENZER
It used to be common in clinical practice to carry out subcutaneous, intrader-
mal, conjunctival or intravascular testing with small doses of CM, in order to
predict a patient's disposition to exhibit hypersensitivity. It turned out, however,
that classic procedures such as a skin test and even intravenous testing yielded
very unreliable results [1,2]. Whereas positive results of such hypersensitivity
tests were often followed by completely symptomless tolerance of the subsequently administered CM, severe and even lethal reactions could sometimes be
observed in examinations subsequent to negative test results. The uncertainty
in interpreting preliminary testing results, combined with the experience that
even the small amounts of CM administered intravascularly in such testing,
could trigger severe anaphylactoid reactions resulting in death, led to the 1967
resolution of the Congress of European Radiologists to stop preliminary testing
in CM administration.
5.3 Is Sedation Indicated Before Administering Contrast Media?
The German Society of Radiology adopted for this recommendation in 1968
[3]. Since this time, refraining from CM testing neither represents malpractice
nor does it possess any medico-legal implications.
In 1990, Japan (Japanese Committee on the Safety of Contrast Media) also
stated that the pretesting used so far should be discontinued, as this was a useless measure for recognizing possible reactions to contrast media [4].
Today one assumes that antigen-antibody reactions, which can be detected in
preliminary testing, are not involved in reactions of hypersensitivity to CM.
Therefore, prophylactic measures aimed at reducing such hypersensitivity
reactions, the possibility of which can never be excluded, and rapid therapeutic
intervention for treating them remain important.
References
1. Stuart C (1965) Die Fragwiirdigkeit der sogenannten Vertraglichkeitstests vor der Anwendung jodhaltiger Kontrastmittel. Der Radiologe 5 : 171
2. Witten DM, Hirsch FD, Hartmann GW (1973) Acute reactions to urograhic contrast
medium. Amer J Roentgenol Radium Ther Nud Med 119: 832
3. Stellungnahme der Deutschen Rontgengesellschaft zur Frage der Vortestung bei Kontrastmitteluntersuchungen (1968) RoFo 108: 126
4. Yamaguchi K et al. (1991) Prediction of Severe Adverse Reactions to Ionic and Nonionic
Contrast Media in Japan. In: Evaluation of Pretesting. Radiology 178 : 363 - 367
5.3
Is Sedation Indicated
Before Administering Contrast Media?
G. WISSER
Anxiety is frequently viewed as inducing undesirable reactions to CM administration. In a survey in 1983, 82 % of almost 1500 radiologists believed that fear
is the most frequent cause of mild, undesirable reactions; 37% even considered
it the main cause of more severe reactions, such as shock, pulmonary and cardiovascular problems and deaths [5].
In 1980, Lalli put forward the hypothesis that all CM reactions are triggered
by a direct effect of the CM on the CNS. Fear and anxiety are seen here
functioning as emotional triggers [4]. He was able to show that the occurrence
of nausea, vomiting and urticaria was significantly reduced through hypnotic
influence prior to CM administration. In contrast, diazepam significantly
increased the incidence of such mild reactions [3]. Patients who became more
anxious as a result of discussions prior to CM administration did not, however,
show a statistically significant increase in undesirable reactions [6]. Furthermore, answers regarding the frequency at which mild CM side effects are
registered depends on the intensity of the questioning [8].
121
122
CHAPTER 5 Prophylactic Measures
Today, esperally nonimmunological (pseudoallergic, anaphylactoid) reactions
are considered the pathomechanisms of CM incidents [7] and one has to advise
against the exclusive administration of sedatives as prophylaxis. In patients at risk
(patients with known allergies; cardiac, pulmonary or hepatic disease; bronchial
asthma; exposure to CM, within the last few days), nonionic CM possibly
supplemented by corticosteroids and/or antihistamines should, be used. Sedation
prior to CM administration may, however, be considered in states of agitation [2]
or in order to avoid vasovagal reactions [1].
References
1.
2.
3.
4.
5.
6.
7.
8.
Bielory L, Kaliner MA (1985) Anaphylactoid reactions to radiocontrast materials. Int
Anesthesiol Clin 23 :97 -118
Elke M, Brune K (1980) Prophylaktische MaBnahmen vor Kontrastmittelinjektionen. Dtsch
med Wschr 105: 250 - 252
Lalli AF (1974) Urographic contrast media reactions and anxiety. Radiology 112: 267- 271
Lalli AF (1980) Contrast media reactions: data analysis and hypothesis. Radiology 134: 1-12
Spring DB, Akin JR, Margulis AR (1984) Informed consent for intravenous contrastenhanced radiography: a national survey of practice and opinion. Radiology 152: 609 - 613
Spring DB, Winfield AC, Friedland GW, Shuman WP, Preger L (1989) Written informed
consent for iv contrast-enhanced radiography - Reply. Amer J Roentgenol153: 189
Wangemann BU, Jantzen JP, Dick W (1988) Anasthesiologische Aspekte allergischer Reaktionen am Beispiel des "Kontrastmittelzwischenfalls". Anaesth Intensivmed 29 : 205 - 214
Thomsen HS (1997) Frequency of acute adverse events to a non-ionic low-osmoloar contrast medium: the effect of verbal interview. Pharmacol Toxicol 80: 108 -110
5.4
Does General Anaesthesia Prevent the Occurrence
of Contrast Media-Induced Side Effects?
G. WISSER
General anaesthesia has frequently been recommended for angiographic
examinations, especially those involving ionic CM. It was claimed that it not
only facilitates the diagnostic procedure (e.g. elimination of CM-induced pain
and defence mechanisms and restlessness on the part of the patient), but that it
also had a protective effect against undesirable CM reactions [5,7].
Prospective, randomized, comparative studies on undesirable side effects do
not exist. Due to the nature of general anaesthesia, reactions to CM, such as
nausea, vomiting, etc., cannot even be observed [9]. CM-induced skin reactions
occur equally often whether the patient is conscious or under anaesthesia [1];
there is not even a demonstrable difference in frequency in CM-induced hypotension in general or spinal anaesthesia [9]. Even the most severe reactions
5.5 Can the Rate of Contrast Media-Induced Side Effects Be Lowered
(anaphylactic-anaphylactoid shock) have been observed under anaesthesia for
both ionic [3,6,8] and nonionic CM [2,4,11].
Thus, general anaesthesia does not provide absolute protection against a CM
incident. Accordingly, the question of whether anaesthesia is indicated should
be decided in terms of an assessment of the individual risks. Mere knowledge
of a CM risk factor does not justify anaesthesia [10]. According to our present
state of knowledge, general anaesthesia cannot be recommended as an alternative to prophylaxis with corticosteroids and/or antihistaminic preparations in
the prevention of potential CM incidents.
References
1. Albrecht K (1956) Das Risiko bei neurochirurgischen Untersuchungsmethoden. Zentralbl
Chir 81: 2107 - 2113
2. Gaiser RR, Chua E (1993) Anaphylactic/anaphylactoid reaction to contrast dye administered in the ureter. J din Anaesth 5 : 510 - 512
3. Gottlieb A, Lalli AF (1982) Hypotension following contrast media injection during general
anesthesia. Anesth Analg 61: 387 - 389
4. Jantzen JPA 4, Wangemann B, Wisser G (1989) Adverse reactions to non-ionic iodinated
contrast media do occu during general anesthesia. Anesthesiology 70 : 561
5. Maus H, Loennecken SJ (1962) Zerebrale Angiographie und Narkose. Fortschr Neurol
Psychiatr 30: 155-165
6. Pfeifer G, Solymosi L, Grimm R, Wappenschmidt J (1984) Anasthesie in der Neuroradiologie. Anaesth Intensivther Notfallmed 19: 57- 59
7. Plotz J, Viehweger G (1974) Die Angiographie der oberen Extremitat in Narkose, lokaler
und regionaler Anasthesie. Prakt Anaest 9 : 225 - 231
8. Sirnmendinger HJ, Just OH (1973) Anaphylaktischer Schock nach Kontrastmittelinjektion.
Z prakt Anaest 8: 370 - 374
9. Tolksdorf W, Raddi U, Rohowsky R, Lutz H (1980) Zur Wahl des Anasthesieverfahrens bei
translumbalen Aortographien. Anaesth Intensivther Notfallmed 15: 400 - 406
10. Wangemann BU, Wisser G (1990) Prophylaxe des "Kontrastmittelzwischenfalls" durch
Allgemeinanasthesie? Radiologe 30 : 141-144
11. Wisser G, Wangemann B, Jantzen JP, Dick W (1990) Anaphylaktoide Reaktion auf ein
nichtionisches Rontgenkontrastmittel in Allgemeinanasthesie. Anaesth Intensivther
Notfallmed 25: 271- 273
5.5
Can the Rate of Contrast Media-Induced Side Effects
Be Lowered by Premedication with Antihistamines?
R.TAUBER
A substantial proportion of CM side effects are probably induced by histamine.
Thus, on the one hand, a rise in the plasma histamine level can be observed after
123
124
CHAPTER
5 Prophylactic Measures
CM administration, and on the other, histamine-induced side effects can be
prevented by a prophylaxis with H I- and H2 -receptor antagonists.
However, it must always be taken into account that HI - and H2 - receptor
blockers only block histamine-induced side effects and therefore only cover
part of the possible spectrum of pathogenesis. Other reaction pathways in the
complement, coagulation and immune systems are not blocked.
Nevertheless, if risk factors exist that increase the danger of X-ray CM side
effects, these patients should receive, premedication with an H I- and H2 -receptor antagonist. These are patients:
- With an allergic diathesis, with hypersensitivity to food and drugs, and those
undergoing blood transfusions.
- Who have already reacted to CM in the past.
- With diseases accompanied by raised histamine levels, e. g. pulmonary
diseases.
- Who are elderly (over 75 years old) or are children.
- With cardiac, respiratory, or hepatic insufficiency.
The intravenous injection of H I- and H2 -receptor antagonists has to be 10-15
min before CM administration; injection should be over for 2 min.
As an HI antagonist, dimetindene maleate can be used (Fenistil) (4 mg for a
body wt. of 40 - 60 kg, 8 mg for a body wt. of 60 -100 kg, and 12 mg for a body
wt. over 100 kg). As an H2 antagonist, cimetidine can be used (Tagamet) (200 mg
for a body wt. of 40 - 60 kg, 400 mg for a body wt. of 60 -100 kg, and 600 mg
for a body wt. over 100 kg).
If patients are correctly premedicated, one can perform urography without
the presence of an anaesthetist. Even in cases of known CM intolerance,
excretory urography need not be performed under anaesthesia. Full resuscitation facilities must, however, always be available.
5.6
Can the Adverse Reaction Rate Be Reduced
by Administration of Corticosteroids?
W.CLAUSS
In patients with known CM hypersensitivity and in those who suffer from
allergy, a two- to six-fold rise in the side-effect rate has to be reckoned with following intravascular CM administration. Reactions are largely independent of
dose and are categorized as pseudoanaphylactoid.
The administration of corticosteroids has been recommended since the
1960s as a promising prophylactic measure [1,2]. It must be emphasized, however, that a prophylactic effect cannot be automatically presumed. Consequent-
5.6 Can the Adverse Reaction Rate/Be Reduced by Administration of Corticosteroids?
ly, it is still important to have the medications and technical apparatus available
that might be necessary for treatment and resuscitation. Neither the pathomechanisms involved in the genesis of anaphylactoid reactions nor the mechanisms operating in corticosteroid prevention or reduction of these reactions
have been fully elaborated. However, in-vitro tests have displayed some features
of corticosteroids that could be drawn upon in clarifying its effects. Thus, they
counteract experimentally produced permeability impairment of cell membranes [3], check the complement-induced lysis of erythrocytes [4], lower the
serum-complement level [5] and counteract both the release of histamine from
mast cells [6] and haemolysis [7].
The unsatisfactory prophylactic effect of corticoisteroids given intravenously immediately prior to CM administration has been explained in terms of the
slow onset of their effects. Results can be improved by increasing the interval (at
least 2 h) between the administration of corticosteroid and that of the CM.
Recourse can also be made to quick-acting corticosteroids, such as triamcinolone acetonide phosphate disodium salt (Volon A solubile) [8]. In recent years,
the good prophylactic effects of oral corticosteroids, when administered with
appropriate lead time before challenge with CM, has been attested to. For
example, the two-part, oral administration of 32 mg each of methylprednisolone
ca. 12 h (6 - 24 h) and 2 h prior to CM administration leads to a significant
lowering of the side-effect rate [9]. Even though prophylaxis with this regime
preceding the administration of ionic CM leads to a lower rate of side effects,
this rate is still higher than the side-effect rate resulting from the administration of nonionic CM without preceding corticoid administration [10].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Fiegel G (1974) Die hochdosierte Glukokortikoid-Therapie beim schweren Kontrastmittelzwischenfall. Med Welt 25: 2158 - 2160
Greenberger PA et al. (1986) Emergency administration of radiocontrast media in high
risk patients. J Allergy Clin Immunol 77 : 630 - 634
Weissman G (1961) Release of lysosomal protease by ultraviolet irradiation and inhibition
by hydrocortisone. Exp Cell Res 25 : 207 - 210
Jennings JF et al. (1966) The effect of hydrocortisone on immune lysis of cells induced by
cytotoxic antibody and complement in vitro. J Immunol 96 : 409 - 414
Atkinson JP et al. (1973) Effect of cortisone therapy on serum complement components. J
Immunol111 : 1061-1066
Greaves MW et al. (1974) Glucocorticoid inhibition of antigen-evoked histamine release
from human skin. Immunolgy 27: 359 - 364
Schreiber AD et al. (1975) Effect of corticosteroids on the human monocyte IgG and complement receptors. J Clin Invest 56: 1189 -1197
Fiegel G (1985) Vermeiden von Kontrastmittelzwischenfallen. Med Welt 36: 1486-1470
Lasser EC et al. (1994) Pretreatment with corticosteroids to prevent adverse reactions to
nonionic contrast media. AJR 162: 523 - 526
Wolf GL (1989) Adverse reactions to intravenous contrast media in routine clinical
practice. Scientific Poster, RSNA 1989
125
126
CHAPTER
5 Prophylactic Measures
5.7
How Important is Pharmacoprophylaxis
of Hyperthyroidism and How Can it Be Performed?
B. GLOEBEL
Should it be necessary to avoid iodine-induced hyperthyroidism secondary to
the use of iodinated X-ray contrast media, prophylactic therapy can be considered. A remark first about the avoidance of hyperthyroidism, however:
It is not always possible to predict those at risk from iodine-induced hyperthyroidism. A probability or assumption is the closest we can get in most cases.
Therapy can usually only reduce the probability of hyperthyroidism, which can
occur even after correctly performed prophylactic therapy. A distinction must
also be made between two cases of the application of iodinated contrast media
- that of non-ionic preparations and that of all others. Non-ionic contrast
media contain so little free iodine and are so biologically stable and display
such rapid renal elimination that they do not pose any increased risk of hyperthyroidism.
In all other cases, the thyroid disease should first be treated adequately if at
all possible.
Table 5.7.1 shows a possible regime for the prophylaxis of hyperthyroidism.
Table 5.7.1. Prophylactic therapy before use of iodinated contrast media
Increased ri k of iodine-induced
hyperthyroidism
500 mg perchlorate orally 2 hour before and again
4 hours after iodine administration, followed by 3 x
300 mg/day orally over 10 days
Perhaps thiamazol in addition:
20 mg/day over 10 days
Reexamination of thyroid function after I and
8 weeks
Manifest hyperthyroidism
500 mg perchlorate orally 2 hours before and again
4 hours after iodine administration, followed by 3 x
300 mg/day orally over 14 days
40 mg thiamazollday over at least 14 days
Reexamination of thyroid function after 1,2,4 and
8 weeks
CHAPTER 6
Informing the Patient
Prior to Contrast Media Administration
6.1
What Is the Patients IJRight to Know"
Prior to an X-Ray Examination Using Contrast Media?
H. J. MAURER and W. SPANN
(The following section was prepared in the context of German law. Many of the
basic principles are of universal application though, naturally, caution should
be exercised.)
Even though no detailed legal regulations exist, informing the patient about
the nature and possible risks of a diagnostic examination has always been an
indispensable part of all preparation. If such examinations or interventions are
performed on a patient who is not adequately informed, they are not in accordance with the law. Only if
a) the examination is indicated,
b) the intervention is performed according to the state of the art, and
c) the patient's consent to the intervention is legally valid
is the examination in accordance with the law.
Consent is considered legally valid only if it was given with clear understanding of the situation, i. e. if it was informed consent. The patient can only
gain such clear understanding of the situation of his or her specific case by
being informed by a physician. Accordingly, adequately informing the patient is
a necessary condition of the lawfulness of consent and thus of the procedure as
well.
During such a consultation the experienced physician can take the opportunity to reassure the patient, reduce his fear of the examination and win his
trust. Anxious patients do not merely make the diagnostic procedure more
difficult through lack of cooperation; when they are administered CM, the
physician must reckon with a higher rate of side effects [1].
If legal proceedings are initiated due to the failure to inform adequately, the
burden of proof rests upon the physician. For this reason, it is necessary at all
128
CHAPTER 6 Informing the Patient Prior to Contrast Media Administration
times to be able to prove that the patient was informed, be it in the form of his
or her signature, witnesses, and/or an entry into the medical me. In the same
way, written record must be kept if the patient waives his or her right to be
informed or if he or she has no further questions regarding the examination or
its attendant risks.
In legal terms, the placing of a catheter and the injection of a CM qualify as
bodily injury. For this reason, every recognized danger or recognized risk
connected to the given diagnostic intervention has to be explained to the
patient, regardless of the frequency of its occurrence. At least under German
law, the referring physician is also partly responsible for informing the patient
[2].
Patients must not just be informed prior to the procedure; they must be given
an adequate opportunity to think it over. In invasive, diagnostic procedures
(e.g. angiography), the discussion should be conducted on the day preceding
the examination. Patients may be informed on the day of the examination in the
case of urography or CT; however, this should occur some time prior to the
procedure and outside the examination room.
The patient should be informed far enough in advance of any examination
reduction in driving fitness, so that he or she does not drive to the examination.
In the case of unconscious or unresponsive patients (emergencies), the
physician has to perform the necessary examination without informing the
patient. He or she can work on the basis of presumed consent and represents in
such cases the interests of the patient in addition to his or her own.
Consent for the examination must be obtained from both parents when the
patient (for example, a child) does not fully understand the situation. If this is
not possible, then the person who has custody of the child must give permission. If the parents refuse to give consent in a life-threatening situation and
there is no time to obtain consent of court, the physician should conduct the
examination anyway.
When explaining to a patient the risks involved in a diagnostic examination
the physician should draw primarily on his own experience. It might also be
helpful to be able to provide statistics from other examiners. The patient also
has a right to know about the various rates of CM side effects (for example, ionic
and nonionic CM). Price alone should not influence a physician's decision.
Outpatients should be informed of rare but possible late reactions as well as
of any effects CM might have on driving a motor vehicle.
References
1. Lalli AF (1974) Urographic contrast media reactions and anxiety. Radiology 112: 267-271
2. Maurer HJ, ClauB W, Granitza A (1983) Alleinige oder geteilte Verantwortlichkeit bei der
Anwendung jodierter Rontgenkontrastmittel. Rontgen- BL 36 : 379 - 383
6.2
What Informations Should Patients Receive in Clinical Trials
6.2
What Special Information
Should a Healthy Volunteer/Patient Receive
Who Is Participating in a Clinical Study of a New Drug?
W. CLAUSS and E. ANDREW
Healthy volunteers or patients (volunteers/patients) participating in clinical
studies not only have rights but also duties that should be conveyed to them in
a comprehensive and understandable fashion both verbally and in writing (volunteer/patient information).
The planning and execution of a clinical study, including obtaining the
informed consent of the volunteer/patient is subject to the laws of the land and
to the European Good Clinical Practice (GCP) guidelines, which are based on
the results of the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and
now recognised around the world. Moreover, the recommendations of the
World Medical Association should be taken into account (Declaration of Helsinki in its most recent version).
Aside from being informed in writing, the volunteer/patient also has the
right to question the physician on all points of the clinical study. The volunteer/
patient declares his voluntary participation, confirmed by the date and
his signature, in the knowledge that he can withdraw his consent at any time
without having to suffer any disadvantage in the course of subsequent
treatment.
Volunteer/patient information has, above all, to take the following points into
account:
- Participation in the study has to be justified and alternative methods of
treatment indicated to the volunteer/patient.
- Participation is voluntary and can be discontinued at any time without
explanation.
- The study involves the testing of a drug not yet admitted to the market.
- A description must be given of the efficacy of the drug already known or
suspected, the safety and the tolerance (frequency and severity of side effects)
of the drug. If no clinical experience exists with the drug whatsoever, then
preclinical results have to be consulted.
- A description must be given of the state of development of the preparation
and of the general goal of the individual study.
- The test design (open, single- or double-blind) must be explained and a
description of the course of the study (preparatory phase, test-induced study
length, follow-up phase) ist to be provided.
- A description of additional demands of the study (diet, blood samples,
prohibited accompanying""medications, confinement to bed and so forth)
must be provided.
129
130
CHAPTER 6 Informing the Patient Prior to Contrast Media Administration
- Information must be provided about taking out an insurance policy covering
possible examination-induced life threatening reactions, which can never be
precluded entirely.
- Information about the the threat to insurance coverage that is entailed by not
immediately reporting side effects or by consenting to additional, simultaneous treatments without the knowledge of the study physician.
- Referemce must be made to the confidential treatment of the resulting test
data, which are kept anonymous and saved electronically.
- Information about the strict protection of personal data from one's file,
which are opened only to authorized persons from the pharmaceutical
company who are subject to agreements of confidentiality and from the
domestic and foreign supervisory agencies.
Clinical studies on children and on mentally disturbed patients are only permissible if the tested preparation is being developed specially for the diagnosis
and/or therapy of certain diseases of these groups or if results obtained from
other groups of patients are not applicable to these groups.
CHAPTER 7
Administration of Contrast Media
7.1
Are Contrast Media Heated to Body Temperature
Better Tolerated?
P.DAWSON
It seems, from first principles, entirely reasonable that CM which are, generally
speaking, injected into patients in high concentrations and large doses might be
better tolerated if delivered at body temperature. Many radiologists use one of
the commercially available thermostatically controlled heating cabinets to
warm their CM to 37°C. In any case, toxicity and tolerance aside, warming the
CM to body temperature significantly reduces its viscosity, making injection
easier, particularly with small needles and catheters [1].
There is, however, little hard evidence available to support the idea that
clinical tolerance is significantly increased thereby. The only recent reasonably
large study (but still only 100 patients) revealed no convincing difference
between two patient groups, one receiving room temperature CM and the other
receiving body temperature CM [2].
It is interesting to note that as regards pain and heat sensation specifically in
arteriography, there does appear to be an association with CM viscosity and at
least some evidence, therefore, that these undesirable side effects may be
diminished by heating the CM [1,3]. The evidence, however, comes from comparative studies of different CM with different viscosities and not from studies
with the same CM at different viscosities (different temperatures) so other
factors than viscosity might well be confusing the picture.
In summary, supporting evidence of benefit is lacking, but heating CM to
body temperature before use is being more and more widely practised and, in
the author's opinion, is to be recommended.
132
CHAPTER 7 Administration of Contrast Media
References
Halsell RD (1987) Heating contrast media. Role in contemporary angiography. Radiology
164: 276 - 278
2. Turner E, Kentner P, Melamed JL, Rao G, Seitz MJ (1982) Frequency of anaphylactoid
reactions during intravenous urography with radiographic contrast media at two different
temperatures. Radiology 143 : 327 - 329
3. Wilcox J, Sage MR (1984) Is viscosity important in the production of blood-brain-barrier
disruption by intracarotid contrast media? Neuroradiology 26: 511- 513?
1.
7.2
Are There Any Guidelines for Maximum Doses
in Angiography?
P.DAWSON
Iodinated CM are mild tissue poisons generally used in large doses. Because
even the low osmolality agents represent a potential osmotic load stress to a
patient, attention must be paid to the total dose and to the time course over
which it is given. Guidelines, sometimes given in terms of ml per kilogram of
patient, are vague since the strength of the solution is not stated. Milligrams
iodine per kilogram (mg lIkg) is the clearest notation since the radiologist
usually has some feel for iodine doses and concentrations but he must still do
some calculations to find what volume of solution he may use. Some examples
will now be given but should not be taken as prescriptive:
1.
2.
3.
An IVU is frequently performed with approx 300 mg lIkg. In a 70 kg man this
is 21 000 mg I (21 g). If a solution of 420 mg Ilml is used ([e. g. "Conray 420"]
the volume required is 21 000/420 = 50 ml (one bottle).
A "high dose" IVU might utilize 600 mg lIkg, i. e. two bottles of 420 mg lIml
strength.
An angiogram might easily require 1000 mg lIkg of patient. If, say, a solution
of 350 mg lIml were utilized thus would be equivalent, in a 70 kg man, to:
1000 x 70/350 = 200 ml (= four bottles).
Such a dose might be considered by many as much as is prudent to give to most
patients, but there is no doubt that more is given on occasion in complex angiography. Naturally, there are some patients at greater absolute or relative risk small infants, frail elderly patients, patients with cardiac or renal disease, for
example - and doses have to be reduced in recognition of these. Working on the
basis of known toxicities we can reasonably suppose that whatever is taken as
the upper limit "allowed" in any given patient may be doubled, in terms of
iodine dose, if a nonionic rather than a conventional ionic agent is used. Digital
systems are helpful when available because they allow images to be obtained
with dilute CM, thereby reducing total dose.
7.4 Are There Any Guidelines for Maximum Doses in Cholegraphy?
7.3
Are There Any Guidelines for Maximum Doses
in Myelography?
1.0. SKALPE
Following the introduction of the nonionic CM iohexol (Omnipaque) for
myelography, complications which can be ascribed to the CM occur very rarely.
Nevertheless, one should keep the dose as low as possible for establishing the
diagnosis. We have never found it necessary to exceed a maximum dose of 3 g I
(10 ml CM at 300 mg lImI) and recommend this as a maximum dose in adults.
Children have a high tolerance for iohexol in myelography. One should bear
in mind that the spinal subarachnoid space is, relatively speaking, larger in
children than in adults. Therefore, in relation to body weight, higher doses are
necessary in children than in adults. We suggest the following guidelines for
maximum doses in children: below 1 year of age 5 ml CM at 180 mg lIml;
1- 4 years 5 ml CM at 240 mg lIml; 4 -12 years 8 ml CM at 240 mg lImI. Above
the age of 12 the same doses as in adults may be used.
7.4
Are There Any Guidelines for Maximum Doses
in Cholegraphy?
V. TAENZER
Biliary elimination of CM is limited by the functional capacity of hepatocytes.
In humans, the biliary transport maximum for the biliary CM, meglumine
iotroxate (Biliscopin), lies around 0.35 mg I min/kg. This implies that in cholegraphy, as opposed to urography, there is only a very limited dose range up to
the transport maximum and up to which dose increases will have the desired
effect of raising CM concentration in the bile. Further dose increases only lead
to heterotopic CM excretion via the kidneys. Adjusted to the biliary transport
maximum, an infusion dose of 50 -100 ml cholegraphic CM in a concentration
of 105 mg/ml (Biliscopin) has proved to be the maximum effective CM dose.
133
134
CHAPTER 7 Administration of Contrast Media
7.5
Can "Maximum" Doses Be Exceeded?
P.DAWSON
In considering dose-related CM toxicity it is important to realize that there are
two different aspects. Firstly, there is evidence that anaphylactoid reactions are,
to some extent, dose related [1]. It is true that they may occur following injection
of a very small dose, even subcutaneously, but, for the most part, appear to be
associated with injections of significant volumes intravascularly b]. Secondly,
there is the question of high dose toxicity [2]. As regards this, the problem is to
define "high dose" and, more difficult yet, to define "maximum permissible"
dose. Everything will clearly be patient-dependent and will be dependent on the
time period during which the total dose is to be given. Clearly, what would be
quite moderate doses for some patients might be disastrous for those with
impaired cardiac reserve and, equally clearly, while several hundred millilitres
of a CM might be acceptable if given in a complex interventional procedure over
a period of 2 or 3 h, this would not be acceptable if given by rapid intravenous
injection over a period of less than 1 min.
Some general guidelines may be given:
Those at risk from what might be described as contrast overdose in absolute
terms include small infants undergoing complex angiocardiographic procedures and otherwise healthy patients undergoing prolonged and complex interventional procedures [2]. Those at risk from what might be described as
relative CM overdose include patients with poor cardiac reserve and with poor
renal function [2]. Low osmolality agents in general, and nonionic agents in
particular, are to be preferred in any cases where absolute or relative CM overdose may be anticipated [2]. The use of these agents does not, however, guarantee total safety, but animal toxicity studies do appear to demonstrate that nonionic agents ought to offer a margin of safety in terms of total dose of some
three times.
No dogmatic statements can be made in this area but, if the procedure is
necessary and if the CM is used carefully in order to minimize the total dose,
then, in the context of the particular patient concerned, his general physical
condition and the urgency of diagnosis and/or interventional treatment of the
disease, some three times whatever maximum iodine dose is considered permissible with a conventional agent may be used in the form of a nonionic CM.
However, renal function is always a concern when high doses of CM are used
and the status of the nonionic agents in this regard has not been clearly
established. Caution is therefore necessary and monitoring of renal function
after a high dose procedure recommended.
7.6 Does the Injection Rate Affect the Tolerance?
References
Ansell G (1987) Radiological contrast media. In: Inman WHW (ed) Monitoring for drug
safety, 2nd ed. MTP Press, Lancashire, pp 337 - 348
2. Dawson P, Hemingway A (1987) Contrast doses in interventional radiology. J Intervent
Radiol 2: 145 -146
1.
7.6
Does the Injection Rate Affect the Tolerance?
P.DAWSON
If a drug is to be injected in large volumes and doses, as is often the case with
intravascular CM, then one naturally assumes that rapid injections would be
less well tolerated than slower injections. The report by Shehadi in 1975 [5] that
in his large series of intravascular CM administrations there was a lower
incidence of adverse effects in injections taking less than 2 min than in those
taking from 3 -10 min was, therefore, somewhat surprising. He found, incidentally, the reverse to be the case for intravenous cholangiography.
Davies et al. [2] observed, on the other hand, an increase in sensation of
warmth with rapid injections but otherwise no difference in the rate of side
effects in comparison with slower injection over 2 min or so.
Animal experiments involving the rapid injection of large doses of CM have
indicated a considerable increase in toxicity [1]. Whereas the LD SO % of sodium
diatrizoate by slow intravenous injection in the dog was 13.2 g/kg of
animal, with rapid injection the LD SO % dropped to 2.7 glkg of animal.
Pfister and Hutter [4] furthermore observed that the incidence of electrocardiographic changes during intravenous urography was related to the
rapidity of injection.
Lorenz has pointed out that drugs which cause histamine release (this
includes CM) are more likely to do so if given by more rapid bolus injection
than by slow infusion [3].
Therefore, notwithstanding Shehadi's interesting observation [5] made in the
context of an excellent and well-regarded large-scale study, the weight of clinical and experimental evidence appears to suggest that rapid injections are
less desirable than slower injections. Certainly, it would appear reasonable to
suggest that in the more susceptible older patients, or in those with known
cardiac disease, a slower injection would be safer where this is consistent with
diagnostic demands.
135
136
CHAPTER 7 Administration of Contrast Media
References
1.
2.
3.
4.
5.
Bernstein EF, Palmer JD, Aaberg TA, Davis RL (1961) Studies on the toxicology of Hypaque90% following rapid venous injection. Radiology 76 : 88 - 95
Davies P, Roberts MB, Roylance J (1975) Acute reactions to urographic contrast media. BMJ
2:434-437
Lorenz W, Doericke A (1985) Histamino liberation induite par les produits anesthesique ou
leurs solvants: specifique ou non-specifique. Ann Fr Anesth Reanim 4: 115 -123
Pfister RC, Hutter AM (1982) Alteration in heart rate and rhythm at urography with
sodium diatrizoate. Acta Radiologica 23 : 107 -110
Shehadi WM (1975) Adverse reactions to intravascularly administered contrast media. AJR
124:145-152
7.7
What Fluids Can be Recommended for Flushing Catheters?
P.DAWSON
Blood coming into contact with foreign surfaces such as catheters is activated
to clot with a consequent risk of thromboembolism if such a clot is reinjected
into the patient. Catheters must therefore be flushed frequently, and this is
perhaps the most important aspect of angiographic technique [3]. Any physiologically acceptable solution may be used to achieve this object - sterile water,
saline, heparinized saline, or CM, for example. In the past CM themselves,
because of their known anticoagulant effects, were sometimes recommended as
flushing solutions [4]. This area has become confused recently, and the confidence of angiographers somewhat eroded, by controversy surrounding the
haematological properties of nonionic CM [2,3,6]. Suggestions have been made
that these agents are in some way procoagulant. There is in fact no basis for this
assertion and all the evidence points to the fact that they are, like their ionic
counterparts, entirely anticoagulant in effect [1]. They are simply less anticoagulant than the ionic agents and therefore not as effective in this role. This
point having been made, however, there is no positive reason why they should
not be used as flushing solutions.
Most angiographers use heparinized saline with heparin concentrations
apparently ranging in different centres from 1 to 10 IV/ml [5]. No study appears
to exist to support the use of heparinization in this way, though it does not, of
course, appear at all unreasonable. Many authorities would recommend the
systemic heparinization of the patient for angioplasty procedures but there is
no consensus on this either [5], except perhaps in the context of coronary
angioplasty, and no controlled study has been carried out to demonstrate its
efficacy.
It has been shown that, at least with multiple side hole and end hole
catheters, the pressure of the flush is as important as the nature of the flushing
7.8 Are Contrast Media Dialysable?
solution. Low pressure flushes the side holes, and indeed sometimes only the
more proximal side holes, and higher pressure is needed to flush the end hole
and prevent clot formation here [3].
It is the author's belief that frequent and vigorous flushing is far more
important than the precise nature of the flushing solution and is the critical
point of good angiographic technique [3].
References
1. Dawson P et al. (1986) Contrast, coagulation and fibrinolysis. Invest Radiol 21 : 248 - 252
2. Dawson P (1988) Non-ionic contrast agents and coagulation. Invest Radiol 23: 310 - 317
3. Dawson P, Strickland NS (1991) Thromboembolic phenomena in clinical angiography: role
of materials and technique. JVIR (in press)
4. Hawkins IF, Herbeth (1974) Contrast material used as a catheter flushing agent: a method
to reduce clot formation during angiography. Radiology 110 : 351- 352
5. Miller DL (1989) Heparin in angiography: current patterns of use. Radiology
172 :1007 -1011
6. Robertson HJF (1987) Blood clot formation in angiographic syringes containing non-ionic
contrast media. Radiology 162: 621- 622
7.8
Are Contrast Media Dialysable?
J. E. SCHERBERICH
Contrast media are readily dialysable depending on their protein binding, their
molecular weight (size of the molecule) and their spatial distribution
(redistribution from organs). The molecular weights of non-ionic monomers
are around 800 Dalton, e. g. iopamidol 777> iopromide 791 and iohexol 821 Dalton, while those of ionic dimers such as ioxaglate, for example, are around
1268 Dalton. The plasma clearance of most modern contrast media lies between
50 and 70 mllmin. Dialysance lies between 90 and 130 mllmin, e. g. for iomeprol
132 mllmin (plasma clearance about 60 mllmin), and remains virtually constant
over the entire period of dialysis [1]. More than 80 % of the contrast material is
removed from the plasma pool after 4-5 hours. Non-ionic monomers (e.g.
iohexol) are eliminated more quickly than ionic dimers (e.g. ioxaglate) [2].
These data relate to a blood flow of at least 200 mllmin and a dialysate flow of
500 mllmin using a high-flux dialyser. No additional dialysis treatment is
required in chronic dialysis patients after CM administration if thyrostatic
premedication is given prophylactically. Immediate haemodialysis treatment
after CM administration does not appear to offer any advantages [3, 4]. In the
case of elective diagnostic procedures, however, the appointment for the CM
examination can, if possible, be chosen immediately before the next scheduled
137
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CHAPTER 7 Administration of Contrast Media
dialysis session. No significant changes of various parameters (including blood
pressure, blood osmolality, blood volume, total protein content) were observed
after administration of 40-225 ml of a non-ionic CM to 10 dialysis patients [3].
Previously, however, the development of pulmonary oedema up to 4- 6 hours
after injection of ionic high-osmolar contrast media as well as hypertensive
crises, hyperkalaemia and cardiac arrhythmias were not infrequent phenomena. Sialadenitis was a rare observation. Intercurrent dialysis is indicated
to maintain diuresis after larger amounts of CM (> 150 ml) in non-dialysis
renal failure patients with a creatinine clearance rate of 20 - 40 mllmin in order
to prevent decline of remaining renal function. However, even more severe
preterminal renal failure does not appear to be exacerbated any further by
non-ionic CM [5].
References
1. Ueda J Furukawa T, Higashino K et al. (1996) Elimination of Iomeprol by hemodialysis. Eur
J Radiol 23: 197 - 200
2. Furukawa T, Ueda J, Takahashi S, Sakaguchi K (1996) Elimination of low osmolality contrast-media by hemodialysis. Acta Radiol37: 966 - 971
3. Younathan CM, Kaude JV, Cook MD, Shaw GS, Peterson JC (1994) Dialysis is not indicated
immediately after administration of non ionic contrast agents in patients with end-stage
renal disease treated by maintenance dialysis. Am J Roentgenol163: 969 - 971
4. Huhn HW, Tiinnis HJ, Schmidt E (1993) Elimination von Riintgenkontrasmitteln durch
Haemodialyse. Nieren-u Hochdruckkrankh 22: 45 - 52
5. Jakobsen JA (1995) Renal effects of iodixanol in healthy volunteers and patients with severe
renal failure. Acta radiol (Suppl. 399): 191-195
7.9
What are the Sequelae of Inadvertent Paravascular
Administration of Iodinated Contrast Media?
W.CLAUSS
Extravasation is a not infrequent event with intravenous administration of
iodnated contrast media (CM). The incidence varies depending on the method
of radiological examination used. Most cases involve only small volumes
« 10 ml), which are quickly absorbed from the connective tissue and are of no
clinical significance.
With the previously usual administration of undiluted, hyperosmolar ionic
CM for ascending phlebography, however, local signs of intolerance such as
pain, phlebitis and, in some cases, also blisters and necrosis of the skin and
subcutis were a more frequent occurrence. Skin grafts and permanent damage
such as restricted freedom of movement, pain and weakness in the limb in-
7.9 What are the Sequelae of Inadvertent Paravascular Administration
volved have been described in some cases. Oedema in the extremities, the
absence of fluoroscopic control of the puncture site and the use of rigid injection needles often made exact intravenous injection and drainage of the
contrast medium difficult. Nowadays, either dilute ionic CM or the locally even
better tolerated low-osmolar non-ionic CM are administered under fluoroscopic control and via plastic canulas and Teflon catheters, and this has led to a
reduction of both the number and the size of extravasations and to a distinct
reduction of local reactions on phlebography of the extremities.
With the introduction of rapid bolus administration for computerised tomography using automatic injectors, extravasations are again on the increase. Difficulties in monitoring the injection site, the high rate of administration and the
fact that the patient often reports sensations of tension and pain too late or not
at all can all lead to the escape of larger amounts of contrast medium or of the
entire bolus. The perivascular injection even of largish amounts of non-ionic
CM (100 to 150 ml) is generally well tolerated, and the depot subsides spontaneously within 1 to 3 days (1,2).
Reports of severe local reactions such as blistering, necrosis of the skin and
sensory and motor disturbances of the limb involved are extremely rare [2,3,4,
5] and the patients have responded to symptomatic therapy without any adverse
sequelae. The need for surgical intervention (fasciotomy) to relieve the
compression caused by the escape of contrast medium and avoid sequelae is
limited to isolated cases [4, 5].
There is no generally accepted procedure for dealing with extravasation.
Attempts to remove the contrast medium by aspiration via the in-situ cannula
have not been very successful. Diluting the perivascular depots of hyperosmolar ionic CM locally by injecting physiological saline solution or sterile
water has also been tried, but has not been taken up generally because of the
large volumes required.
The general recommendation is to elevate the affected limb in order to
reduce the hydrostatic pressure in the capillaries and, consequently, to facilitate
absorption of the contrast medium [6].
Cooling of the affected skin region to induce vasoconstriction is also recommended with the aim of alleviating local pain and preventing the further spread
of damage to the skin and subcutaneous tissues [7].
The enzyme hyaluronidase (15 to 200 U) is applied topically with the aim of
enlarging the distribution space for the contrast extravasation and, hence, of
speeding up absorption [8]. There are only isolated reports of success using this
treatment, which cannot be definitively assessed because of the lack of
systematic studies. Similarly, there is no definitive proof of the benefit of
topically applied corticosteroids to inhibit inflammation.
The aim of surgical intervention is to drain the tissue area involved. It is
reported to provide good functional results and to prevent the development
of skin necrosis if performed within the first 6 hours after massive extravasation [9].
A "State of the Art" publication on recognition, prevention, and treatment of
extravasation was issued by Cohan et al [10] in 1996.
139
140
CHAPTER 7 Administration of Contrast Media
References
1. Cohan RH, Dunnick NR, Leder RA, Baker ME (1990) Extravasation of nonionic radiologic contrast media: efficacy of conservative treatment. Radiology 174: 65 - 67
2. Miles SG, Rasmussen JF, Litwiller T (1990) Safe use of an intravenous power injector for
CT: experience and protocol. Radiology 176 : 69 -70
3. Pond GD, Dorr RT, McAleese KA (1992) Skin ulceration from extravasation of lowosmolality contrast medium: a complication of automation. AJR 158 : 915 - 916
4. Young RA (1994) Injury due to extravasation of nonionic contrast material (letter). AJR
162: 1499
5. Memolo M, Dyer R, Zagoria RJ (1993) Extravasation injury with nonionic contrast
material. AJR 160 : 203
6. Yucha CB, Hastings-Tolsma M, Szeverenyi M (1994) Effect of elevation on intravenous
extravasations. J Intraven Nurs 17: 231- 234
7. Elam EA, Dorr RT, Lagel KE, Pond GD (1991) Cutaneous ulceration due to contrast extra-
vasation: experimental assessment of injury and potential antidotes. Invest Radiol
26: 13-16
8. Few BJ (1987) Hyaluronidase for treating intravenous extravasations. Am J Matern Child
Nurs 12:87
9. Loth TS, Jones DEC (1988) Extravasations of radiographic contrast material in the upper
extremity. J Hand Surg [Am] 13 : 395 - 398
10. Cohan RH, Ellis JH, Garner WL (1996) Extravasation of radiographic contrast material:
recognition, prevention, and treatment. Radiology 200 : 593 - 604
CHAPTER
8
Adverse Reactions and Their Pathophysiology
and Management
8.1
What Adverse Reactions Can be Expected
After Intravascular Administration
of Iodine-Containing Contrast Media?
R.G. GRAINGER
The ideal radiological contrast medium (RCM) should produce no adverse
reaction (AR) and the patient should be unaware that he has received an injection, either intravenous or intraarterial. No RCM yet developed has achieved
this ideal performance but with the low osmolar contrast media (LOCM) major
gains have been made in this respect for both intravenous and intraarterial
injection.
AR may be due to the hyperosmolality of the CM and are therefore concentration, volume and dose dependent, or they may be of unknown cause generally described as anaphylactoid because of a similarity to true anaphylactic reactions. These anaphylactoid reactions are neither clearly osmolality nor
dose - dependent and deaths have been recorded with test doses as small as 1 ml.
The time of onset of AR may be immediately during the injection but are
usually delayed a few minutes. About 60 % of early reactions begin within 5 min
of the injection; another 30 % begin within the next 10 - 20 min. The patient
must therefore not be left unobserved, at least during this period.
Intravenous Injection
There is no general consensus as to what should be regarded as an AR. For
example, a hot flush is a physiological consequence of the injection of a large
volume of very high osmolar fluid, i. e. 50 -100 ml high osmolar contrast media
(HOCM) at 300 mg IIml concentration, which has five times the physiological
osmolality.
142
CHAPTER 8
Adverse Reactions and Their Pathophysiology and Management
These AR to intravenous injections are, however, not entirely dependent on
osmolality, as ioxaglate (which has the lowest osmolality of current LOCM but
which is ionic) produces more AR on intravenous injection than the nonionic
LOCM, but fewer AR than ionic HOCM. It may well be that ionicity as well as
osmolality is a factor in the production of AR (particularly nausea, vomiting,
minor skin reactions) on intravenous injection.
Minor Reactions
The more frequent minor AR to RCM are, in descending order of frequency,
1.
2.
3.
4.
5.
6.
Hot flush especially affecting the face, neck, external genitalia.
Pruritis, minor hives or urticaria.
Nausea, vomiting, disordered taste, sneezing.
A general feeling of anxiety by the patient.
Coughing and dyspnoea.
Pain at the injection site sometimes projected proximally along the vein.
The incidence of these minor sensations is much more frequent (up to
10%-20%) with HOCM than with LOCM (2%-4%), depending on the concentration, volume, hypertonicity of the RCM, patient reactivity and anxiety,
and whether a hot flush is regarded as an AR.
Many intravenous injections of LOCM cause no discomfort or AR and the
patient may be unaware that an injection is being made.
Intermediate AR
Intermediate AR are more serious degrees of the symptoms mentioned above,
especially urticaria, vomiting, dyspnoea and anxiety.
Bronchospasm with increasing dyspnoea and moderate hypotension may
occur and the patient may feel apprehensive and anxious. The incidence of
these intermediate reactions is about 0.5 % -1.0 % for HOCM and probably onefourth of this incidence for LOCM.
Severe AR
Severe AR are usually severe manifestations of the above-mentioned minor and
intermediate reactions, especially dyspnoea, bronchospasm, hypotension, severe
apprehension sometimes accompanied by uncontrolled restlessness, angioneurotic oedema of the glottis, one or more grand mal convulsions and disturbed
consciousness. Bronchospasm may become severe and the airway may be threatened by severe laryngeal and neck oedema. Cardiovascular collapse may develop suddenly with pulmonary oedema, severe hypotension, shock with diminished cardiac venous return, cardiac arrhythmias and possibly cardiac arrest.
Full emergency cardiorespiratory resuscitation is imperative, demanding
well-organized and rehearsed procedures with immediate access to a crash
trolley complete with DC defibrillator and competent medical assistance, including an experienced anaesthetist. The incidence of these severe reactions is
up to 0.2 % for HOCM injections and up to 0.04 % for LOCM injections.
8.1 What Adverse Reactions Can be Expected After Intravascular Administration
Death
In a few patients the severe AR may become extreme and may not respond even
to the most energetic, expert and immediate resuscitation. The most common
causes of death are cardiorespiratory collapse, pulmonary oedema, deepening
coma, intractable bronchospasm and airway obstruction.
In a very few patients, sudden death may occur shortly after the injection,
presumably from cardiovascular shock and arrhythmia but without prodromal
symptoms.
The mortality rate from intravenous RCM injections is not known with any
degree of precision and retrospective analyses of large series provide mortality
rates ranging from 1 in 15,000 to 1 in 170,000 intravenous injections of HOCM.
A mortality range of 1 in 40,000 to 1 in 80,000 is likely. It is uncertain whether
this rate will be significantly reduced with LOCM injections, but it seems likely
that the mortality rate may be reduced by a factor of two or more with injection
of these newer and more sophisticated products.
Intra-arterial Injections
All of the above AR may occur following intra-arterial injection. The incidence
is lower by perhaps a factor of two or three, compared with intravenous injection of the same product.
Peripheral arterial injection (carotid, vertebral or limb arteries) of RCM at
osmolalities above 600 mOsm/kg water invariably causes a hot flush sometimes
with severe pain in the injected arterial territory. This feature is definitely
osmolar dependent and is greatly reduced in frequency and in severity when
diluted HOCM (for digital imaging) or LOCM are injected. Injections of RCM
into the aorta may cause substantial flushing, pain in the distal territory,
headache, vasodilatation and hypotension which are much more frequent and
severe with HOCM than with LOCM injections. Pulmonary artery injections
may cause coughing, chest discomfort and dyspnoea, again more severe with
HOCM injections. Visceral injections either with HOCM or LOCM do not
usually cause discomfort.
It is important that the patient be forewarned of any likely discomfort following RCM injection and he should be reassured that the symptoms, although
uncomfortable, are usually transient and rarely require treatment.
Factors Predisposing to Adverse Reactions
A previous AR to RCM is the most important predisposing factor and increases
the risk of a severe AR to a second similar injection by about 6 -10 times the
usual rate. History of asthma or bronchospasm is also an important predisposing factor, increasing the AR rate by about 5 -10 times. Other predisposing
factors are a history of allergy or atopy, heart disease, renal disease, diabetes
mellitus, anxiety, dehydration, phaeochromocytoma, and sickle cell anaemia.
143
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CHAPTER
8 Adverse Reactions and Their Pathophysiology and Management
Most of the above predisposing factors probably predispose to AR to a subsequent injection of either HOCM or LOCM, but the frequency of AR to LOCM
is possibly up to 10 times less than to HOCM. Nonionic LOCM should always be
preferred to HOCM when the patient has any factor which makes AR more
likely to develop.
An even more important consideration is for the medical team to attempt to
avoid any injection of RCM in these patients if there are any alternative
diagnostic procedures they might employ (e.g. MRI or Ultrasound) which
could provide the required information.
8.2
Do Late-Occurring Adverse Reaction to Contrast Media
Necessitate Longer Supervision of the Patient?
[see also 8.5,8.6,8.7]
P. DAVIES
Definition of Delayed (Late-Occurring) Adverse Reactions
Delayed reactions have been defined as those that occur after the patient has
left the department [3]. The time spent in the department after the injection is
rather variable. Further, there are several types of delayed reactions:
venous problems thrombosis and skin necrosis,
rashes;
3. a "flu-like syndrome";
4. parotitis;
5. cardiac syndromes worsening of heart failure and cardiac arrest.
1.
2.
Time of Onset of Acute Reactions
Acute reactions are clearly those that occur while the patient is under observation in the department. Acute deaths and severe life-threatening reactions with
ionic (high osmolar) agents occur early, most within 15 min, but about 10%
occur after this time and some later than 60 min [1].
About two-thirds of such reactions occur within 5 min of injection [1] so that
observation of the patient is most important early on. It is the author's practice
when performing a urography to stay in the examination room talking to the
patient until asked by the radiographer to inspect the 5-min film (about 7 min)
which makes a natural break. After a brief inspection to check on the compression band (if used) further observation is left to the radiographers.
Some patients may suffer a cardiac arrest. This is an event which may occur
at any time. The difficulty in such cases is to determine whether it could truly
8.2 Do Late-Occurring Adverse Reaction to Contrast Media Necessitate
be attributed to the injection and some cases have been reported before an
injection was made [4].
Are Delayed Reactions Serious or Fatal?
In none of the studies from Nottingham were delayed deaths reported and the
author is not aware of any studies indicating that delayed life-threatening
reactions occur.
In the Bristol study [2] the most important serious reaction was worsening
or onset of heart failure in patients recovering from heart attacks. It has been
noted that deaths in patients suffering from cardiac disease tend to be delayed
beyond 5 min; after an hour it is difficult to be sure the death is due to the contrast medium [4].
Some patients suffer a constitutional illness which they certainly regard as
serious enough to confine them to bed.
With high-osmolar agents, late skin necrosis requiring skin grafting occurred sometimes after extravasation of CM beneath the skin, although usually
there are no sequelae. Unlike acute rashes, the delayed rashes appear to be
reproducible on challenge but no large study has been done to test this observation. When it recurs the rash is the same as it was on the previous occasion.
Acute rashes do not predict delayed rashes and in any case only affect one-third
of cases on challenge [5].
Heart failure may be avoided by not examining patients who have suffered a
myocardial infarction until they are fully recovered from the cardiovascular
instability. Previous heart disease was not found to be a risk factor in the Nottingham study [2].
Do Late Reactions Occur More or Less Frequently
with Non-ionic Agents?
The null hypothesis is that there is no difference in the frequency of late
reactions between ionic and non-ionic media and this must be disproved in
order to demonstrate greater safety of one or the other.
Venous problems are certainly lessened by the use of low osmolar agents but
about 10 % of patients report arm pain after an injection of a low osmolar
medium [2].
Heart failure should be less frequent because of the lowered osmolality but
no study has shown this and some cardiac problems occur when no injection
has been made [3].
There is less pain after extravasation and so skin necrosis should occur less
frequently.
Rashes and parotitis were reported by McCullough, Davies and Richardson
[2] to be more common with a non-ionic agent. This seemed inherently unlikely and when more cases had been studied the combined results (reported by
Davies at the ICR Paris [4]) showed that there was no statistically significant
145
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CHAPTER 8 Adverse Reactions and Their Pathophysiology and Management
difference in the incidence or rashes between the two groups of CM. Parotitis
may, however, be more common with low osmolar media. Thus some reactions
are reduced, others have the same incidence for the two groups of CM and very
large numbers in controlled trials are required to answer the more interesting
questions [2].
One relatively recent issue should be raised here. There is some evidence that
skin reactions, some particularly severe, may be more common with the
non-ionic dimers than with other agents, ionic or non-ionic (see also 8.5).
References
1.
Davies P, Roberts MB, Roylance J (1975) Acute reactions to urographic contrast media. BMJ
1: 434-437
2. McCullough M, Davies P, Richardson RE (1989) A large trial of intravenous Conray 325 and
Niopam 300 to assess immediate and delayed reactions. Br J Radiol 62: 260 - 265
3. Pendergrass HP, Tondreau RL, Pendergrass EP, Ritchie DJ, Hildreth EA, Askovitz 51 (1958)
Reactions associated with intravenous urography: historical and statistical review. Radiology 71: 1-12
4. Davies P (1989) Abstract of the International Congress of Radiology, Paris. Abstract 2173,
p 344
5. Wofram R, Dehouve A, Degand F, Wattez E, Lange R, Crehalet A (1965) Les accidents
graves par injection intraveineuse de substances iodees pour urography. J Electrologie 47:
346-357
8.3
What Adverse Reactions to Contrast Media
Are Dose Independent or Dependent?
H.KATAYAMA
Adverse reactions can be divided into two categories: physicochemotoxic and
idiosyncratic reactions [3]. The physicochemical reactions are directly related
to dose and are primarily due to the hypertonicity and viscosity of the CM.
Idiosyncratic reactions are not considered to be dose related and can occur
with so-called small doses of 1 ml or less of CM. Clinical symptoms are shown
in Table 8.3.1.
It has been claimed that the incidence of reactions with infusion pyelography
is no greater or less than that with conventional pyelography. The results from
Ansell's survey do not support this claim. The incidence of reactions appears to
be at least three times greater with infusion pyelography. According to Ansell,
taking a dividing line at 20 g of iodine, there were fewer cases of severe reactions below this level. Most of them were in patients with a history of cardiac
disease or allergy.
8.3 What Adverse Reactions to Contrast Media Are Dose Independent or Dependent?
Table 8.3.1.
Clinical symptoms of
adverse reactions to CM
Physicochemotoxic reaction
(dose related)
Idiosyncratic reaction
(not dose related)
Heat sensation
Life-threatening or fatal
reaction
Severe hypotension
Loss of consciousness
Convulsion
Pulmonary oedema
Urticaria
Larnygeal oedema
Bronchospasm
Cardiac arrest
Vascular pain
Hypervolemia
Endothelial injury
Erythrocyte damage
Decreased renal function
Arrythmia
Paralysi and convulsion
Coagulation deficit
Table 8.3.2. Prevalence of adverse drug reactions by dose (from [4])
Dose (ml)
<20
21-40
41-60
61-80
81-100
> 101
No entry
Cases with ionic CM
Case with nonionic CM
Total (n)
ADR
(n) (%)
Total (n)
ADR
(n) (%)
4139
17286
11135
3684
103231
29488
321
916 (22,13)
3235(18,71)
I 824 (16,38)
736 (19,98)
11681 (11,32)
2920 (9,90)
8401
13585
7940
4994
120792
12344
307
334(3,98)
652(4,80)
411 (5,18)
247 (4,95)
3024 (2,50)
564 (4,57)
ADR, adverse drug reactions.
However, according to Katayama's survey [4], for ionic CM the prevalence of
adverse reactions was lower in the subgroup receiving more than 80 ml; for
nonionic CM, the prevalence was lowest in the subgroup receiving 81-100 ml
(Table 8.3.2). There is general agreement that there are dose-related or
-dependent adverse reactions, but injection rates are factors which clearly bear
on the incidence of adverse reactions. Dose of contrast media and rate of
injection should be considered together.
References
1. Ansell G et a1. (1980) The current status of reactions to Lv. CM. Invest Radiol [Suppl]:
32 -39
2. Ansell G (1970) Adverse reactions to CA. Invest Radiol 6: 374 - 384
147
148
CHAPTER 8 Adverse Reactions and Their Pathophysiology and Management
3. Committee on Drugs of the American College of Radiology (1977) Prevention and
management of adverse reactions to intravascular contrast media. American College of
Radiology, Chicago, pp 1- 3
4. Katayama H et aI. (1990) Adverse reaction to ionic and non-ionic CM. Radiology
175: 621- 628
8.4
What Are the Mediators of Anaphylactoid Reactions
to Iodinated Contrast Media?
P.DAWSON
The mechanisms of major anaphylactoid reactions to iodinated CM remain
unclear. The consensus emerging is that classical anaphylaxis involving IgE
antibodies is not involved, though see also 8.7 and 8.8.
CM are known to be capable of activation of the complement system, though
by which pathway is uncertain. The role of this in major reactions is certainly
not established and in some studies appears to occur rather routinely both in
vitro and in vivo.
Histamine has long been considered the major mediator in CM major
reactions. It can be released from mast cells by direct, nonimmunological
mechanisms. CM are certainly capable of this but the problem is that such
release of histamine can be found, once again, routinely in patients receiving
contrast and often not at significantly higher levels in patients experiencing
major reactions. However, it is difficult to dismiss the idea of a role for histamine since it is capable of producing at least four of the major abnormalities
which characterize severe reactions, namely bronchospasm, oedema, urticaria
and hypotension.
Bradykinin may elicit the same responses as histamine but is considerably
more potent on a molar basis than is histamine. Elevation of plasma bradykinin
levels has been noted following CM injection clinically. The production of
bradykinin involves a complex sequence of proteolytic events beginning with
the activation of factor XII, which is, incidentally, the initiating part of the
coagulation/contact system. This initiation may take place because of endothelial injury by CM (more marked with high osmolality agents) or, perhaps, by
direct contact activation by the agents themselves.
Another intriguing fact concerning bradykinin is that it can also produce
mobilization of arachidonic acid and thus provide the basis for the production
of leucotrienes and prostaglandins. These are, indeed, widely held to play at
least some role in anaphylactic and anaphylactoid reactions generally.
One clinical study in the context of intravenous injections demonstrated no
significant increase in the levels of leucotrienes C4 but other studies, with a
variety of CM, have demonstrated significant increases in PGI2 thromboxane
8.5 How Often Can Late Reactions be Expected after Administration of Radiographic
Az, but no change in thromboxane Bz. These observations certainly suggest that
some CM are capable of stimulating vascular endothelium, and perhaps white
cells, to release prostacyclin.
It must be stressed that too little work has been done in this area because of
its difficulty and that the individual and joint roles of various mediators cannot
yet be dogmatically stated.
8.5
How Often Can Late Reactions be Expected
after Administration of Radiographic Contrast Media?
(see also chapter 8.2)
K. BROCKOW and J. RING
Late reactions to radiographic contrast media (RCM) are defined by the
majority of authors as adverse reactions occurring one hour or more after infusion of RCM [1]. Others broaden this definition to reactions occurring after
two hours or after the patient has left the department. Due to a lack of standardisation and differences in study design, clinical classification, and observation
periods, the incidences in different studies vary widely between 0.4 % and 39 %.
Most of the studies were conducted prospectively and rely only on the results of
questionnaires. The more reliable studies indicate that the incidence of late
reactions to RCM may lie in the range of 5% [1-4]. There seems to be no
significant difference in the incidence of late adverse reactions to ionic and
non-ionic RCM; only local pain is reported to occur more often after usage of
ionic (14.5 % vs. 10.5 %) and skin rash more often after application of lowosmolar non-ionic RCM (5.5% vs. 2.9%) [5]. There is evidence that the new
isotonic dimeric RCM, Iotrolan (Isovist®) and Iodixanol (Visipaque®), are
associated with a higher risk of inducing late reactions in comparison to monomeric RCM. This resulted in the withdrawal of Isovist-280 for intravenous use
from the market. The majority of these reactions are allergy-like skin reactions,
which occur more frequently probably by a factor of two as compared to monomers [3]. The reasons for these differences and the underlying pathophysiology
are presently under investigation.
References
Brockow K, Ring J (1997) Anaphylaktoide Reaktionen nach Infusion mit Riintgenkontrastmitteln. Allergologie 20 : 400 - 406
2. Beyer-Enke SA, Zeitler E (1993) Late adverse reactions to non-ionic contrast media: a
cohort analytic study. Eur Radiol 3: 237 - 241
1.
149
150
CHAPTER 8 Adverse Reactions and Their Pathophysiology and Management
3. Delayed allergy-like reactions to X-ray contrast media (May 1996). Second expert meeting
on mechanism, Wiesbaden, European Radiology 6 (5): insert
4. McCullough M, Davies P, Richardson R (1989) A large trial of intravenous Conray 325 and
Niopam 300 to assess immediate and delayed reactions. Br J Radiol 62: 260 - 265
5. Yoshikawa H (1992) Late adverse reactions to non-ionic contrast media. Radiol
183: 737 -740
8.6
What are the Clinical Manifestations of Late Reactions
to Radiographic Contrast Media?
(see also chapter 8.2)
K. BROCKOW and J. RING
Exanthematic skin eruptions (pruritic urticarial or maculopapular exanthema), urticaria, angioedema, persisting pain at, or proximal to, the injection
site, gastrointestinal complaints with nausea, abdominal pain or vomiting and
flu-like symptoms with headache, arthralgia, fever, shivering and fatigue are the
clinical symptoms described most often in the literature [1]. The incidence of
late reactions is 0-4 - 9.3 % for rash and other skin manifestations, 0.04 - 2.7 %
for pruritus, 0.05-6.8% for gastrointestinal symptoms, 0.9-14.7% for flu-like
symptoms and up to 13 % for persisting pain at, or proximal to, the injection
site. A symptom complex with appetite loss, nausea, headache, abdominal pain,
constipation, diarrhoea, productive cough, parotitis and taste disturbance has
earlier been termed "iodism". However, because no relationship to the plasma
iodine concentration was demonstrated, this term is no longer justified. The
majority of symptoms of late reactions to RCM are mild. Severe reactions are
reported extremely rarely. They occur predominantly in patients with preexisting cardiac or renal diseases. Clinically, they may present with dyspnoea,
laryngeal oedema and anaphylactoid shock. Fatalities have also been reported
to occur after use of RCM, which were manifest in the form of acute vasculitis
or toxic epidermal necrolysis [2,3]. Symptoms related to acute renal failure may
also be observed only hours to days after the administration of contrast agents.
This subject is treated in a separate chapter.
References
Brockow K, Ring J (1997) Anaphylaktoide Reaktionen nach Infusion mit Rontgenkontrastmitteln. Allergologie 20 : 400 - 406
2. Goodfellow T, Holdstock GE, Brunton FJ, Bamforth J (1986) Fatal acute vasculitis after
high-dose urography with iohexol. Brit J Radiol 59 : 620 - 621
3. Kaftory JK, Abraham Z, Gilhar A (1988) Toxic epidermal necrolysis after excretory pyelography. Int J Dermatol 27: 346 - 347
1.
8.8 Are Antibodies to Radiographic Contrast Media Known?
8.7
What is the Pathophysiology of Late Reactions
to Radiographic Contrast Media?
(see also chapter 8.2)
K. BROCKOW and J. RING
Whereas the pathophysiology of immediate reactions to RCM is considered to
be pseudo-allergic, there is evidence that late reactions could be truly allergic in
nature [1]. We found skin reactions after 48 to 96 hours with both intracutaneous and patch tests in patients who developed late maculopapular skin
eruptions after use of RCM [2]. This finding was also confirmed by others, who
demonstrated positive skin prick and intracutaneous tests in patients with late
reactions to RCM [3]. The dermatohistology of the late reaction shows a perivascular lymphocytic infiltrate without epidermal involvement. Together with
the clinical symptoms of maculopapular or urticarial skin eruptions and the
course of the reactions, these findings indicate that either cellular (type IV)
hypersensitivity or a late phase reaction might playa role [4]. However, more
studies of the pathophysiology of late reactions to RCM are needed in order to
answer this question definitively.
References
1. Ring J (1991) Angewandte Allergologie. MMV Medizin, Munich
2. Brockow K, Ring J (1997) Anaphylaktoide Reaktionen nach Infusion mit Rontgenkontrastmitte1n. Allergologie 20: 400 - 406
.
3. Kanzaki T, Sakagami H (1991) Late-phase allergic reaction to a CT contrast medium
(Iotrolan). J Dermatol18 : 528 - 531
4. Ring J, Brockow K (1996) Mechanisms of pseudo-allergic reactions due to radiographic
contrast media. ACI International 8 (4) : 123 -125
8.8
Are Antibodies to Radiographic Contrast Media Known?
R.C. BRASCH
Allergy is one of the mechanisms proposed for CM toxicity. This theory incorporates the assumption that antibodies reactive with CM molecules exist in
humans either as naturally occurring antibodies or as antibodies induced by
prior exposure to CM itself or by exposure to structurally similar molecules. It
is possible and precedented for atopic individuals to produce antibodies,
induced by one chemical, that crossreact with another chemical; for example,
151
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CHAPTER 8 Adverse Reactions and Their Pathophysiology and Management
antibodies induced by penicillin may also produce an allergic reaction to
cephalosporins.
There can be little doubt that antibodies reactive to CM exist in humans.
Harboe et al. in 1976 observed sudden death in a patient caused by interaction
between an IgM antibody and ioglycamide [3]. In this startling case the antibody was a paraprotein, present in very high concentration, and upon injection
of the CM a gelatinous precipitate formed in the antecubital vein, right heart
and pulmonary vessels. Subsequently, Bauer reported on the extensive immunological characterization of this anti-CM antibody [1].
Additional patients suffering severe CM reactions with demonstration of antibody activity towards the offending agent were reported by Kleinknecht et al. [4]
(iothalamate induction of dyspnoea, bronchospasm, pulmonary oedema, and
renal failure) and by Wakkers-Garritsen and co-workers [5] (dyspnoea, circulatory
collapse, and unconsciousness). Adding to the evidence for existence of antibodies
to CM is the report from our laboratory showing that antibody binding activity
(Farr radioimmunoassay system) in the sera from 27 reacting patients was significantly elevated as compared to assay results from nonreacting control patients [2].
For the present, critical unanswered questions are
1.
2.
what proportion of all patients suffering severe CM reactions have anti-CM
antibodies, and
what is the optimal assay system to detect these potentially reacting patients?
References
1.
2.
3.
4.
5.
Bauer K (1978) Antigen-antibody like reaction of ioglycamide with an IgM paraprotein in
vivo and in vitro. In: Zeitler E (Hrsg) Neue Aspekte des Kontrastmittel-Zwischenfalls.
Schering, Berlin, pp 71-78
Brasch RC, Caldwell JL (1976) The allergic theory of radiocontrast agent toxicity:
demonstration of antibody activity in sera of patients suffering major radiocontrast agent
reactions. Invest Radiol11 :347 - 356
Harboe M, Folling I, Haugen OA, Bauer K (1976) Sudden death caused by interaction
between a macroglobulin and a divalent drug. Lancet 79/80: 285 - 288
Kleinknecht D, Deloux J, Homberg JC (1974) Acute renal failure after intravenous urography: detection of antibodies against contrast media: Clin Nephrol 2: 116
Wakkers-Garritsen BG, Houwerziji J, Nater JP, Wakkers PJM (1976) IgE-mediated adverse
reactivity to a radiographic contrast medium-case report. Ann Allergy 36 : 122
8.9
Are There Allergies to Contrast Media?
R.C. BRASCH
A considerable body of evidence has been accumulated indicating that certain
patients suffer immediate antibody-mediated adverse drug reactions (ADR) to
iodinated CM. ADRs clinically resemble known allergic symptoms, including
8.10 Can Sensitization Due to Frequent Contrast Media Administration Be Observed?
urticaria, bronchospasm, laryngeal oedema, facial swelling and circulatory
collapse. Virtually every large epidemiological study has shown an unusually
high incidence of CM reactions among allergic individuals, particularly
asthmatics. Further supporting the allergic hypothesis is the fact that antibodies (IgG and IgE) have been successfully induced in rabbits [2] and guinea
pigs [1] using CM bound to carrier proteins. Further, the degree of spontaneous
protein binding observed with different CM correlates directly with the rate of
ADRs. Guinea pigs, in which anti-CM antibodies have been induced, have been
shown to suffer anaphylactic death when challenged with iodinated CM [1]. In
Sect. 8.8 specific case histories were described of patients with severe reactions
in whom specific anti-CM antibodies were demonstrated. These antibodies may
occur naturally (without prior exposure to the specific allergen) or may be
induced by exposure to CM themselves or to structurally similar molecules. We
have all had contact with halogenated benzene rings (like CM) and such
exposure in atopic individuals may induce antibody formation.
Current scientific challenges include the development of highly sensitive and
specific immunoassays for anti-CM antibodies. These may permit identification
of the allergic individual prior to exposure or may indicate which of several CM
could be administered safely without antibody reactivity. Not all ADRs to CM
need to be on an allergic basis; differing mechanisms may be operative in different patients.
References
Brasch RC (1980) Evidence supporting an antibody mediation of contrast media reactions.
Invest Radiol1S [Suppl]: S29-S31
2. Brasch RC, Caldwell IL, Fudenberg HH (1976) Antibodies to radiographic contrast agents:
induction and characterization of rabbit antibody. Invest Radiolu :1- 9
1.
8.10
Can Sensitization Due to Frequent Contrast Media
Administration Be Observed?
R.C. BRASCH
Generally, the large epidemiological studies of adverse drug reactions (ADR) to
iodinated CM have shown no increase in the reaction rates for patients with
previous exposure to CM. Sandstrom [2] reported his experience with over
7000 patients, some of whom had as many as seven previous CM studies and
noted no relationship between number of exposures and rate of reactions. More
recently, Katayama et al. [1] reported on observations in 337647 patients
receiving either ionic or low-osmolar nonionic CM; rates for ADRs were
153
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CHAPTER 8 Adverse Reactions and Their Pathophysiology and Management
significantly lower using the nonionic CM. However, there was no increase in
reactivity among the patients with prior CM exposure (6.9%) when compared
to patients with no history of prior CM administration (8.6 %). Of course, these
epidemiological reports do not totally exclude the possibility that a given
patient may be sensitized by CM. It should be noted that CM have a relatively
short residence time within the body due to their rapid elimination by
glomerular flltration, thereby precluding the lengthy exposure that may be
required to induce an immunological response. As mentioned earlier, patients
may be sensitized by prior exposure to chemicals structurally similar to CM,
any halogenated benzene ring for instance, and antibodies so induced may
cross-react when CM is administered.
References
Katayama H, Yamaguchi K, Kosuka T, Takashima T, Seez P, Matsuura K (1990) Adverse
reactions to ionic and nonionic contrast media. A report from the Japanese Committee on
the Safety of contrast Media. Radiology 175 : 621- 628
2. Sandstrom C (1955) Secondary reactions from contrast media and the allergy concept. Acta
Radiol [Diagn] (Stockh) 44: 233
1.
8.11
Can Epileptogenicity and Arachnoiditis be Observed
After Myelography with Non-ionic CM?
1.0. SKALPE
Compared with ionic CM the epileptogenicity and frequency of post myelographic arachnoiditis with the non-ionic CM metrizamide (Amipaque) were
very low. With the introduction of the "second generation" non-ionic CM, such
as iohexol (Omnipaque), iopamidol (Iopamiro) and iopromide (Ultravist),
these problems seem to be virtually eliminated. Thus, in our department we
have not seen any case of post-myelographic epileptic seizure or arachnoiditis
during our more than 14 years of experience with iohexol myelography,
comprising more than 2,500 examinations.
However, the problem of epileptogenicity is not completely eliminated.
Epileptic seizures have been occasionally reported in the literature following
lumbar and cervical myelography with both iohexol and iopamidol. In these
cases relatively high doses have been used, ranging from 3000 to 4500 mg
iodine. We therefore recommend keeping the dose as low as possible. With a
proper technique, excellent quality lumbar and cervical myelograms are obtained with doses from 1700 to 3000 mg iodine. We therefore suggest a
maximum dose of 3000 mg iodine.
CHAPTER
9
Clinical Use of Iodinated Contrast Media for the
Visualization of Vessels, Organs and Organ Systems
9.1
Cerebral Angigraphy
1.0. SKALPE
Following the introduction of a series of noninvasive imaging modalities (CT,
MRI, Doppler sonography) during the last two decades the indications for
cerebral angiography have been markedly reduced and, consequently, the
number of examinations has been dramatically diminished, in most centres by
more than 50 %. Thus, angiography is usually not indicated in head trauma, or
in brain tumours, both of which were important indications for cerebral angiography prior to the CT era. One may expect this trend to continue, since CT and
MRI angiography will reduce the need for conventional cerebral angiography
even further.
The most important indications for cerebral angiography today are diseases
of the cerebral vessels:
a) Degenerative lesions (arteriosclerosis),
b) arteritis,
c) aneurysms and
d) arteriovenous malformations.
These indications will hold for the foreseeable future. One reason for this is the
remarkable progress in endovascular treatment of these lesions in recent years.
Technique
The examination is usually performed via the transfemoral route under local
anaesthesia. Following puncture of the femoral artery and introduction of the
guide wire a preshaped catheter is introduced. Selective injections are then performed in both carotid arteries and in the left vertebral artery. We always start
the examination with angiography of the aortic arch in patients with
156
CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
arteriosclerosis. A pigtail catheter is placed with the tip proximal to the
brachiocephalic artery in these patients.
In conventional angiography using a cut-film changer the dose of CM is
8 -10 ml (300 mg IIml) in the carotids, 6 ml (300 mg I/ml) in the vertebral artery and 60 ml (350 mg I/ml) in the aortic arch. The injections are performed with a pressure injector. In intra-arterial digital subtraction angiography
(IA-DSA) the dose per injection may be markedly reduced. However, since
biplane exposure is not available in these systems, the number of injections
must be increased. Thus, the total amount of CM in grams of iodine will be
about the same.
The examination is usually easy to perform and may be completed within
half an hour. Selective injections may be a problem in arteriosclerotic patients.
Direct puncture and catheterization of the common carotid artery can be performed in these cases. In our department direct puncture is performed once or
twice a year, whereas some centres use this approach routinely. The transaxillary or transbrachial route is used only in exceptional cases, since these carry a
higher risk for local complications than the other methods.
Complications
In our opinion most complications in cerebral angiography are related more to
the examination technique than to toxic effects of the CM. In a study of more
than 2500 cerebral angiographies we found that there was no relationship
between the occurrence of complications and
the number of CM injections per artery,
the maximum amount of CM to one artery,
3. the total amount of CM injected.
1.
2.
More than one third of the complications were totally unpredictable, occurring
after short-lasting examinations with no technical problems.
The most frequent complications in cerebral angiography are hemiparesis,
dysarthria, visual disturbances and disturbances of consciousness. These are
seen in 1 % - 2 % of patients. In the majority the disturbances are transient with
full recovery within 24 h. Permanent sequelae are extremely rare - 0.2 % in the
material mentioned above.
We believe that the majority of these complications are caused by embolism.
During the catheterization procedure embolic material may be detached from
arteriosclerotic lesions of the intima. Thrombus may form on the catheter wall
and also within the catheter lumen and in the syringes where aspirated blood
may come in conctact with the syringe wall. Such complications can, to some
extent, be prevented by a meticulous technique. Thus, aspiration of blood into
syringes should be avoided. This is even more important with nonionic than
with ionic CM, since ionic CM have a stronger anticoagulant effect than nonionic CM. Furthermore, recent reports have shown that nonionic CM in mixture
with blood generates thrombin, whereas this is not seen with ionic CM. It has
been suggested on the basis of these in vitro experiments that nonionic CM may
9.1 Cerebral Angiography
cause thromboembolism more often than ionic ones. This has not been our
experience. We have used iohexol (Omnipaque) routinely for cerebral angiography for the last 14 years and compared with our previous experience with
the ionic CM metrizoate (Isopaque Cerebral) there has been a minor reduction
of the complication rate from 2 % to 1.3 %.
The following precautions are recommended when using nonionic CM in
angiography: frequent flushing of the catheter with heparinized saline and
minimal aspiration of blood into the syringes. Syringes should be plastic rather
than glass, since in vitro experiments have demonstrated greater and faster
thrombin generation in glass syringes than in plastic ones. Aspirin, which effectively reduces platelet aggregation, should be given 12 h prior to the examination. Following these guidelines, the full advantage of the defmitely better
biocompatibility of nonionic CM is obtained.
Although ionic CM are well tolerated in cerebral angiography with only
minor complaints from the patients following injections into the cerebral arteries, these side effects are even less with nonionic CM. This is of practical
importance in selective injections into the external carotid artery, where ionic
CM often cause considerable pain and unpleasant warmth, whereas nonionics
usually induce no unpleasant effects at all.
Local complications at the puncture site are very rare. Haematomas may
occasionally occur, but are very rarely of clinical significance. Thrombosis of
the femoral artery with total obliteration of the lumen has been reported, but
this is extremely rare. However, it is important for the clinician to be aware of
these possibilities, so that proper treatment can be instituted before irreversible
damage ensues.
In conclusion, although ionic CM are relatively well tolerated in cerebral
angiography, we recommend nonionic CM for this examination.
References
1. Fareed J, Walenga J, Saravia GE, Moncada RM (1990) Thrombogenic potential of nonionic
contrast media? Radiology 174: 321- 325
2. Skalpe 10 (1988) Complications in cerebral angiography with iohexol (Omnipaque) and
meglumine metrizoate (lsopaque Cerebral). Neuroradiology 30 : 69 -72
3. Skalpe 10, Nakstad P (1988) Myelography with iohexol (Omnipaque): a clinical report with
special reference to the adverse effects. Neuroradiology 30 : 169 -174
4. Skalpe 10, Sortland 0 (1989) Myelography. Lumbar-thoracic-cervical with water-soluble
contrast medium. Textbook and atlas 2nd edn. Tano, Oslo
5. Stormorken H, Skalpe 10, Testart MC (1986) Effect of various contrast media on
coagulation, fibrinolysis, and platelet function. An in vitro and in vivo study. Invest Radiol
21: 348-354
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
9.2
Spinal Angiography and Phlebography
A.THRON
Spinal Angiography
Why?
The visualization of the blood vessels supplying the spinal canal, spinal cord,
and cauda equina is presently only possible by means of selective angiography,
since, due to the smallness of the structures (anterior spinal artery < 1 mm), a
high degree of spatial and contrast resolution is required. Noninvasive procedures such as US or MRI do not yield comparable images. Even with flush
aortography, the branch vessels from the segmental arteries to the axial
skeleton, and especially to the spinal canal, cannot be adequately demonstrated.
For this reason, selective study of the segmental arteries branching off from the
aortic arch or of their homologues is the method of choice. Before the introduction of digital subtraction angiography (DSA), the photographic fIlm subtraction of standard cut-fIlm angiography was required to eliminate overlapping by bony structures. This procedure was not only very time-consuming and
expensive, but was also diagnostically unsatisfactory, since, frequently, diagnostic assessment was not possible until the fIlm subtractions were available. Given
that a complete selective spinal angiography requires serial angiograms of
30 - 35 individual arteries, it is easy to see what an advance the introduction of
DSA represented. It makes a substracted image - with somewhat less spatial
resolution but higher contrast resolution - and thus diagnostic information
immediately available. The advantageous contrast resolution enables the injection of less concentrated CM solutions. Combined with the obligatory use of
nonionic CM which are less neurotoxic and less damaging to vascular endothelium, the previously much feared spinal angiography has become a safe
examination procedure.
When?
Spinal angiography is indicated in the following situations: suspected spinal
vascular malformation (AV malformation, cavernoma); suspected spinal dural
AV fistula; preoperatively, and in tumours of the spinal cord or spinal column.
The clinically tentative diagnosis of a spinal infarct generally does not
represent an indication. This diagnosis first has to be deduced from: the clinical
picture (acute transverse lesion with zonal pain), an inconspicuous result of
other imaging procedures (MRI, myelography), an unimpressive analysis and, if
applicable, anamnestic signs (embolizing heart disease, condition following
aortic surgery, dissecting aortic aneurysm). It is almost impossible to prove that
a spinal infarct results from the occlusion of an artery supplying the spinal cord.
9.2 Spinal Angiography and Phlebography
This is due to the great variability in the arteries supplying the spinal cord and
to their small calibre, which only allow inconstant and segmental visualization.
Even if a vascular occlusion can be proven, this would still not have specific
therapeutic consequences. Often the diagnosis can be corroborated by MRI follow-up examinations.
An indication can, however, arise if, in a subacute presentation, the findings of
a MRI examination raise the question of a differential diagnosis of a spinal vascular malformation. It is difficult to say whether spinal angiography in search of
a spinal vascular malformation or a dural AV fistula is indicated in progressive,
clinical, transverse spinal cord syndrome even without such findings. As a rule,
the suspected clinical condition should be corroborated through evidence of
conspicuous dilated vessels in the subarachnoid space. In spinal AV dural fistula
with localization of the "angioma" in the dura mater spinalis and drainage of the
shunt via superficial veins of the spinal cord, this vascular dilatation can be very
inconspicuous. In most cases modern MR tomographs can display these abnormally dilated vessels as empty structures; CM enhanced images in the TI
sequence can present the result more clearly. The MRT in the T2 sequence presents central inner medullary spinal cord damage as hyperintensity over long
segments. This corresponds to chronic venous myelopathy, resulting from excessive pressure and volume strain on the spinal venous system. A myelography
before spinal angiography is, as a rule, no longer necessary.
Tumours of the spinal cord or spinal column are a relative indication for
angiography. Such a procedure should provide the operator with information
about spinal feeders in the neighbourhood of the space-occupying lesion and
allow him to make an assessment of the degree of vascularity and of the possibility of its preoperative embolization.
Premises
1.
2.
Selective spinal angiography should only be performed, if at all possible, at
centres specializing in it and possessing sufficient experience. Facilities for
DSA have to be considered practically obligatory today. The operator has to
be well-acquainted with spinal vascular anatomy and possess enough information to confirm there is a good indication.
From the patient's viewpoint, the same premises hold for spinal angiography
that hold for other examinations involving the administration of iodinated xray CM or for other angiographies requiring a transfemoral approach (see
Sect. 9.3).
How?
Selective spinal angiography can practically only be performed via the transfemoral route. If this path of entry is impossible, only diagnostically inadequate
survey angiography or individual-vessel studies in the cervical region are possible via a transbrachial or axillary procedure.
After puncture of the inguinal artery, a catheter sheath should always be
used, since the changing directions in which the segmental arteries branch off
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
along the course of the aorta may make it necessary to change the catheter
repeatedly. The catheter used has to display a curvature of its tip; on the one
hand, it has to be adjusted to the changing lumen width of the aorta, and on the
other it has to permit the catheter tip to slip into the ostia of the intercostal or
lumbar arteries. If the catheters are not shaped by the examiner himself, he has
to have several potentially suitable tip curvatures at his disposal. The order in
which the ostia of the lumbar and intercostal arteries are probed is unimportant. However, it is advisable to maintain an examination protocol in
which it is noted which vessels have already been visualized. A metal marker
projected paravertebrally on the patient's back facilitates rapid determination
of the catheter level. The catheter tip should not occlude the ostium and if
aspiration of blood is difficult in small vessels, one has to be careful to keep the
catheter connection free of air.
For visualization of individual segmental arteries, 2 - 4 ml nonionic CM are
injected, using the DSA technique, in a concentration of 200 mg lIml and in a
standard cut-film technique in a concentration of 300 mg lIml. In the case of
the confirmation of an AV malformation, selective angiography can be performed, depending on shunt volume, with 5 ml CM (in exceptional cases more)
in the above-mentioned concentrations. A series of pictures taken laterally should then be made, something that can be omitted in the event of
normal findings. The length of an angiographic series, even in the search for
vascular malformations, should not be less than 4 - 5 s. The exploration of the
supra-aortic arteries (vertebral artery, costocervical trunk and thyrocervical
trank) requires a less curved universal or headhunter catheter. An injection
dose of 4-8 ml CM (200-250 mg lImI) is required for the vertebral artery.
Since no more than a total of 300 ml nonionic CM (at a concentration of
300 mg lIml) should be administered, in rare cases involving older patients, a
second session might be required for a complete spinal angiography. The preoperative visualization of the vascular supply of a spinal tumour can be limited
to the corresponding region of the spinal column; however, in tumours located
in the spinal cord (e.g., haemangioblastoma), the radicular arteries merging
into the spinal artery, above and below the tumour should also always be included.
In the search for the feeders of an AV malformation in the spinal cord or
subarachnoid space, complete spinal angiography is necessary due to the
frequency of multiple feeders. In spinal AV dura fistula, a complete thoracolumbar study is desirable. In case this creates problems in the often older
patients, a more limited study may also suffice if the shunt-feeding vessel is
detected. One should under no circumstances hold spinal angiography to be
negative if the search for a suspected spinal vascular malformation was not
complete because some segmental arteries, the pelvic cavity or the craniocerebral transition were omitted! A complete spinal angiography requires the
visualization of both sides of the iliolumbar artery, the lumbar arteries, the
intercostal arteries, the costocervical trunk, the thyrocervical trunk, and the
vertebral and carotid arteries. If there are no AV shunts, a visualization of the
medullary-surface veins, directly responsible for draining the spinal cord, cannot be expected with the CM amounts given above.
9.2
Spinal Angiography and Phlebography
Complications I: Those Induced by the Method
The potential complications related to the technical procedure correspond
generally to those that can occur when the same procedure is applied to angiography of other vascular regions (see for example, Sect 9.3 "Angiography of the
Extremities").
In order to avoid injuring the vascular wall with a catheter with marked tip
curvature, a soft guidewire protruding in front of the tip should be used for the
passage through the pelvic arteries. Injuries to the vascular wall at the ostia of
the segmental arteries can lead to circumscribed dissections with or without
the occurrence of spasm; they are almost always free of sequelae if the problem
is immediately recognized and the catheter is removed. Due to the numerous,
rope-ladder-Iike, extraspinal collaterals, the vascular supply to the spinal cord is
as a rule maintained even in the case of a complete obstruction of passage of a
segmental artery. This is the case as long as the lumen obstruction does not
extend all the way to the point where a radicular artery that supplies the spinal
cord exits from the obstructed artery. Thus, the correct positioning of the catheter tip and a careful catheter injection with obviously free CM flow are
clearly necessary if spinal cord damage is to be avoided. All other potential
complications (secondary bleeding, iatrogenic AV fistula, fever, nerve damage)
are to be avoided or treated according to the instructions found in the section
9.3 on angiography of the extremities.
Complications II: Those Induced by the Iodinated Contrast Medium
The following complications can be induced by the iodinated CM:
1.
2.
3.
4.
5.
6.
Hypersensitivity reaction up to anaphylactoid shock (see Sects. 8.1, 8.S).
Cardiovascular reaction (see Sects. 3.4, 4.7).
Disturbance of kidney function (see Sects. 3.7, 4.9).
Coagulation disorders (see Sect.3.3).
Damage to the intima or endothelium (see Sect. 3-11).
Neurological symptoms of irritation and disturbed function such as cortical
blindness, myoclonus, and signs of partial to complete paraplegia.
The cause of specific neurological disorders may vary greatly. Clinically, one can
hardly distinguish between vascular occlusion due to embolic material or
coagulation disorders and toxic effects on vessels due to the CM used. Neurological
deficits can be transient with full recovery or may result in a lasting deficit.
If symptoms of spinal irritation become manifest (electrical tingling in the
extremities, myoclonus) all further CM injections must be avoided, unless these
symptoms involve already existing spinal symptom from spinal injury.
Direct CM-induced organ damage to the spinal cord has been a problem to
be taken seriously in both intentional and unintentional studies of the spinal
arteries. CM myelopathy, formerly the model of an intermedullary microcirculatory disturbance, is in my own experience avoidable, if the above examination technique is used, and nonionic CM with little damaging effect on the
endothelium and of low neurotoxicity are employed.
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Conclusions
Selective spinal angiography using a DSA technique is the method of choice for
visualizing AV malformations in the spinal canal; in cases where the latter is
suspected, it absolutely must be used. Only by its use can the precise location of
the AV shunt be determined, and the possibility and risks of treatment by
surgery or embolization be assessed. Spinal angiography concomitant with
operations on tumours of the spinal cord and vertebral column can also help
improve the results of therapy. If the technique described here is followed and
the obligatory use of nonionic CM accepted, previously feared complications
can be reduced to such an extent that the approach to the case and discussions
with the patient are associated with less anxiety.
Spinal Phlebography
Why?
Epidural venography practically stopped being utilized as a diagnostic procedure once CT and MRI allowed visualisation of even smaller, subtle spaceoccupying lesions in the neighbourhood of the spinal canal. Prior to this the
procedure had been performed by a few specialists in order to recognize lateral
disk prolapses, small extradural space-occupying lesions, or epidural angiomas
that had escaped myelographic detection.
When?
Today the use of spinal phlebography can only rarely be justified and so little
will be said about it here. This procedure may be indicated when, after all other
diagnostic procedures (myelography, MRI, spinal arteriography) have been
exhausted, the finding of a so-called varicosis spinalis with progressive symptoms of spinal disorder has remained uncertain. If, for corresponding circulatory disturbances of the spinal cord, an abnormal AV communication cannot be
confirmed in the region of the dura mater spinalis, it would also be conceivable
(though presently only hypothetically) that an obstruction of the drainage of
the surface veins of the spinal cord into the epidural venous system might exist.
In individual cases, this mechanism has been verified, when for example, due to
agenesis of the inferior vena cava or other serious venous dysplasias, the epidural venous system has to take on the entire collateral drainage.
How?
The contrast visualization of the internal and external vertebral plexus of veins
can be achieved through (a) intraosseous venography or (b) retrograde catheter venography. In the first case, the CM is injected into a spinous process of the
vertebra or, in the neck region, into the cancellous bone of a vertebral body. In
direct catheter venography using a transfemoral approach, the external and
9.3 Angiography of the Extremities
internal vertebral venous plexus can be visualized via the ascending lumbar
veins in the lumbar region and by exploring the vertebral veins in the cervical
region. In both cases, bilateral vascular catheterization with simultaneous CM
injection is desirable, since in one-sided only injections, incomplete filling all
too frequently results, with a consequent danger of misinterpretation. Moreover, for the complete filling of the vertebral venous plexus over long stretches
in the lower vertebral column segments, the inferior vena cava must be compressed using an inflatable rubber cuff. Injection pressure and volume depend
on the catheter positioning.
Complications
These correspond to those in direct catheter venography in other regions (see
Sect. 9.4).
Conclusions
Spinal phlebography is seldom used now in the routine diagnosis of vertebral
and spinal space-occupying lesions. It is reserved for very specialized questions
relating to circulatory disorders of spinal cord blood flow.
9.3
Angiography of the Extremities
H.-J. MAURER
Why?
The purpose of angiography is to depict pathological changes of the arterial
system with a view to appropriate therapy.
Even though angiography using a cut-film changer or the medium-format
technique is still often used internationally, arterial digital subtraction angiography (DSA) should, if available, be employed in order both to reduce the
radiation dose and to save contrast material with the aim of reducing dosedependent reactions. Apart from special vascular examinations in the thoracic
region and cardiography, venous DSA has been abandoned primarily because
of the unsatisfactory quality of imaging, but also because of the relatively large
amount of contrast medium required. Arteriography of the abdominal and
pelvic region and of the lower extremities down to the trifurcation can be
performed satisfactorily with CT or MR angiography. Arterial DSA or mediumformat arteriography is, however, still preferable for the demonstration of
small-calibre arteries. The spatial reconstruction of the aorta and its branches
following CT or MRI free from overlapping in the abdominal and pelvic region
provides a almost clear view of pathological changes. On the other hand, the
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
medium-format technique and DSA provide magnified images of vascular
regions of interest immediately following general arteriography with or without changing the catheter position.
Only non-ionic monomeric preparations should be used as contrast material; the use of non-ionic dimeric contrast media (CM) will depend on a future
assessment of the benefits and risks of the late reactions observed with these CM.
When?
Before invasive procedures requiring contrast media are performed, an attempt
should be made to make a diagnosis using Duplex Doppler or Colour Doppler
sonography depending on the detailed case history. If, however, an invasive
procedure, e.g. angioplasty, is planned from the very start, arteriography may be
the procedure of first choice because it can be followed immediately by the
interventional procedure.
As regards the value of ultrasound examinations and/or arteriography and
CT or MR angiography, it is often the attitude of the potential vascular surgeon
that counts, since some of them are prepared to perform the interventional
procedure on the basis of the quality and yield of the ultrasound studies without further invasive diagnostic procedures.
Conditions
1.
2.
As with any examination with iodinated CM, the examiner should always be
provided with the following information: Case history, clinical findings,
results of non-invasive vascular studies, medication at the time of the examination in view of the possibility of interactions with the CM, known allergies,
previous hypersensitivity reactions particularly to CM, clinical diagnosis
and question.
The level of stenoses or occlusions can be concluded from the level of the
intermittent claudication.
The referring doctor must ensure that neither the cardiovascular system nor
the kidneys or other organs might present a contraindication. The clinical indication for the examination must be carefully reviewed and the benefits weighed against the risks in the presence of impaired thyroid or kidney function;
The decision should be made in consultation with the refering clinician. The
same applies with a known history of allergy or previous CM reaction.
Methods
Lower extremities, including the abdominal aorta with or without visualisation
of the renal arteries, using the Seldinger technique:
1.
2.
Retrograde transfemoral,
antegrade transbrachial or
9.3 Angiography of the Extremities
3. in special indications, antegrade demonstration of the vascular system of the
lower extremity with antegrade puncture of the femoral artery. Insertion of
the catheter from the opposite side via the aortic bifurcation is, however, also
possible.
Upper extremities: For the demonstration of the arterial system of an arm,
transfemoral access with an appropriately preshaped catheter is recommended;
if necessary, the catheter can be advanced as far as the trifurcation to obtain
better images of the arteries of the lower arm and hand. Antegrade or retrograde puncture of the brachial artery is often sufficient for arteriography of the
lower arm and hand.
CT or MR angiography might be better for examinations of the supraaortic
branches - left subclavian artery, brachiocephalic trunk with the right subclavian artery - with the added benefit of 3-D visualisation.
Should access to the subclavian artery on the required side be impossible
because of pathological changes the pelvic arteries or aorta, access from the
brachial artery of the opposite side with an appropriately preshaped catheter
may be advisable.
The further development of catheters now allows the use of 4 F (Hagen,
1997) and 3 F (Fitzgerald et al., 1998) catheters, as a result of which Fitzgerald
et al. report that even ambulatory arteriography is possible as long as certain
precautions are taken. The image quality is quite adequate with both catheter
sizes.
Procedure
Under sterile conditions, one of the above-mentioned arteries is punctured and
a lock introduced, through which the desired catheter is inserted: a pigtail
catheter in the case of aortography and a preshaped catheter for examinations
of the arm. If necessary or desired, the catheter can be changed without
retraumatising the arterial wall.
The position of the pigtail catheter in aortography is determined by the clinical question.
In the case of conventional angiography (cut-fUm changer), a test run is required to check the correct position because of the continuous automatic
advance of the patient; extreme bowlegs or knock knees might present difficulties in the area of the knees or distal lower legs and feet. In the case of both
conventional and digital subtraction arteriography, the medium-format
technique requires that the low- or non-absorbing areas between or around the
extremities must be covered with aluminium fUters or be screened with collimators on the equipment. The dose measurement integrating over the entire
field would otherwise lead to underexposure.
In the case of DSA, every vascular section of interest must be set.
In the interest of reproducibility, non-ionic CM should always be injected
with a high-pressure syringe. Up to 100 ml CM (300-370 mg iodine/ml) are
injected for conventional aortography; the first fUm is triggered after a slight
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
delay, the others according to preset data. Despite the 5 -7 positions required in
i. a. DSA, only about half this amount of CM is necessary as long as no additional films are required. The course of the pelvic arteries or the start of the deep
femoral artery may require additional adjustments without the need for any
significant increase of the amount of CM required. The same also applies to
additional selective or superselective demonstrations of arterial regions of interest after an appropriate change of catheter.
If spasm occurs or is suspected, the examination should be repeated after i. a.
administration of a spasmolytic.
Angiography of the arm or of the distal lower arm and hand requires 1020 ml non-ionic CM (300-370 mg iodine/ml) and 5-10 ml, respectively, both
with the conventional technique and with i. a. DSA.
If possible, a total of no more than 300 ml non-ionic CM (300-370 mg
iodine/ml) should be administered for angiography. This guideline may be
exceeded in the individual case after consideration of the patient's general and
cardiovascular condition. However, close supervision for up to 24 hours and,
possibly, 48 hours after the examination is then required (see Sects. 7-2, 7.5).
If, despite all efforts, the arteriograms of the lower legs are unsatisfactory,
resort can be had to intraoperative arteriography through puncture of the distal
section of the superficial femoral artery or of the popliteal artery.
Angiography of the arm and lower arm or hand always leads to good visualisation of the veins, which is lacking on aorto-arteriography (lower extremities). If the venous system in this latter region does fill, however, then a pathological situation, e. g. arteriovenous shunt, is usually present.
To our knowledge, translumbar artography is now used only in isolated cases
and is mentioned here only for the sake of completeness.
With the patient in the abdominal position, the aorta is punctured from the
left dorsal direction at the level of the iliac crest or L III, the tip of the needle or
Teflon catheter gliding along the vertebral body. Pulsating (aortic) blood
indicates that the needle or catheter is in the correct position; A test injection
will confirm this, but will also reveal intramural and/or paraaortic pools of CM.
The position of the catheter or needle is then corrected as necessary. The
amounts of CM required by the respective method - cut-film changer, medium
format or DSA - are then injected. To avoid organ complications on incorrect
positioning of catheter or needle, care should always be taken not to inject
larger amounts of CM into the left renal artery or the superior mesenteric
artery. Substantial extravasation can occur even on correct positioning of
the catheter or needle, as planned surgery performed immediately afterwards
shows.
Complications, Method-Related
1.
Haematomas of varying severity can occur on puncture of an artery; It
is a regular occurrence on direct aortography, with pain often being reported in the lumbar region, and it may even lead to impairment of kidney
function. Injury to the wall of the adjacent vein on arterial puncture can
9.3 Angiography of the Extremities
2.
3.
4.
5.
6.
7.
8.
occasionally result in an arteriovenous aneurysm, which then requires treatment.
In patients with a history of clotting disorders, haemostasis at the end of
angiography must be performed and followed up with particular care.
Material defects of the lock, guidewire and catheter or changes in the
properties of repeatedly used, i. e. sterilised, disposable material, can result in
bending, breakage and fragmentation, the debris from which can be washed
away into a peripheral artery or, in the case of i. v. DSA, into the heart or lungs
and must be removed.
Febrile reactions during and after angiography are not always attributable to
the CM, so that, wherever possible, other possibilities must be checked, e. g.
a) inadequate resterilisation of disposable material,
b) pyrogens in the injected contrast medium solution.
Malpositioning of the patient, which can lead to injury to the ulnar nerve, for
example, must be avoided.
Injury to a nerve on arterial puncture usually provokes an immediate
reaction which does not in general have any prolonged sequelae, however. On
the other hand, extensive haematomas - although rare - lead to lesion of a
nerve or, in the axillary region, a plexus; close follow-up is required in such
cases so that rapid remedial action can be taken.
Both puncture and the introduction of lock, guidewire or catheter can
dislodge arteriosclerotic particles, leading to peripheral embolism corresponding to the size of the particles with typical symptoms of embolism. If
necessary, the embolus or emboli must be removed.
In rare cases and despite careful, gentle insertion, a guide wire can undermine a plaque, penetrating the wall of the artery, either remaining there or
being deflected back into the lumen. The test injection after introduction of
the catheter over the guidewire need not always reveal this dissection, so that
the examination proceeds as planned and the mistake is not noticed until the
fIlm or the monitor is viewed: Residues are unusual in such cases. In another
case the CM may run off only slowly and spread like a dish in the arterial
wall; residues are rare in this case as well.
If the tip of the catheter lies under a plaque during the injection, the high
pressure can force a varying amount of CM into - and partly through - the
wall to be seen after the end of the examination as a mural infIltrate or
extravasate.
Complications, Contrast Medium-Related
It is well documented that the use of monomeric, non-ionic contrast media has
led to a marked reduction in the number and severity of the reactions observed
(Katayama). It is possible that the use of non-ionic dimers will lead to a further
reduction of adverse reactions, although their efficacy and tolerance must fIrst
be carefully documented and evaluated.
1.
2.
"Allergic" reaction ranging to anaphylactoid shock (see Sects. 8.1, 8.3, 8.4).
Cardiovascular reaction (see Sects. 3-4, 4.7).
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
3. Impairment of kidney function (see Sects. 3.7, 4.9, 4.10).
4. Clotting disturbances (see Sect. 3.3) and damage to endothelium (see Sect.
3.11).
5. Reaction of the CNS with occasional disturbance of vision ranging to
unilateral or bilateral amaurosis (see Sect. 3.10).
Wherever possible, it should be immediately determined whether the event is a
"allergic" anaphylactoid or a primary cardiovascular reaction, since the therapy
will differ accordingly.
Apart from acute reactions, late reactions occurring as much as 24 hours
after the examination have also been reported; it has also been known for reactions to occur even later. The patient should, therefore, be observed closely after
the end of the examination. While this is no problem in the case of in-patients,
close collaboration with the referring general practitioner or hospital must
exist in the case of out-patients undergoing angiography.
The management of acute complications demands the availability in the
radiology department and if possible in the angiography room itself of the
drugs and equipment required for appropriate therapy, e. g. defibrillator, intubation kit, instruments for venesection.
Out-patients undergoing angiography must be kept under observation for at
least 2 - 3 hours in the examining department or on a recovery ward before
being returned to the care of the referring doctor or hospital.
If a moderately severe or severe reaction is observed in a radiological
practice, it is advisable to arrange for an ambulance with an emergency doctor
to take the patient to an intensive care unit.
If, despite all precautionary measures - including prophylaxis (see Chap. 5)
and proper performance of the angiographic examination - a serious incident
necessitating treatment and possibly with a fatal outcome should nevertheless
occur, the examiner should take a sample of venous and, if applicable, arterial
blood as well as - if at all possible - a sample of CSF to help his defence in the
event of litigation (type and concentration of the CM); the batch of the CM used
should also be recorded in the report. Because a fatal outcome to a CM reaction
can have various causes, a forensic post-mortem examination should be arranged in such cases.
Conclusion
Because dose-dependent reactions can occur on intravascular use of iodinated
CM, intraarterial DSA is the method of choice for aorto-arteriography of the
lower extremities. Although it is superior in the abdominal region in particular,
CT angiography requires the intravenous injection of a fairly large amount of
CM. For the demonstration of smaller arteries, however, i. a. DSA or the
medium-format technique is still superior to CT and MR angiography.
Only non-ionic preparations should be used as contrast material.
Although there is no "pattern" to the way patients react and the known tests
1) have their own complications rate and 2) are not sufficiently meaningful,
9.4 Phlebography
generous use should be made of prophylaxis (see Chap. 5). Because, according
to Lalli, the patient's apprehensiveness makes him more susceptible to
reactions, the doctor's explanatory chat with the patient is particularly important in this connection.
It goes without saying that a detailed record must be kept of the examination,
including the explanation to the patient, as well as about every methodological
complication and every reaction to the contrast medium. It is also essential to
keep an accurate record of concurrent medication and of any drugs given or
measures instituted because of a CM reaction. This may be of importance in the
clarification of a CM incident.
9.4
Phlebography
B. HAGEN
The development of Doppler sonography, especially of Colour Doppler, has
greatly limited the indications for phlebography over the last few years [1,2].
From a radiological point of view, however, the general consensus is that
phlebography is superior to all other non-invasive alternative procedures
(including Colour Doppler, impedance plethysmography and phlebodynamometry) as regards morphological precision and specificity [3,4,5].
The following catalogue of radiological indications can be compiled for
phlebography:
Extrafascial venous system:
- Surgical planning and strategy for the treatment of varices.
- Differential diagnosis of primary/secondary varicosis if the sonographic
finding is unclear.
- Secondary varicosis for presence/exclusion of an indication for surgery.
- Recurrent varicosis postoperatively or after repeated obliteration.
- Congenital venous malformations, particularly before planned surgery.
2. Intrafascial venous system:
- Suspected thrombosis with an ambiguous clinical and sonographic
finding.
- Suspected pelvic vein thrombosis.
- Presence/exclusion of an indication for fibrinolysis and thrombectomy,
follow-up under fibrinolysis.
- Follow-up under long-term anticoagulation.
- Postthrombotic early and late syndrome.
- Recurrent thrombosis.
3. Special indications:
- Traumatic and iatrogenic venous lesions.
- Expert opinion and forensic questions.
1.
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
- Thrombosis and venous compression syndrome in the axilla-shoulder
region (TIS, Paget-Schroetter, mediastinal tumours, indication for stent
implantation).
Contraindications for Phlebography
Absolute: First trimester of pregnancy.
2. Relative: Severe anaphylactoid reaction after previous eM injection.
Severe impairment of renal function.
Manifest hyperthyroidism, toxic adenoma.
Pregnancy (2nd/3rd trimester).
Phlegmasia coerulea dolens.
1.
Prerequisites (see Extremity Angiography Sect. 9.3)
Methods
I. Lower extremities and pelvis:
-
Ascending leg-pelvis phlebography, phleboscopy as described by May (3).
Ascending compression phlebography as described by Hach (6).
Varicography.
DSA of the pelvic veins (Figure 9.4.1).
Fig. 9.4.1.
Condition of a 33-year-old
patient after fibrinolysis of a
Paget-v. Schroetter
syndrome, progress check.
Injection of 15 ml nonionic
CM (300 ml IIml).
Diagnosis: restenosis of the
subclavian vein at entry
to superior vena cava, with
collateralization
9.4 Phlebography
II. Arm and shoulder phlebography (unilateral or simultaneously bilateral):
- Standing series using the DSA technique, if necessary as functional
phlebography (in TIS).
- Standing series with the film-changer technique.
Phleboscopy after May and compression phlebography after Hach are now
standard procedures or the methods of choice in the demonstration of the veins
of the lower extremities. It must be emphasised that demonstration of the pelvic
vein should be an integral part of any phlebography of the lower extremity.
Since both of these methods describe not only the morphology of the veins, but
also functional phenomena (e. g. the direction of CM flow in the perforating
veins), conventional film technique (cassette fIlm or medium format camera)
should be used.
The pelvic veins, the inferior vena cava and the veins of the upper extremity
and shoulder girdle including the mediastinum can, however, also be demonstrated with the DSA technique. Puncture of the femoral vein and the previously customary transfemoral needle or catheter phlebography can be abandoned
in most cases in favour of the less invasive procedure of DSA of the pelvic veins
and vena cava performed from the foot. Although definition is limited with this
technique and susceptibility to artefacts is increased, it is still good enough in
most cases for a satisfactory diagnosis to be made (Figure 9.4.1).
Catheterisation via the pelvic vein is required only if there is a need for
selective examinations (e.g. of the internal iliac vein, the azygous vein, the renal
vein and suprarenal vein) and in therapeutic intervention (therapy of varicocele, cava filter, stents).
Procedure
An amount and iodine concentration of a non-ionic, low-osmolar CM adequate
to the indication and the patient's body weight is injected through a butterfly
cannula (21G) via one of the numerous veins of the dorsum of the foot (preferably the vena hallucis dorsalis).
CM Amount and Concentration in Phlebography
Ascending leg-pelvis phlebography:
a. Varicosis: 50-75 mllextremity, 250-300 mg 11m!.
b. Thrombosis: 75 -100 mllextremity, 250 - 300 mg 11m!.
2. Varicography:
30 - 50 ml, 150 - 200 mg 11m!.
3. DSA of the pelvic vein:
30 ml (300 mg 11m!) flushed with an equivalent amount of physiological NaCI
solution.
4. DSA of the shoulder veins:
20 ml (200 mg 11m!) flushed with an equivalent amount of physiological
NaCI solution.
1.
171
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Standard pWebography involves, under fluoroscopic control, 3 films of the
lower leg on external and internal rotation and of the region of the knee joint
on external rotation to assess the opening of the small saphenous vein, a further
2 films of the thigh and 1 film of the pelvis on condition that a 40-cm image
intensifier format is available. Valsalva's manoeuvre is used for visualising valvular incompetence of the great and small saphenous veins and of the feeder
veins. It also allows analysis of the function of the perforating veins to a certain
extent, so that information can also be gained about recirculating or real circulations. The extent of such recirculations in the still compensated and decompensated stage in particular has become a focal point of pWebological interest
and, consequently, of the surgical treatment of varices in recent years [5].
The CM can be efficiently diverted from the superficial to the venous system
and the direction of flow in the perforating veins can be assessed by the brief
supramalleolar application of an inflatable cuff. The calf muscles are massaged
after the end of the examination to express the CM from varicose convolutions.
These physical measures are accompanied by active dorsal and plantar flexion
of the foot. An elastic bandage is then applied around the knee area and the
patient is instructed to perform active walking exercises.
If the findings in the pelvic region are ambiguous (e. g. questionable pelvic
vein spur, compression phenomena, demonstration of collateral circulations), a
further pedal injection should be given in the same session for the specific
visualisation of the pelvic veins under DSA conditions, if available. 20 mg Buscopan is administered before the injection to eliminate artefacts caused by
bowel movements.
Complications
Examination-Induced Complications
Local haematomas can develop at the puncture site under anticoagulation or
fibrinolysis, particularly if the intravascular pressure increases due to the inflatable cuff. Vasovagal dysregulation ranging to blackouts can occur, especially
in younger patients with an unstable vasomotor system, as a result of the pain
caused, above, all by repeated attempts at puncture as well as under the conditions of orthostasis. Valsalva's manoeuvre, the head-down position and forced
manual compression of the calf veins should be avoided in the presence of fresh
thrombosis, since case reports suggest that any of these can lead to mobilisation
of the thrombus with consequent of pulmonary embolism.
Catheter phlebography can lead to the complications also found in arterial
examinations: Dissection of the venous wall, perforation, thrombosis, arteriovenous fistula formation secondary to repeated puncture attempts and local
haematomas, particularly in patients on anticoagulant therapy.
9.4 Phlebography
CM-Induced Injuries
Painful dissection can occur on inadvertent injection into the venous wall. Local
complications of this kind can lead to trophic disturbances with vesiculation
and tissue necrosis if hyperosmolar, ionic and higWy concentrated CM.
A distinction must also be made between systemic (see Sect. 8.1) and
specifically local intravascular CM injury. The latter can be acute or delayed. A
corresponding distinction is also made between the pain of the injection, the
postphlebographic thrombopWebitis of the punctured vein and deep vein
thrombosis. These side effects constitute damage to the sensitive venous endothelium of varying severity.
According to May harmless, reversible superficial thrombophlebitis of the
punctured vein is observed in about 20 % of patients after administration of
ionic CM [7].
The incidence of deep leg vein thrombosis in association with phlebography
is disputed. While such complications were recorded quite frequently with use
of the formerly customary ionic, high-osmolar CM, they have become extremely rare - at least clinically - in the modern era of non-ionic, low-osmolar
CM. A relatively high incidence of initial thrombosis can, nevertheless, be
found with the much more sensitive radiofibrinogen test. This was particularly noticeable in randomised studies (right-left comparison), in which the
accumulation of fibrinogen was demonstrated in up to 60 % of cases on use
of ionic, hyperosmolar CM, but in only a few cases with non-ionic CM
[8,9].
As in the arterial system, CM-induced pain in the veins is a signal that the
endothelial tolerance threshold has been crossed. The causes of the injurious
effect are primarily the hyperosmolality and secondarily the chemotoxicity
of the CM. Reducing the concentration, particularly of ionic CM, can greatly
reduce the intravascular pain. In the case of ionic monomeric substances, however, the concentration must be reduced to about 150 mg IIml in order to
bring the osmolality down to a value which guarantees virtual freedom from
pain during the injection. In contrast, the injection of non-ionic, monomeric
or dimeric CM in a concentration of 250 mg IIml or less is completely painless
[9]·
Conclusion
Phlebography of the lower extremities should be performed as ascending legpelvis phlebography using the technique described by May and modified by
Hach.
In special indications, phlebography of the pelvis and inferior vena cava and
of the upper extremity including the shoulder girdle and mediastinum can be
performed as DSA. Because of local, objectively and subjectively unpleasant
side effects, only low-osmolar and non-ionic CM (preferably in a concentration
of 250 mg I/ml) should be used for phlebography, since these agents have the
least adverse effect on the venous endothelium. Despite the development of
173
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
alternative procedures, pWebography has been able to maintain its position in
angiographic diagnosis thanks to its low invasiveness, the use of modern, welltolerated CM and its high diagnostic quality.
References
1.
Cronan JJ (1993) Venous thromboembolic disease: The role of US. Radiology 186: 619630
2.
3.
4.
5.
6.
7.
8.
9.
Fobbe F, Koennecke H-C, EI Bedeni M, Heidt P, Boese-Landgraf J, Wolf K-J (1989)
Diagnostik der tiefen Beinvenenthrombose mit der farbkodierten Duplex-Sonographie.
Fortschr. Rontgenstr. 151, 5 : 569 - 573
May R, Nissl R (1973) Die PWebographie der unteren Extremitaten. 2. Aufl, Thieme, Stuttgart
Weber J, May R (1990) Funktionelle PWebologie. 1. Aufl, Thieme, Stuttgart New York
Hach W, Hach-Wunderle V (1996) PWebographie der Bein- und Beckenvenen. 4. Aufl,
Schnetztor-Verlag
Hach W, Hach-Wunderle V (1985) PWebographie der Bein- und Beckenvenen. 3. Aufl,
Schnetztor-Verlag
May R (1977) ThrombopWebitis nach PWebographie. Vasa 6,169
Albrechtsson U, Olsson CG (1979) Thrombosis after PWebography: A comparison of two
contrast media. Cardiovascular Radiology 3 : 9 -18
Hagen B (1985) Die Objektivierung der Endothelvertraglichkeit nichtionischer und ionischer Kontrastmittel mit dem Radio-Jod-Fibrinogentest bei der BeinpWebographie. In:
Klinische Pharmakologie der Kontrastmittel, Hsg. von E. Zeitler, Schnetztor-Verlag, Konstanz, S. 94-105
9.5
Direct Lymphography and Indirect Lymphangiography
H. WEISSLEDER
Why?
The noninvasive imaging examination procedures of US, CT, MRT and quantitative radionuclide imaging of the lymph vessels have largely replaced
lymphography as routine diagnostic tools [14]. However, morphological
changes in epifasciallymph vessels and lymph nodes situated along them may
still only be delineated by lymphographic methods.
The sharpness of detail in these procedures is still clearly superior to that of
other examination techniques [15].
For the assessment of centrally located lymphatics, lymph nodes and the
thoracic duct, oily CM have to be used (direct lymphography) [3,10]. Because of
its known complications, however, the use of this technique is only advisable if
there is a clear indication. In general, lymphography should not be performed
9.5 Direct Lymphography and Indirect Lymphangiography
if any worsening of the disease from the side effects of the examination may be
anticipated.
For contrast visualization of the peripheral lymphatics in the extremities, the
trunk, and the face and neck region, nonionic, dimeric, water-soluble, iodinated
CM that are tolerated well are indicated (indirect lymphangiography) [5-7,16,
19,21]. Operative exposure and direct puncture of lymph vessels is not required
for this examination.
When?
As a rule, lymphographic examinations represent the last stage of the
diagnostic process. In malignant diseases of the lymphatic system, assessment
is usually possible by means of US, CT and/or MRI. Direct lymphography with
oily CM is only indicated if these other imaging procedures do not provide
definitive information.
In primary lymphostatic oedema of the extremities, the use of oily CM is,
other than in a handful of exceptions, obsolete and to be viewed as malpractice.
Direct lymphography is only acceptable today to answer a few very specific
questions with therapeutic implications (in a preoperative examination, for
example).
For assessing morphological changes in peripheral lymphatics, indirect
lymphangiography with water-soluble CM is to be considered the method of
choice [8,9,16,18,19,22]. In contrast to direct lymphography, it usually also
provides an assessment of all primary lymph vessels and precollectors in the
body surface region. The technique does not require exposure of peripheral
lymphatics and thus is technically much easier to perform; examinations take
less time and require less instrumentation.
At the present time, the use of indirect lymphangiography is concentrated on
localized and generalized soft tissue swellings of the extremities and the trunk
associated with primary or secondary lymphoedema or their combined forms
such as lipolymphoedema or phlebolymphoedema [5, 6, 20].
Premises
1.
2.
In general, an initial examination providing a basic clinical diagnosis is
mandatory before all lymphangiographic examinations. In addition, one
should have the results of preceding US, X-ray diagnostic, radio-isotope, and
MRI examinations.
As in other examinations involving iodinated X-ray CM, their use is relatively
contraindicated in latent or manifest hyperthyroidism or in patients with
known CM allergies. Contraindications to X-ray exposure should also be
considered.
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CHAPTER 9 Clinical Use of Iodinated eM for the Visualization of Vessels and Organs
Methods
Direct lymphography
1.
2.
The upper extremities: for visualizing the epifascial lymph collectors and
axillary lymph nodes, the oily CM is infused into an exposed lymph vessel on
the back of the hand. CM infusions on the palmar aspect of the distal forearm
are also possible.
The lower extremities, pelvic and lumbar lymph nodes, throracic duct: for
visualizing the ventromedial, epifascial, lymph vessel bundle and the inguino-pelvic and lumbar nodes the CM is infused into a lymph vessel on the
back of the foot. By means of a retromalleolar infusion, the collectors of the
epifascial, dorsolateral bundle can be demonstrated. To assess subfascial
lymph vessels, the CM has to be injected intramuscularly (into the calf
muscles).
The technique of CM administration has basically remained unchanged since
the introduction of direct lymphography [11-13]. After labelling of superficial
lymph vessels by means of a subcutaneous injection of dye (patent blue or
violet - with attention to side effects), the desired lymphatic is isolated under
local anaesthesia. Then, the vessel is punctured with a special cannula. An automatic infusion pump is required for CM administration with an injection rate
of 5 -10 mllh. In diseases not accompanied by considerable lymph node
enlargement, an infusion of 5 ml per lower extremity may be sufficient. As a
rule, undesirable side effects result from larger volumes. In the region of the
upper extremities, 2-3 ml CM usually suffices to fill the lymphatics and regionallymph nodes.
During infusion of oily CM, pain along the course of the epifasciallymphatics may occur if there is an imbalance between vessel capacity and infusion
rate. This pain results from rupture of the vascular wall. In such cases, the rate
of infusion should be reduced or the infusion interrupted for a short time. If
allergic reactions occur, it is necessary to stop the CM infusion and initiate
appropriate treatment without delay.
After completing the CM infusion, anteroposterior (AP) X-ray films are
made of the extremities and of the trunk at two levels (the lymphangiogram
comprises the filling phase). In order to visualize the lymph nodes free of any
superimposition, the same series of films is repeated ca. 24 h later (the lymphadenogram comprises the storage phase).
Indirect lymphangiography
A subepidermal infusion of appropriate, water-soluble CM permits the visualization of peripheral lymphatics, and incompetence of the lymphatic valves. It
also permits an assessment of primary lymph vessels [7]. The CM is generally
infused into toes, fingers or into the backs of the feet or hands. Other injection
sites are possible, depending on the clinical question posed. In localized
oedema, for example, the CM can also be infused into the face and neck region
or in the trunk.
9.5 Direct Lymphography and Indirect Lymphangiography
The diagnostic value of visualization of the peripheral lymphatics is largely
dependent upon injection technique. This, in turn, is firmly based upon accurate subepidermal positioning of the cannula tip. Following puncture, the
cannula tip should remain just visible through the skin. During infusion, an
epidermal wheal is produced with a dark centre and a lighter border. This
indicates accurate cannula location.
The infusion rate is on the average, 0.15 mllmin. Slower infusions lead to
decreased contrast density in the lymph vessels. A total amount of 2 - 4 ml CM
per puncture site is sufficient.
Peripheral lymphatics and, under certain conditions, dilated primary lymph
vessels also can usually be demonstrated a few minutes after infusion begins.
The first X-ray fIlm is made 3-5 min after the start of infusion in order to
register local changes in the area of the puncture site. Later, these changes may
be overshadowed by the CM collection and thus escape detection. In addition,
fIlms should be taken at intervals of ca. 5 min until the desired area is visualized.
In contrast to the case with direct lymphography, however, lymphatics can only
be assessed here over a length of approximately 40 cm. This is the result of the
relatively rapid diffusion of CM through the vessel wall. Visualization of the
lymph nodes is not possible with indirect lymphangiography.
Complications I: Those Induced by the Method
Direct Lymphography
Wound infections, delayed healing of wounds, lymphangitis, erysipelas, and
cutaneous necrosis are side effects that have to be reckoned with in direct
lymphography [1]. Inaccurate positioning of the cannula can lead to extravasation and unwanted CM intravasation in neighbouring veins. The frequency
of allergic reactions to the dye used, patent blue/violet, is put at 0.1 %-1.5%.
Allergic reactions can also be triggered by skin desinfectants [1].
Indirect Lymphangiography
No complications of indirect lymphangiography are presently known. A slight
burning sensation during infusion in the area of the puncture on one or both
sides was commented (on by ca. 10 % of the 150 patients of our own series. It was
never necessary to interrupt the examination. If pain becomes intolerable,
however, the infusion rate should be reduced. The burning sensation is not
induced by the CM, but is a result of local tissue irritation by the subepidermal
infusion. In isolated cases, small cutaneous ulcers have been observed in the
area of puncture. They healed in a few days without treatment and without
sequelae [19].
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Table 9.5.1. Pulmonary complications and deaths after direct lymphography with oily CM.
Results from two composite statistical studies based on 32000 and 40500 examinations,
respectively
Complications or deaths
Pulmonary embolism
Lipiodol pneumonia
Pulmonary oedema
Death
Study results
Keinert [IJ
Kohler and Viamonte [2J
1 :400
1:2500
1:3200
1: 1800
1: 1400
1: 1900
1: 10000
1: 13500
Complications II: Those Induced by the Contrast Medium
Direct Lymphography
Allergic reactions to the oily, iodinated CM are to be expected in 1: 800 examinations on the basis of accumulated data. CM-induced foreign-body reactions with
subsequent fibrosis of the lymph nodes [4] and paravascular foreign-body reactions in cases of extravasation can lead to a reduction of the transport capacity of
the lymphatic system. In lymphostatic oedemas of the extremities, this usually
results in a worsening of the disease. Passage of the oily CM into the venous
system results in microemboli in the lung [1,2]. There is a direct relationship between the frequency of pulmonary complications (Table 9.5.1) and the CM dose
administered. Volumes of less than 3.5 ml per lower extremity are usually well
tolerated. Lung diseases accompanied by marked limitation of function are to be
viewed as contraindications to direct lymphography. Cerebral, renal and cardiac
complications (1: 2700 - 5000) are possible, though rare. CM passage into the liver
usually has no sequelae. According to the literature, temporary temperature rises
(dose dependent) have to be reckoned with in 10 % - 20 % of examinations [1]. The
frequency of nausea and vomiting is put at 4 %.
Indirect lymphangiography
Allergic reactions triggered by nonionic CM are possible, though rare (see
Sects. 4.1,4.2) [6]. Nothing is presently known about other CM-induced complications.
Conclusions
Since the use of oily CM can lead to severe complications, direct lymphography
should only be performed if valuable diagnostic information will be gained
from it and procedures involving lower risk have not produced an unequivocal
diagnosis. The routine use of oily CM is no longer justified today. Direct
9.5 Direct Lymphography and Indirect Lymphangiography
lymphography is contraindicated if a worsening of the disease can be expected
from the side effects associated with the examination. This can generally be
assumed to be the case in primary lymphoedema. For the visualization of
lymphatics in peripheral regions (indirect lymphangiography), nonionic, dimeric, water-soluble, X-ray eM that are well-tolerated should be exclusively used.
References
1. Keinert K, Kohler K, Platzbecker H (1983) Komplikationen und Kontraindikationen. In:
Liining M, Wiljasalo M, Weissleder H (eds) Lymphographie bei malignen Tumoren.
Thieme, Stuttgart
2. Koehler PR, Viamonte Jr M (1980) "Complications". In: Viamonte M Jr, Riiffimann M (eds)
Atlas of lymphography. Thieme, Stuttgart
3. LUning M, Wiljasalo M, Weissleder H (1983) Lymphographie bei malignen Tumoren.
Thieme, Stuttgart
4. Oehlert W, Weissleder H, Gollasch D (1966) Lymphogramm und histologisches Bild bei
normalen und pathologisch veranderten Lymphknoten. ROFO 104: 751-758
5. Partsch H, Stober! C, Urbanek A, Wenzel-Hora B (1988) Die indirekte Lymphographie zur
Differentialdiagnose des dicken Beines. Phlebol Prokt 17: 3-10
6. Partsch H, StOber! C, Wruhs M, Wenzel-Hora B (1989) Indirect lymphography with
iotrolan. Recent developments in nonionic contrast media. In: Taenzer, Wende (eds)
Thieme, Stuttgart 178-181
7. StOber! C, Partsch H (1988) Indirekte Lymphographie. Odem 105 -107
8. Tiedjen KU (1993) Traumatisches LymphOdem und lymphatische Kollateralkreislaufe.
Phlebol 22: 140 -147
9. Tiedjen KU, Schultz-Ehrenburg U, Knorz S (1992) LymphabfluBstOrungen bei chronischer
Veneninsuffizienz. Phlebol 21: 63 -71
10. Viamonte M Jr, Riittirnann A (1980) Atlas oflymphography. Thieme, Stuttgart
11. Viamonte M Jr, Riittirnann A (1980) Technique. In: Viamonte M Jr,Riittirnann A (eds) Atlas
of Lymphography. Thieme, Stuttgart
12. Weissleder H (1965) Die Lymphographie. Ergeb Inn Med Kinderheilk 23 : 297 - 334
13. Weissleder H (1981) Lymphographie. In: Fromrnhold W(ed) Erkrankungen des Lymphsystems. Thieme, Stuttgart
14. Weissleder H (1986) Stellenwert der direkten Lymphographie. Odem 68-76
15. Weissleder H (1988) Aktueller Stand bildgebender Verfahren in der Lymphodemdiagnostik. Odem 42 - 48
16. Weissleder H (1990) Zwei schonende Methoden der LymphgefaBdiagnostik. Herz Gefasse
10: 8-16
17. Weissleder H (1995) Indirekte Lymphangiographie. In: Miiller KHG, Kaiserling E (eds) LymphgeHillsystem, Lymphatisches Gewebe, vol I. Springer, Berlin Heidelberg New York Tokyo
18. Weissleder H, Brauer JW, Schuchhardt C, Herpertz U (1995) Aussagewert der FunktionsLymphszintigraphie und indirekten Lymphangiographie beim Lipodem-Syndrom. Lymphol19: 38-41
19. Weissleder H, Weissleder R (1989) Interstitial lymphography: initial clinical experience
using a dirneric non-ionic contrast agent. Radiology 170: 371-374
20. Weissleder H, Weissleder R (1989) Vergleichende indirekte Lymphan??0iograph?und
Lymphszintigraphie bei Lymphodemen der Extremitaten. Lymphologica 71-77
21. Wenzel-Hora B, Partsch H, Berens von Rautenfeld D (1985) Sirnultane indirekte Lymphographie. In: Holzmann H, Altmeyer P, Hor G, Hahn K (eds) Dermatologie und Nuklearmedizin. Springer, Berlin Heidelberg New York
22. Wenzel-Hora B, Partsch H, Urbanek A (1985) Indirect lymphography with lotasul. The
initial lymphatics 1: 117 -122
179
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
9.6
Angiocardiography
M. THORNTON and P. WILDE
Why?
The indications for angiocardiography can be divided into those for congenital
and those for acquired heart disease, with the latter being the major contributor
to the need for this investigation in terms of numbers. Acquired heart disease is
dominated by ischaemic heart disease, but acquired valvular heart disease
remains common. All chambers of the heart can be imaged, as can the great vessels and the coronary arteries, but some chambers are more often studied
because of clinical need.
The left ventricle is the commonest chamber to be imaged. This can give
information on left ventricular function with particular detail of any areas that
are not contracting normally, as occurs, for example, following myocardial infarction, cardiomyopathy, or other disease processes. During catheterization of
the left ventricle, pressure measurements are taken which are valuable in assessing both ischaemic heart disease, valvular heart disease, and other acquired
and congenital disorders of the heart.
The great arteries can be imaged by aortography and pulmonary angiography, providing valuable information in specific conditions. Aortography is
useful in assessing aortic valve disease, the aortic root, and in congenital heart
disease. The branches of the proximal aorta may also be imaged, either from an
aortic injection or selectively, and the brachiocephalic artery, carotids and subclavian arteries may be imaged, too. The pulmonary artery is studied from a
right heart catheterization in congenital heart disease, in pulmonary hypertension, and in the investigation of pulmonary embolism.
Selective coronary angiography is extremely important, and selective catheterizations of the right coronary artery, the left coronary artery, and coronary artery
bypass grafts can all be performed during cardiac catheterization. Coronary
arteriography, usually combined with left ventriculography, is one of the most
commonly performed invasive investigations worldwide. A routine examination
for ischaemic heart disease includes a left ventriculogram and selective coronary
angiograms. In the case of significant mitral valve disease, other causes of raised
cardiac filling pressures, congenital lesions, and pulmonary hypertension, cardiac
catheterization may be performed to assess both the left and right sides of the
heart. Catheterization of the right heart may be combined with pulmonary
angiography in patients with suspected pulmonary emboli for whom non-invasive imaging has not been adequate and also in patients with life-threatening
pulmonary emboli for whom interventions are being considered (thrombolysis,
percutaneous thrombectomy, and inferior vena cava filtration).
In the assessment of complex congenital heart disease, it is often necessary to
catheterize most chambers of the heart and the great vessels. Accurate in-
9.6 Angiocardiography
Fig.9.6.1. Left ventriculogram in a 30° right anterior oblique: in diastole (A) and systole (B)
formation on coronary artery anatomy is also often required, as this may be aberrant. Whilst much important information can be obtained from non-invasive
investigations (electrocardiography, chest radiography, echocardiography, computed tomography, and magnetic resonance imaging) no technique other than
selective coronary angiography gives adequate information on coronary anatomy
and disease in adults. In paediatric angiocardiography, adequate information on
coronary artery anatomy can be obtained from aortography. Interventional techniques, which are becoming more complex and greater in their range of applications, rely on angiocardiography to direct the interventions. The commonest of
these interventions is angioplasty and stenting for occlusive coronary artery
disease. In congenital heart disease, angiocardiography is required not only in the
initial investigations, but often subsequently, after surgical intervention.
When?
The place for angiocardiography in the investigation of cardiac disease has to
be within a diagnostic strategy, with the non-invasive imaging techniques being
used if the required information can be achieved without cardiac catheterization. Most patients will have had electrocardiography and chest radiography,
both of which may provide a diagnosis. Much complex cardiac disease can be
adequately investigated by echocardiography. The particular attraction of echocardiography is that it uses ultrasound and there is thus no known risk to the
patient. In addition, in many cases the echocardiogram provides all the information on the anatomy of the cardiac chambers and valves. In many
instances, left ventricular function can be assessed by echocardiography, and
only if there is a need to image the coronary arteries is angiocardiography
performed. Angiocardiography may often be performed on patients for whom
the technical quality of the echocardiogram is inadequate or where the abnormality lies in a site not visualised well by echocardiography, such as the pulmonary arteries, which are surrounded by air. Left ventricular function and
perfusion can also both be assessed by isotope cardiac studies, which do involve
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Figs. 9.6.2 and 9.6.3. Selective left coronary angiogram: Fig. 2 is a 60° left
anterior oblique and, Fig. 3
is a 40° right anterior oblique. In this patient the circumflex artery (A) is small.
The left main stem (B), left
anterior descending artery
(C) , diagonal artery (D),
and a septal branch (E) are
all demonstrated
9.6.2.
E....
9.6.3.
9.6 Angiocardiography
the injection of a pharmaceutical that emits ionising radiation, but which are
otherwise non-invasive. Excellent anatomical information on the heart is often
available from magnetic resonance imaging (MRI), but the spatial resolution of
MRI is not yet good enough to visualise coronary artery disease. Excellent
images of congenital heart disease, aortic disease, and the of left ventricle,
however, are available with the most advanced MRI machines.
In general, therefore, angiocardiography is required for cardiac disease when
detailed images of the coronary arteries are needed, when inadequate information on cardiac chambers or valves has been achieved from echocardiography
or MRI, or when intervention is expected to be undertaken. Therefore, many
patients with cardiac murmurs, valvular heart disease, aortic disease, and some
congenital heart defects no longer require angiocardiography. However, there
will still be many patients who benefit from the precise anatomical and physiological information provided by angiocardiography.
The advantages of angiocardiography over the non-invasive techniques
include the ease of obtaining pressure measurements (can be obtained to a
limited degree on echocardiography), the ability to proceed to intervention
(especially in coronary artery disease), and the opportunity to sample blood for
gas saturations from the cardiac chambers and great vessels, which is particularly valuable in congenital heart diseases. The disadvantage of angiocardiography is that it exposes patients to ionising radiation and iodinated contrast media (CM); here is also the important factor of the initial expense of
setting up a cardiac catheterization laboratory and the marginal cost of each
study, which is relatively high. Invasive procedures remain somewhat uncomfortable and unpleasant for patients, and there is also the risk of catheter complications for blood vessels, the heart, and distal organs.
There are several conditions for which angiocardiography is being replaced
by other techniques. In valvular heart disease, echocardiography is the standard
imaging modality, with MRI beginning to be used more frequently. This is
because the important data on pressure gradients across valves can be
measured on echocardiography using Doppler ultrasound, and information on
the size and contractility of cardiac chambers can also be assessed. Left ventricular function assessment is now routinely made on echocardiography, with
cardiac isotope studies and MRI also being used. Whilst the assessment of congenital heart disease often involves several modes of imaging, much data on
initial diagnosis and follow-up can be readily obtained on echocardiography or
MRI. Imaging the thoracic aorta for aneurysms, dissection, or trauma,
traditionally a field dominated by angiography, is now easily achieved with
computed tomography (CT) or MRI, with trans-oesophageal echocardiography
being used when CT or MRI are equivocal or contra-indicated.
How?
In general, angiocardiography is similar to other angiographic techniques, but in
a cardiac catheterization laboratory there is equipment available for continuous
electrocardiographic and pressure measurements, and biplane imaging is often
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Fig. 9.6.4. Selective right
coronary angiogram in a
30° anterior oblique demonstrating: conus branch (A),
right atrial branch (B), right
ventricular branch (C), and
posterior descending artery
(D) are all demonstrated
available. Angiocardiography is frequently performed with single plane imaging
due to the expense of biplane equipment, but this does slightly increase the length
of the study and the volumes of CM used. In the case of biplane studies, two
angiographic projections of the same CM injection can be recorded.
During angiocardiography, pressure measurements are continuously monitored using a pressure transducer from the catheter tip; during right heart
catheterization, pressure measurements are recorded from both chambers of
the right heart and the main pulmonary arteries. Wedge pressure measurements are also recorded, giving an indirect measure of the pressures in the left
atrium. Samples for blood gas analysis can also be sampled from the left and
right heart, which is very useful in assessing intra-cardiac shunts.
In a conventional cardiac catheterization laboratory, the study is recorded on
35-mm cine film, which provides excellent spatial resolution and good contrast
resolution and is relatively cheap. However, digital angiocardiography is replacing the older cine equipment. The advantages of digital angiocardiography
are: easier replay, lower film cost, and easier storage. In addition, the digital
systems allow for reproducible measurements of left ventricular function and
measurements of coronary stenoses, which were not available on cine systems.
The disadvantages are: the high capital equipment costs and the greater cost of
digital archiving (CD or digital tape). A further disadvantage of digital angiocardiography is (currently) slightly poorer spatial resolution and a slower frame
rate. The use of digital angiography elsewhere in the body has, by virtue of digital subtraction, led to the use of smaller volumes and less concentrated
solutions of CM. The respiratory and, even more so, cardiac motion in cardiac
imaging have not enabled these potential advantages to be fully utilised.
9.6 Angiocardiography
Cardiac motion has precluded the use of arteriography with intravenous injections of CM, which in non-cardiac work have proved useful with digital subtraction techniques.
Vascular access is usually obtained from the right common femoral artery or
the right common femoral vein, as in other angiographic procedures. The
femoral artery is punctured below the inguinal ligament using a Seldinger or
modified Seldinger technique, and a guide-wire (usually with a I-shaped
leading-end) is introduced into the femoral artery and thence to the iliac artery.
Since several catheter changes are required, during angiocardiography, a
vascular introducer sheath is usually placed to allow for atraumatic catheter
exchanges. If a right-heart catheterization is to be performed simultaneously, an
introducer sheath is then placed in the common femoral vein to allow catheter
changes on the venous side. Recently, the tendency has been to use smaller
catheters and introducer sheaths, and 6 French catheters are commonly used for
diagnostic work. Only occasionally are smaller catheters used in adults (smaller catheters are selected as appropriate in paediatric cases). During interventional procedures, catheters and introducer sheaths up to 8 French, and
occasionally larger ones are used. Angiocardiography may be performed from
a brachial artery puncture or "cut-down", but the complication rate from this
upper limb approach is slightly higher than from the common femoral artery
puncture [1,2] and is not used in most centres, unless there is difficulty with
access from the common femoral artery (often advanced atherosclerosis of the
iliac arteries). In a few centres, experienced operators favour the brachial route
as a routine approach. Pigtail catheters are commonly used for pump injections
into the aorta, left ventricle, right atrium, right ventricle, and pulmonary
arteries. The pigtail catheter has end and side holes, and even during a large
rapid injection the tip of the catheter does not point towards the vessel wall and
thus should avoid intimal trauma and its complications. For special situations,
selective catheters are used which are preshaped to aid intubation of specific
vessels (commonly, coronary arteries and coronary artery bypass grafts).
Contrast Media and Catheter Selections
The selection of contrast media, as in other angiographic situations, should be
of the least concentrated formulation necessary to achieve the best image;
however, in angiocardiography where digital subtraction is not possible and
high resolution imaging of fine detail is required the more concentrated
solutions of CM are generally used. Non-ionic low osmolar CM of 370 mg
iodine/ml concentration is very commonly selected, although some operators
choose 350 mglml or even 320 mg/ml iodine concentration. The lower rate of
both minor and major complications achieved with non-ionic CM have meant
that ionic CM are no longer much used. The CM is pump injected for aortography and for left and right ventriculography to deliver the larger volumes
required. Hand injections are normally used for selective catherizations.
The left ventriculogram is performed with the pigtail catheter, directed
under X-ray screening across the aortic valve and positioned free in the left
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CHAPTER 9 Clinical Use of Iodinated eM for the VisuaIization of Vessels and Organs
ventricle such that the mitral valve apparatus is not compromised. A 35 or
40-ml pump injection of non-ionic CM at 12 mlls with a 0.5-S rise time is then
given while the cine or digital acquisition is recorded. This gives a 3-S bolus,
which allows the function of the left ventricle to be observed over a few cardiac
cycles. The usual projections are the 30° right anterior oblique and 60° left
anterior oblique; however, if only one projection is used the right anterior
oblique is generally chosen.
Selective left coronary angiography is usually performed using a left Judkins
catheter with a 6- 8 ml hand injection of CM at a rate which opacifies the coronary artery until CM refluxes into the sinus of Valsalva. Usually, five projections
are acquired to visualise the left main stem, the left anterior descending, and the
circumflex arteries. A flexible approach to selection of views is needed to ensure
that all major branches are well seen. Cranial and caudal angulations are
frequently added to standard oblique projections. The right coronary artery is
selectively catheterized using a Judkins right catheter; only 2- 5 ml of CM are
required to opacify the whole artery, and the simpler anatomy is usually
demonstrated with only three projections. Coronary artery bypass grafts are
selectively catheterized with special graft catheters, and grafts from the left
internal mammary (internal thoracic) artery are catheterized with preformed
specific catheters. CM is hand injected with volumes of between 6 and 10 ml.
The right ventriculogram is performed infrequently in adults; it is carried
out with a pigtail catheter, and a volume of CM is selected that will adequately
opacify the ventricle, usually 40 ml. Pulmonary angiography is performed with
a pigtail catheter using a 50-ml pump injection at 20 mlls with a 0.5-S rise time
if a common trunk study is required. The left and right pulmonary arteries are
often imaged separately, with smaller volumes of CM, usually pump injected
selectively into the right and left pulmonary arteries. In this case, 30 ml are
injected in each side The distal pulmonary arteries may be imaged with a
pigtail catheter or multi-purpose catheter with lO-ml hand injections. The
projections and the number of acquisitions will depend on the purpose of the
study and will differ from patient to patient.
Aortography is performed to visualise the aortic arch and thoracic aorta. In
some instances this will be to demonstrate regurgitation through the aortic
valve, but more often it will be to study the aortic arch (trauma or dissection)
or to identify the origins of coronary artery bypass grafts or the origins of the
head and neck arteries. Aortography is achieved with a pigtail catheter placed
in the ascending aorta and using a pump injection of 50 ml CM at a rate of
20 mlls with a 0.5-S rise time. A single projection is often sufficient, but a second
view may be helpful in difficult cases. The examination must be suited to the
anatomy of each patient and the clinical situation, but commonly used projections would be a 60° left anterior oblique and a 30° right anterior oblique.
Interventional Procedures
During interventional procedures, similar techniques to those used in
diagnostic angiocardiography are employed. In coronary angioplasty and
9.6 Angiocardiography
stenting, special catheters and devices are used, but the same CM (non-ionic
CM of 370 mg iodine/ml) are used, as good opacification to maximise contrast
is required. Interventional techniques are often prolonged and complex, with
many angiograms being taken to assess the progress of the procedure. It is
important for the operator to keep in mind the total volume of CM used and the
effects it will have on the patients' circulation and other organs.
Similar techniques with specially developed catheters are available to perform the closure of a patent ductus arteriosus or a valvuloplasty. The diagnosis
and treatment of pulmonary embolism is sometimes performed using catheter
techniques from the right femoral vein. Pulmonary emboli may be thrombolysed from a catheter in the pulmonary artery, or large emboli may be either
aspirated or dispersed.
Complications
Complications can be conveniently divided into those related to the CM and
those related to the technique. CM-related complications are unusual with nonionic agents, and when they occur, are usually minor (e.g. urticaria or nausea).
Major reactions to non-ionic CM are rare, require urgent attention, and will
probably prevent completion of the study.
Technique-related complications are more common and can be classified as
those related to the puncture site and those related to the heart. Puncture-site
complications include haematomas, which are commoner with larger-diameter
catheters and the use of heparin, and infection, which should be avoidable with
good aseptic technique. False aneurysm formation occurs when haemostasis is
not achieved following the procedure and should be avoidable with good compression of the puncture site. Embolization of thrombus, atheroma, or introduced material may occur down the femoral artery or, more significantly, up the
head and neck vessels. These complications can best be avoided with
meticulous technique and the minimum number of catheter exchanges, and
then with the use of guide-wires that are atraumatic. Other complications that
may occur at the puncture site include arterio-venous fistula formation in the
groin and femoral artery occlusion or dissection, both of which should be rare
and should only occur in patients in whom the arterial puncture proved very
difficult.
Cardiac complications from angiocardiography include cardiac arrhythmias,
which are common and are usually brief and of no consequence. However,
severe life-threatening cardiac arrhythmias do occur and can be fatal unless
quickly identified and treated. Cardiac rupture may occur but is very rare, and
myocardial infarction can supervene, especially during coronary angiography
in patients with severe coronary atherosclerosis. Sudden death may occur without warning in unstable patients during cardiac catheterization. A study in 1979
of over 7,500 patients undergoing coronary angiography reported a death rate
of 0.51 per cent in patients studied from a brachial puncture and 0.14 per cent
in patients studied from a femoral puncture. In this same study, cerebral
ischaemia occurred in 0.17 per cent in the brachial sub-group compared to 0.08
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
per cent in the femoral sub-group [1]. A more recent report on a cohort of over
220,000 patients [2] also revealed a four-fold local increase in vascular complication rate from brachial punctures as compared to femoral punctures, but a
similar overall death rate of 0.10 per cent. The risk of a local vascular complication from a brachial puncture is between 1 and 2 per cent [1,2]. Complications
to the coronary arteries include dissection, occlusion, and embolization.
Dissection may occur during selective coronary catheterization, especially in
patients with advanced atherosclerosis of the main stem of the left coronary
artery, whereby the incidence of death in a large series of patients was found to
be 0.55 per cent compared to an overall incidence of death during coronary
angiography of 0.10 percent. Dissection may also occur during angioplasty and
can usually be treated with an arterial stent placed over the intimal dissection.
These interventions require the operator to have extensive experience of interventional cardiac radiology and cardiological treatments. It should be stated,
however, that most complications are best avoided by experience and good
technique, and major complications should be rare in a well-run cardiac catheter laboratory.
Conclusions
In conclusion, despite the possible complications and the development of lessinvasive imaging techniques, there remains an important role for angiocardiography. Currently, angiocardiography provides the only method of defining
coronary artery anatomy. Interventional cardiology continues to expand the
scope of disorders that may be treated percutaneously, and these all require
angiocardiography. In most operators' practice, non-ionic CM have replaced
ionic CM because of greater tolerance and safety. Important differences in
paediatric patients should be emphasised: it is easier to over-dose very young
patients with CM, especially those with complex congenital heart disease; but
while it is important to minimise the CM dose, this should not be to the extent
that the study is compromised.
The newer digital angiocardiographic equipment is becoming superior to
cine angiocardiography, but the greatest benefit of this type of imaging is
during interventional procedures when the speed of reviewing images reduces
the duration of the procedure and can thus reduce complications.
References
1.
2.
Davis K, Kennedy JW, Kemp HG et aI. (1979) Complications of coronary arteriography
from the Collaborative Study of Coronary Artery Surgery (CASS). Circulation 59: 1105
Johnson LW, Lozner EC, Johnson S et aI. (1989) Coronary arteriography 1984-1987: A
report of the Registry of the Society for Cardiac Angiography and Interventions. I. Results
and complications. Cathet Cardio-vasc Diagn 17: 5
9.7 Angiographic Procedures for the Liver, Spleen, Pancreas and Portal Venous System
9.7
Angiographic Procedures for the Liver, Spleen, Pancreas
and Portal Venous System
W.RODL
Preparation of the Patient
1. General Preparation
- Written declaration of informed consent of the patient on the day before the
examination.
- Fasting for at least 4 h prior to examination, at the most one cup of tea is permitted.
- Determination of coagulation status, and of creatinine and urea.
- Shaving of the inguinal region.
2. Special Preparations for Abdominal Angiography
- Diet low in fibre and gas-reducing measures on the day before examination.
Intestinal hypotonia (1 ampoule Buscopan or Glucagon IV) prior to the CM
injection, especially in intra-arterial DSA.
- Plain radiograph for exclusion of residual CM in abdomen. Prior information from US, CT and/or MRI.
- In selective transhepatic portal venous catheterization, for the purpose of pancreatic venous sampling, production of a guiding "venous map" of the portal
vein by means of indirect mesenteric and splenic portography on the day before examination. Peroral contrast imaging of the gallbladder on the eve of the
examination in order to decrease the risk of gallbladder perforation.
Indications and Indication-Specific Angiographic Procedures
In principle, angiography can be performed as standard with a cut-film changer
(today hardly available) or as intraarterial DSA.
Liver
Coeliac arteriography, selective and superselective hepatic arteriography and
superior mesenteric arteriography should be performed to clarify the following
questions:
- Preoperative vascular anatomy prior to segment resection or transplantation.
- For specific issues, discovery of focal lesions and search for metastases (e. g.
vascular metastases in carcinoid (Fig. 9.7.3) or colorectal tumours), discovery
of a hepatoma in cirrhosis.
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Fig. 9.7.1. Focal nodular hyperplasia of the liver. The richly vascular tumour in the right lobe
can be seen in the arterial (a), capillary (b) and parenchymatous phase (c)
- Differential diagnostic classification of vascular tumours such as haemangioma, focal nodular hyperplasia (Fig. 9.7.1) or adenoma, and haemangioendothelioma.
- Chemoembolization accompanying hepatocellular carcinoma (HCC) and
liver metastases.
- CT portography after selective catheterization of the superior mesenteric
artery.
Spleen
Coeliacoarteriography or selective splenic arteriography should be performed
in the following situations:
- Preoperative vascular anatomy.
- Post-traumatic conditions.
Pancreas
Coeliacoarteriography and selective hepatic arteriography or splenic arteriography to answer the following questions:
- Preoperative vascular anatomy, e. g. accessory or replaced hepatic artery
prior to a resection of the head of the pancreas.
- Differentiation between pancreatitis and carcinoma of the pancreas (vascular encasement).
- In suspected insulinoma: first, superselective angiography of the hepatic
artery and/or the gastroduodenal artery on the one hand and of the splenic
artery on the other to localize tumours of the head, body or tail of the pan-
9.7 Angiographic Procedures for the Liver, Spleen, Pancreas and Portal Venous System
Fig. 9.7.2. Insulinoma of the tail of pancreas. Coeliac angiography demonstrates the round,
vascular tumour (arrowheads) which has displaced the vessels in the area of the tail of the
pancreas
creas (Fig. 9.7.2); secondly, percutaneous, transhepatic portal venous catherization with superselective venous sampling from the veins of the head,
body and tail of the pancreas to localize tumours directly (Fig. 9.7.4).
- In suspected gastrinoma: superselective, arterial catherization of the arteries
of the head, body and tail of the pancreas. Superselective, intra-arterial secretion (IA-S) stimulation by injection of small doses of secretin (30 units
Sekretolin), simultaneous venous sampling, the first time via a transfemoral
catheter from the right hepatic vein and then peripherally, from a cubital
vein, 30, 60, 120, and 210 s after IA-S stimulation. An increase in gastrin of
over 50 % in the 30-S sample from the hepatic vein provides an indirect clue
to gastrinoma localization.
Portal Venous System
- In portal hypertension, indirect spleno- and/or mensenteric portography for
the differentiation of pre-, intra- and post-hepatic obstruction and for the
demonstration of any collateral circulation or hepatofugal flow.
- Direct hepatic phlebography in suspected post-hepatic obstruction.
- In pancreatic diseases with suspected splenic vein thrombosis and collateral
circulation, indirect splenoportography.
- Alternative procedures are Colour Doppler and MR angiography.
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Fig. 9.7.3 a, b. Carcinoid metastases in the liver. In the capillary phase (a), but even more
impressive in the parenchymatous phase (b), richly vascular carcinoid metastases have been
visualized in the liver by selective hepatic arteriography
Contraindications
1. Definite Contraindications
- For puncture, Quick's value under 50 %, thrombocyte count under
80,ooo/cm3 •
- For CM injection, creatinine above 2 mg%.
2. Relative Contraindications
-
General allergic diathesis.
Known CM hypersensitivity.
Known hyperthyroidism.
Patient over 50 years of age with nodular goitre: danger of a compensated,
autonomous adenoma with the triggering of a thyreotoxic crisis after CM
injection.
- Lack of therapeutic implications.
Arterial route of entry (transbrachial, transaxillary) is unsuitable given
clinical situation and frequency of complication.
9.7 Angiographic Procedures for the Liver, Spleen, Pancreas and Portal Venous System
Fig. 9.7.4 a, b. Transhepatic portal catheterization in insulinoma. After transhepatic
puncture, the catheter is introduced up to the hilus of the spleen and to the root of the
mesenteric artery. To determine the hormone level 4 - 6 ml blood is selectively drawn from
the splenic artery (a) and superior mesenteric vein (b) and from the portal confluence for
laboratory investigation
Examination Technique
Puncture and Vascular Approach
1.
General
- Local anaesthesia by injection of a 1 % local anaesthetic: in transfemoral
puncture 10-15 ml, in transaxillary, 10 ml, in transbrachial, 5 ml.
- Puncture following skin incision by Seldinger technique. Introduction of
a catheter sheath only if multiple catheter change is anticipated and transfemoral approach used.
2. In coeliac angiography, selective hepatic angiography, or splenic angiography and in indirect splenic and/or mensenteric angiography, routinely, transfemoral approach: retrograde puncture 3- 4 cm below the inguinal ligament.
Only in exceptional cases (stenoses of the iliac arteries or of the adominal
aorta, the presence of a bifurcation prothesis or other factors resulting in a
higher risk of complications) is a transaxillary approach (right axilla
routinely punctured 7 cm laterally to the deepest point of the armpit) or a
transbrachial approach (brachial artery in the bend of the elbow above the
medial condyle of humerus) utilized.
3. In selective hepatic vein sampling with or without phlebography, routinely a
transfemoral approach is used; only in deep vein thrombosis of the leg or
pelvis is an ante cubital or transjugular approach used.
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Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
4. In selective pancreatic vein sampling (suspected insulinoma) by means of
percutaneous, transhepatic, portal venous catheterization, transhepatic
approach under ultrasound and/or fluoroscopic control.
- Puncture site is the 9th -11th intercostal space in the midaxillary line, on
the right. Direction of puncture: T-12.
Puncture with an in-dwelling catheter needle. Removal of the inner
needle. Retraction of the catheter until portal blood drains. Make sure of
intraportal catheter position by means of CM injection.
Substitution of a J-wire with a moveable core.
Introduction of a headhunter catheter (5 F) and placement of the catheter
tip, first in the splenic hilum, then in the peripheral mesenteric branches.
Stage-by-stage retraction of the catheter accompanied by superselective
pancreatic vein sampling at each stage (6-8 ml each time) and by the
marking of the sampling position on a venous map previously drawn up
(indirect splenomesenteric portography on the previous day).
Blood samples sent to laboratory for chemical analysis. The topographical
correlation of the hormone peak with the sampling location makes insulinoma localization possible (Fig. 9.7.4).
Catheter Selection
For Arterial Use
- In the transfemoral approach for flush aortography (not obligatory),
pigtail catheter, 65 em, 5 F, high-flow. In selective or superselective catheterization, cobra or sidewinder catheter with side holes, 70 em, 5 F, highflow.
- In transaxillary or transbrachial catheterization, 4 F catheter, 100 em.
2. For Venous Use
- In transfemoral hepatic vein catheterization, cobra or sidewinder catheter
with side holes, 70 em, 5 F.
- In transjugular or transbrachial approach, 4 F catheter, 100 em.
- In transhepatic portal venous catheterization, in-dwelling catheter set and
cobra or headhunter catheter with side hole, 4 - 5 F, 70 em.
3. Guidewire Selection
- Bent-tip wire (3-mm J-wire) with moveable core, fitting catheters (150 em)
with following calibres (in inches): 0.032,0.035,0.038.
- For superselective catheterization, Terumo guide with flexible tip, 150 em,
0.035 in. in calibre.
4. eM Selection and Administration
CM of choice are nonionic, uroangiographic CM. In standard angiography,
76% CM are used; in intra-arterial DSA, 20%-30% eM. In both, CM is
administered intraarterially. In general, only one-third as much CM is required in intraarterial DSA as in standard angiography.
For suggested flow rates of CM administered in different procedures, see
Table 9.7.1.
1.
9.7 Angiographic Procedures for the Liver, Spleen, Pancreas and Portal Venous System
Table 9.7.1. Administration of CM in different imaging procedures. Quantities (ml) and flow
rates (ml/s)
Imaging procedure
CM (ml)
300 mg iodinelml
Flow rate
(mUs)
60
10-15
15-18
10-15
Aorta
SA
lA-DSA
Coeliac trunk
SA
[A·DSA
30
10
5-6
5
20
5-10
4-5
4-5
30
5-10
4-5
5
Hepatic artery
SA
[A·DSA
Splenic artery
SA
[A·DSA
Superior mesenteric artery
SA
[A-DSA
50
10-15
4-5
up to 10
Transhepatic portography
SA or lA-DSA
5-10
(by hand)
Transfemoral hepatic phlebography
SA or lA-DSA
Indirect portography
as pharmaco-angiography:
Indirect mesenteric portography
or splenic portography
lA-DSA
5-10
5- [0
Prior injection of a vasodilator.
e. g. 1- 2 ampules of tolazoline
hydrochloride [25-50 mgJ
dilute with 10 ml aC[)
15-20
8-12
IA-DSA: intraarterial subtraction angiography;
SA:
standard angiography.
Complications
General Complications
These vary according to the route entry. The rate of complications rises from
1.73 % for the transfemoral approach to 3.29 % for transaxillary or transbrachial
approach. General complications are found due to the use of CM. Local complications arise due to the puncture (bleeding, arteriovenous fistula, aneuryms),
the guidewire or catheter (dissection. perforation, thrombosis) andlor compression (thrombosis, haematoma). A feared complication is the mistaken
injection of CM into a lumbar artery or into the artery of Adamkiewicz (paraplegia), resulting from the selective visceral catheter coming out of the vessel
during the examination (less than 1 %).
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Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Specific Complications in Percutaneous, Transhepatic Portal Venous Catherization
- Subcapsular and/or intraparenchymatous haematoma of the liver.
- Puncture of the pleura with pneumothorax and/or haemothorax.
- Puncture of the gallbladder with biliary peritonitis (emergency operation!).
Aftercare
The puncture site should be digitally compressed until bleeding ceases, then a
compression bandage applied and the patient restricted to bed for at least 6 h.
In portal venous catheterization, as in every puncture of the liver, pulse and
blood pressure should be checked every half hour for 4 h.
IA-DSA, intraarterial digital subtraction angiography; SA, standard angiography
Conclusions and Assessment
Angiographic procedures provide reliable information on the anatomy and
haemodynamics of the arterial and venous system of the upper abdominal
organs, especially of the portal venous system. In the sequence of procedures
employed, angiographic studies are used to supplement US, CT and MRI. In the
abdomen, standard angiography is still justified as a routine technique
especially in the GI tract but also in the upper abdominal organs. All selective
and superselective procedures, however, are today increasingly being performed as intra-arterial DSA.
In the liver, spleen and pancreas, angiography is indicated for preoperative
clarification of vascular anatomy and for demonstrating any vascular anomalies.
In vascularised focal lesions of the liver, hepatic arteriography has been
replaced by US, CT, MRI and 99m-Tc-HIDA scintigraphy. This is true both for
diagnosis of the type of haemangioma, focal nodular hyperplasia or adenoma
involved and for the detection of HCC or the metastases of a carcinoid.
In the pancreas, vascular encasement is an indication of a malignant tumour
in the differentiation between pancreatitis and carcinoma of the pancreas. To
locate gastrinomas, e. g. in Zollinger-Ellison syndrome, superselective intraarterial secretin stimulation followed by angiography and simultaneous
peripheral venous blood sampling to determine hormone levels is performed.
The topographical correlation of the gastrin peak with the site of secretion
stimulation retrospectively allows indirect localization of the gastrinoma.
In suspected insulinoma, superselective pancreatic angiography is combined
with superselective pancreatic vein sampling by means of percutaneous, transhepatic, portal venous catheterization. Here also, the topographic correlation of
the hormone peak (directly from the corresponding pancreatic vein sampling)
with the sampling site provides the retrospective clue to insulinoma localization.
9.8 Computed Tomography in the Liver, Pancreas and Spleen
When performing preoperative examination of the portal venous system in
portal hypertension and in searching for perisplenic, hepatofugal flow and
collateral circulation, indirect splenoportography, performed as pharmacoangiography, is still the method of choice today. Direct, transfemoral, hepatic
vein catheterization with hepatic venography is the method of choice for delineating a post-hepatic obstruction with hepatic vein thrombosis.
For these reasons angiographic procedures continue to playa role in this age
of modern imaging techniques.
9.8
Computed Tomography in the Liver, Pancreas and Spleen
A. ADAM and P. DAWSON
Why?
CT is currently being challenged in certain areas by MRI but it still remains the
investigation of choice for the examination of the liver, pancreas and spleen
when US has failed to provide a diagnosis. The development of spiral/helical CT
technology has boosted the power and potential of CT. It reduces imaging time,
thereby allowing multiphase contrast enhanced scanning, and, by acquiring a
whole volume data set, provides the basis for superior 3-dimensional image
reconstructions. CT provides an overall view of the upper abdomen and this is
a great advantage as diseases affecting one of these three organs frequently
present with secondary abnormalities in the other two. For example, pancreatic
carcinoma may be associated with hepatic and, occasionally, splenic metastases.
Another example is cirrhosis of the liver due to chronic alcoholism which may
be associated with pancreatitis and splenic varices.
Another advantage of CT scanning is that, following administration of CM, it
can provide important information about the vascularity of the organs being
examined. The viable parts of the pancreas following a severe attack of
pancreatitis can be identified and hepatic or splenic infarction can be
demonstrated.
The exquisite contrast sensitivity of CT and its ability to measure and display
X-ray attenuation accurately can provide diagnostic information such as the
occurence of haemorrhage in a pancreatic pseudocyst and can demonstrate
minute amounts of calcification in the pancreas in the cases of chronic
pancreatitis.
Using dynamic fixed level serio CT with a contrast agent bolus, global and
regional organ perfusion may be calculated for liver, spleen and pancreas. In the
liver the contributions of hepatic artery and portal vein may be calculated
separately.
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When?
CT has become widely available in recent years and routine examination following the injection of intravenous CM is indicated when a US study has not
provided a diagnosis. MRI is challenging CT, especially in the investigation of
liver disease, but the speed and convenience of CT and the ease with which
interventional procedures can be performed, combined with its more widespread availability, make it preferable to MRI in most centres.
More invasive studies, such as CT hepatic arteriography (CTA), CT-arterioportography (CTAP) and CT following hepatic intra-arterial Lipiodol (HIAL)
are usually reserved for patients with primary or metastatic liver tumours being
considered for partial hepatic resection. These studies are usually considered as
the definitive investigations of such patients and are performed when all other
examinations, including angiography, have not demonstrated a lesion in the
part of the liver which is to be preserved at surgery.
Which Contrast Medium?
Dynamic CT scanning, CTA, CTAP and delayed CT scanning are performed
using water-soluble, iodinated CM. Although small differences have been
demonstrated in the rate of diffusion of different CM into the hepatic parenchyma, the magnitude of these differences is not such as to affect the choice of
CM in practice. In making the selection, the principles applied are those which
govern the choice of CM for intravascular use in general.
Nevertheless, one point which must be considered specifically is the volume
and rate of injection of the CM to be employed for dynamic CT studies of the
liver: a 4s-g iodine dose is often given as 150 ml of 300 mgllml CM. It is well
known that patients with normal cardiac function can tolerate an acute intravascular volume expansion of 11. The volume of 150 ml of 300 mgllml ionic CM
is equivalent to - 500 ml of normal saline. This volume load of CM has been
accepted as safe in adequately hydrated patients with normal cardio-renal
function who undergo anglographic procedures. The only difference between
the method of CM delivery employed in angiography (3 ml kg bw/h) and the
technique usually employed in CT is that the CM is delivered over a minute or
so with due regard for the patient's cardiac function. Non-ionic CM, which has
approximately half the osmolality of ionic CM, can be used as an alternative for
patients with abnormal cardiae function. In patients with normal baseline
serum creatinine levels, there is no abnormal elevation of serum creatinine at
24, 48 and 72 h after the procedure. In patients with serum creatinine levels
greater than 1.5 mg/dl (132.611molll) a non-contrast-enhanced CT scan should
be obtained. If results from the non-contrast-enhanced CT scan are negative
in a patient with clinically suspected liver metastases, the use of MRI should
be considered.
Lipiodol injected selectively into the hepatic artery is taken up by tumours in
a variety of patterns. Normal hepatic parenchyma also takes up the Lipiodol,
but the CM is cleared from normal liver within approximately 1 week, whereas
9.8 Computed Tomography in the Liver, Pancreas and Spleen
it is retained in tumours. In general, vascular tumours such as hepatomas take
up Lipiodol in a diffuse manner, whereas avascular lesions may not retain it at
all or may demonstrate uptake only around the periphery of the lesion. It is
thought that Lipiodol is taken up by tumours due to some abnormality of
neoplastic vasculature which encourages leakage of CM into tumour. Another
explanation is that Kupffer cells clear Lipiodol from the normal hepatic
parenchyma but, as such cells do not exist within neoplastic tissue, Lipiodol is
retained within the latter. Usually approximately 10 ml Lipiodol emulsion is
injected into the hepatic artery and the CT scan is performed 7 -10 days later
but both the contrast volume and the timing of the examination vary considerably from centre to centre. The technique is now little used in Europe and
the USA.
Promising results were obtained in recent years with intravenously administered emulsified oily CM. These are taken up by the liver parenchyma and
focal lesions appear as low attenuation masses within the opacified hepatic
parenchyma on CT. Several such agents have been tried over the years but most
of them have proved too hepatotoxic for clinical use and the future of this
approach to the development of more liver specific agents is in doubt.
Which method?
The Spleen
Specific examinations of the spleen by CT scanning are rarely performed and
the organ is usually inspected when a study of the liver is done, in which case
the volume of contrast and timing of scans is determined by the type of liver
study being performed. Nevertheless when splenic lesions are being sought
specifically it is best to administer approximately 150 ml of 300 mgllml CM as
described below for dynamic liver CT but to delay scanning until 80 -120 S after
the beginning of the injection. This is because scans performed soon after the
injection of CM are likely to show patchy areas of unequal attenuation due to
differential flow patterns in the red and white splenic pulp. Later on, equalisation of splenic and parenchymal opacification increases the likelihood of
lesions being detected and reduces the number of false-positive and falsenegative results.
The Pancreas
The pancreas is scanned typically to detect tumour (carcinoma or neuroendocrine), to detect and assess the severity of pancreatitis and to assess the
involvement of blood vessels.
Unlike the liver the pancreas has an arterial blood supply and the pancreatic
parenchyma enhances earlier than that of the liver.
Helical scanning allows data acquisition of a volume as small as that of the
pancreas to be obtained in a very short time interval even if fine collimation
(e. g. 4- 5 mm) is used. A reliable pump injection of - 100 ml of 300 mgllml con-
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
trast agent at 3 or 4 mlls should be used. The scanning begins at, say, 30 s after
the beginning of the infusion. 4 or 5 mm collimation and a pitch of 1.5 would be
typical. A first scan may be carried out in a cranio-caudal direction and may be
followed by a less fine collimation (8 -10 mm) second scan in a caudo-cranial
direction taking in the pancreas again but then covering the liver in portal
venous enhancement phase.
Occasionally, CT arteriography is performed for the demonstration of vascular neoplasms of the pancreas such as neuroendoctine tumours. A catheter is
inserted selectively into the coeliac axis in the angiography suite. The patient is
transferred to the CT unit. 50 ml of 300 mgllrnl contrast agent is injected at, say,
1-2 mlls. Scanning begins immediately with a collimation of 4-5 mm and a
pitch of 1.5.
The Liver
The liver has a dual blood supply. The normal liver is supplied some 75 - 80 %
by the portal vein and some 20 - 25 % by the hepatic artery, while metastases
take virtually 100 % of their supply from the hepatic artery. An understanding
of this basic anatomy, physiology and pathophysiology is essential to planning
liver scans and to understanding where pitfalls lie in wait.
If, as is usually the case, hypovascular metastases (e. g. colorectal) are sought,
then a portal venous scan will suffice. Some 150 ml of 300 mgllml strength contrast agent is infused at 3 mlls and scanning begins at 60 -70 s after commencement of the infusion. Spiral technique allows completion of the scan
before the 'equilibrium phase' is reached (120 s or so onward).
If 'hypervascular' tumours (e.g. neuroendocrine metastases, carcinoid) are
suspected, scanning in the hepatic arterial phase may be useful. In this case
scanning begins at 20 - 25 s after the beginning of infusion. This will be typically completed in time to be followed by a well-timed portal venous phase scan as
described above. In the hepatic arterial phase, hypervascular lesions may be
seen as hyperdense with respect to surrounding normal liver parenchyma, but
are nevertheless usually seen as hypodense lesions in the portal venous phase,
Some possible pitfalls should be noted. The enhancement in the hepatic
arterial phase may be just enough to render isodense lesions which, precontrast, were hypodense. Less likely, but possible, the initial hepatic arterial
enhancement of a very hypervascular lesion may be sufficiently great as to
render the lesion isodense in the later portal venous phase.
Compared with enhanced CT, use of dynamic sequential hepatic CT does not
necessarily markedly increase the number of patients correctly diagnosed as
having liver metastases, but the number of lesions detected can be increased by
as much as 40 %, and this is a most important consideration for patients being
considered for partial hepatic resection.
Delayed hepatic CT. Delayed hepatic CT is a technique which exploits the
presence of CM within hepatocytes 4 - 6 h after the initial injection. This represents the small percentage of CM 'vicariously' taken up (and ultimately
excreted by the liver). Provided that an adequate iodine load, at least 45 g has
9.8 Computed Tomography in the Liver, Pancreas and Spleen
been used initially, a 20 Hounsfield unit (HU) or so elevation of hepatic CT
number is seen at 4-6 h.
Delayed hepatic CT is a very sensitive technique in the detection of hepatic
metastases and has a lower false-positive rate than CTAP. Indeed, it has been
promoted as a means of resolving persisting questions about the nature of possible false positive lesions seen at CTAP. Nevertheless, few centres use this
method routinely, mainly because it is inconvenient to schedule patients to be
examined 4- 6 h after the initial injection of CM.
(T Hepatic Arteriography (CTHA)
Occasionally this special technique is used in the search for hypervascular liver
metastases. A catheter is inserted in the hepatic artery in the angiography suite
and the patient is transferred to the CT suite. 100 ml of 300 mgllml contrast is
injected at 2 mlls. Scanning begins immediately. Spiral/helical scanning allows
the scan to be completed before contrast appears, after recirculation, in the
portal vein and enhances normal liver resulting in loss of the original increase
in conspicuity of any hypervascular lesions.
CT hepatic arteriography has been shown to be more sensitive that incremental dynamic CT for specific lesion detection. Approximately 30 % - 55 % of
patients will have additional lesions detected.
A significant proportion of patients will have accessory hepatic arteries
which must be catheterised, otherwise lesions supplied by those arteries will be
missed. These metastases receive virtually all their blood supply from the hepatic artery, unlike the normal hepatic parenchyma, which is supplied by both the
hepatic artery and portal vein. CTHA identifies metastases as hyperdense in
relation to background hepatic parenchyma. Vascular lesions are easier to
visualise on CTHA than relatively avascular tumours. One of the pitfalls of
hepatic CTHA is that layering or unusual flow patterns may result in the liver.
These patterns correspond to main or subsegmental branches of the hepatic
artery, which are more or less opacified. Hepatic contrast differences result
primarily as a result of flow going to one portion of the liver through the
catheter, while the adjacent portion of the liver does not receive CM and thus is
not opacified.
CT Arterioportography. In CTAP, CM is injected into the superior mesenteric
artery, using a volume flow rate injector. The liver is imaged using spiral mode
30 s alter the beginning of CM infusion 90 ml of 300 mgllml CM at 2 mlls. CTAP
is a 'super' intravenous bolus contrast-enhanced CT study in which the injected
CM is, in effect, delivered selectively into the portal venous supply without distribution to, and dilution with, the central blood volume. This results in greater
hepatic parenchymal enhancement and contrast differentiation between focal
lesions and background. CTAP is easier to implement than hepatic artery injection CT because the catheter tip needs only to be placed in the superior
mesenteric artery distal to any anomalous hepatic artery branches. Parenchymal enhancement of 80 -100 HU can be achieved, compared with the
parenchymal enhancement of 50 -70 HU achieved with an intravenous bolus
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
injection. Faster spiral/helical scanning allows the whole liver to be scanned
before recirculating contrast peaks, after recirculation, in the hepatic artery and
thence, by specifically enhancing the lesions, reduces their conspicuity.
Perfusion defects may be observed due to incomplete admixture of enhanced
blood in the superior mesenteric vein with unenhanced blood in the splenic
vein, resulting in hypoperfusion of the left hepatic lobe. In addition, central
metastases may compress central portal vein branches, resulting in hypoperfusion defects. Although non-tumourous attenuation differences are significantly more frequent with CTAP than with dynamic CT, they are seldom a
diagnostic problem because of their geographical pattern. In patients in whom
it is unclear whether a hypoperfusion defect or a true local lesion exists, it is
advisable to perform a delayed hepatic CT study 4- 6 h after CTAP. However,
lesions may be missed in areas which have not opacified sufficiently and it is
important not to interpret CTAP in isolation from a conventional dynamic
study and, if necessary, other examinations such as US and MRI.
CT Angiography
The primary acquisition of a true volume data set in spiral/helical scanning
allows superb 3-dimensional reconstructions of vascular anatomy to be made.
The speed of the scanning technique also allows high vascular blood levels of
contrast agent to be maintained throughout the examination without use of an
excessive total load. The technique is being exploited in hepatobiliary and
pancreatic disease to determine, without the need for invasive conventional
angiography, the presence of vascular anomalies and the relationship to, and
involvement in, the disease process.
What are the complications of these procedures?
All methods of CT which utilise iodinated CM may be associated with idiosyncratic reactions, with disturbances of renal or cardiovascular function or
clotting and with a number of other phenomena described elsewhere in this
book. CT arteriography, CT arterioportography and Lipiodol CT may also be
associated with various complications of angiography described in the relevant
chapters.
Patient tolerance of hepatic intraarterial Lipiodol CT is usually excellent in
cases of selective hepatic artery injection. Occasionally, non-selective injection
into the coeliac axis is utilised and this sometimes results in certain side effects
immediately after the injection: approximately one-third of patients experience
nausea or vomiting which regresses spontaneously in 15 - 20 min. In patients
with an accessory hepatic artery arising from the superior mesenteric artery, an
attempt to inject Lipiodol selectively into the accessory hepatic branch may
result in a reflux of Lipiodol into the superior mesenteric artery. In such
patients diarrhoea may be observed for approximately 6 h but this tends to
resolve without sequelae. Acute cholecystitis requiring cholecystectomy has
been described following hepatic artery injection of Lipiodol.
9.9 Visualization of the Gastrointestinal Tract
Conclusions
In the investigation of the liver, spleen and pancreas, dynamic CT following the
intravenous injection of CM should follow US scanning when the latter has
failed to provide a diagnosis. In patients being considered for partial hepatic
resection in whom dynamic CT has not revealed any lesions in the part of the
liver which is to be preserved, CTAP is probably the investigation of choice. If
this procedure reveals definite lesions, surgery is contraindicated. If very small
lesions of questionable significance are detected, it is best to proceed to surgery
and confirm the presence of such lesions with intra-operative US rather than
deny the patient the chance of a cure.
9.9
Visualization of the Gastrointestinal Tract
C. I. BARTRAM, B. LAERMANN and P. O'BRIEN
Why?
Air provides naturally occurring contrast within the gastrointestinal tract,
though of limited value during fluoroscopy, when radiopaque intraluminal contrast agents are essential to show the outline and mucosal detail. There are four
basic methods for imaging during fluoroscopy:
Mucosal views, where only a small volume of contrast is given to coat the surface of the collapsed structure, e. g., in the stomach to show the mucosal fold
pattern.
2. Single contrast filled views to demonstrate the outline of the structure and
fine mucosal detail in a narrow band, where the edge of the structure is
viewed tangentially. Large intraluminal lesions will be seen as filling defects
in the column of barium.
3. Compression views to show fine mucosal detail en face, as opposing walls of
the bowel are squeezed together.
4. Double contrast, where the lumen is fIlled by gas. This has several effects. The
structure is distended, and the volume may be adjusted to achieve maximum
definition of any abnormality. Barium suspension within the bowel will pool
in dependent areas, but otherwise all excess will drain off, leaving a thin
mucosal coating. As gas is radiolucent, the mucosal surface coating is visible
both en face as well as tangentially. This provides the highest definition of the
mucosal surface texture that is possible fluoroscopically.
1.
The original contrast agent used was bismuth, popularised by Rieder in Germany for the examination of the stomach. Barium sulphate suspensions soon
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replaced bismuth, being less expensive and less toxic. Specific formulations
have been developed for different examination techniques and to counter the
problems any contrast agent is subjected to in the gastrointestinal tract. The
requirements for single contrast are less complex than for double contrast
usage. The barium particles must remain in suspension and not clump together,
which is termed "flocculation". The suspension must be able to withstand
marked changes in pH and to resist flocculation in the small bowel. The latter
is a particular problem, as the amphoterically charged mucous rapidly flocculates pure barium sulphate preparations. With earlier suspensions, any delay
in small bowel transit or excess secretions rapidly induced flocculation and led
to the term "malabsorption pattern". Modern suspensions are very resistant to
flocculation. This will occur only after gross delay in transit and may not be
seen in coeliac disease per se.
High density (HD) barium suspensions were developed in the 70S and gave
outstanding views of the fine mucosal detail of the upper gastrointestinal tract.
Suspensions capable of delivering high definition of the mucosal surface
texture throughout the gastrointestinal tract are needed to combat the competition from endoscopy.
Physicochemical Factors
Controlling the Behaviour of Barium Suspensions
The mucosal detail produced by various barium sulphate preparations varies
considerably. High resolution is achieved if fine mucosal detail, such as the
areae gastricae in the stomach, the villous pattern in the small bowel, and the
innominate groove pattern in the colon, is observed. Commercial preparations
contain various ingredients, but always include a polymeric dispersing agent,
most often the polysaccharide carrageenan, which has a dramatic effect on the
behaviour of suspensions in vivo.
The other components have some influence on the performance of the suspension, but are more important for the long-term stability and sterility of the
product.
Studies of several commercially available barium products suggest that high
definition on double contrast is related to the following features:
- low viscosity,
- high density,
- a particle distribution that includes a significant number of particles
10 - 20 mm in diameter,
- barium particles with a low effective surface charge,
- a water soluble polymer that forms an interface between the particles in suspension and aqueous solution.
9.9 Visualization of the Gastrointestinal Tract
Viscosity
Preparations of low viscosity are needed for double contrast examination of the
GI tract. The suspension must flow freely around the colon or stomach, so that
all parts are evenly coated and any excess agent drains away. Viscosity is an
important parameter in defining the behaviour of the system. Anderson et al.
[8] investigated the viscosity of barium suspensions using a concentric cylinder
rheometer. Several preparations were examined that showed either plastic or
pseudo-plastic behaviour. In plastic behaviour, a finite force per unit area must
be applied to the suspension before flow is initiated. In pseudo-plastic suspensions, flow starts immediately any force is applied. Plastic preparations have
been found to be best suited for double contrast examination of the upper GI
tract.
The performance of suspensions such as 100 % w/v BaSO4 particles (BaSO 4 +
Baryte #1, containing a significant amount of large particles up to 10 pm) in
3.39% w/w of chondroitin-4-sulphate solution as the polymer is shown
in Fig. 9.9.1. The data are identical for increasing and decreasing shear rate
curves. The suspensions are not thixotropic and with decreasing chondroitin
concentrations the Bingham stress yield approaches zero (TB ~ 0, Fig.
9.9.2).
The Bingham yield stress values (t B ) are low, which can be seen as Newtonian
behaviour. (Table 9-9.1; Fig. 9.9.1) This behaviour signifies that the suspension
flows as soon as any force is applied and is therefore plastic in type. A plot of
the relative viscosity 'Zr ('Zr = viscosity of the suspension/viscosity of the polysaccharide solution) as a function of the BaS04 volume fraction, <p, is given in
Figure 9.9.2. The Dougherty-Krieger equation has been used to predict the
2.5
•
•
2
•
Cll
0..
0.1
shear stress I Pa
0.09
A
0.08
viscosity I Pas
0.07
linear (A)
III
0.06 ~
";;; 1.5
III
~
0.05 .~
Ui
<a
Ql
1
y
.s::::.
III
0.5
•
=0.0121x + 0.0417
R2 =0.9998
50
•
100
0.03
0
lil
'>
0.02
•
0
0
III
0.04
150
0.01
0
200
shear rate I S-l
Fig. 9.9.1. Rheogram of 100 % w/w BaS04 particles in chondroitin (3.39 % w/w)
205
206
CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Table 9.9.1.
Bingham yield stress for
BaS04 particles in various
concentrations of chondroitin
Chondroitin concentration
%w/w
lPa
8.06
6.56
5.00
3.39
1.72
0.4261
0.2472
0.1505
0.0417
0.0193
fO
change in viscosity of the suspension with respect to that of the continuous
phase. The Dougherty-Krieger equation [1] is given as:
rz =.!l =
rzo
(1- ~)-['ll</>m
<Pm
where the parameter [rz] is the dimensionless intrinsic viscosity, and defined as
the slope of the rzr versus <P plot as <P approaches zero. In samples composed of
equal-size, non-interacting spheres the intrinsic viscosity is predicted
theoreticallyto be [rz] = 2.5. In samples containing electrically charged particles
the intrinsic velocity [rz] increases with the zeta potential [2]. The maximum
packing fraction (<Pm) is defined as the maximum solid volume fraction permitting flow at which the viscosity of the suspension becomes infinite. The
maximum volume fraction for random packing has been obtained by computer
simulation, as <Pm"" 0.6 [3]. The best fitting of the Dougherty-Krieger equation
has been obtained with the values of [rz] = 2.99 and <Pm = 0.50, a reasonable
result, considering the deviation from the ideal system. Experiments conducted
with preparations containing particles of smaller diameter, i. e. 3 p.m and 1 p.m,
Fig. 9.9.2. Relative viscosity
versus BaSo4 volume fraction; experimental data for
chondroitin-BaSo4 suspensions and the fitted curve
for the Dougherty-Krieger
equation
100.00
r---------:----,
90.00
80.00
70.00
- - D-K Equation
... Experiment
60.00
50.00
40.00
30.00
20.00
10.00
0.00 ~==~=:...-_+_----l
0.00
0.20
0.40
0.60
9.9 Visualization of the Gastrointestinal Tract
resulted in a Dougherty-Krieger equation fit with a comparable maximum
volume fraction, but an increase of intrinsic viscosity with decreasing particle
size.
Particle Size
The range and distribution of particle size within a barium sulphate suspension
has a significant effect on suspension performance. Optimum results for double
contrast examination of the stomach were achieved with a particle size range of
0.5 pm to 30 pm [4 -7]. The large particles in a low viscosity suspension tend to
settle into mucosal grooves, thus imaging them more effectively [8]. Significant
numbers of larger particles are found in double contrast agents such as XOpaque or E-Z-HD (E-Z-EM Inc, Westbury, NY). Such preparations contain
particles ranging in size up to 18.8 pm (1 %) or higher (0-4 %) in diameter. These
barium sulphate preparations are both of "high density" and "low viscosity"
and include some large particles and a decreased portion of dispersion agents.
Related work by Briggs et al. [9] confirms these conclusions. The distribution
of particle sizes of the barium sulphate in the preparations, Liquid HD and EZ-Paque, and the original barium sulphate powder used in their manufacture,
USPamin and Baryte#l, have been studied. USPamin has a particle size
distribution centred about a 3-pm mode (range 1- SlIm). The Baryte#l contains
a significant number of particles in the 5 to IS-lIm range, with some larger than
20 mm. The median particle size of Liquid HD is given as 2.4 mm. This suspension contains a mixture of both types of barium sulphate with a significant
number of large particles. Standard density barium suspensions such as
Barosperse, Baritop and Micropaque contain particles smaller than 10 lIm.
Electrostatic Charge
Barium sulphate is itself neutral. However, a particle charge may be induced by
its environment and changes in the pH, electrostatics, or the nature of the surface ions the particle is in contact with.
Motimoto investigated the particle charge determination of barium sulphate;
the particles are positively charged with excess barium ions and negatively
charged with an excess of anions [10]. This result explains the controversial
results of Reyerson [11], who found a negative charge on barium sulphate in
H20, compared to Buchanon and Heymann [12], who showed a positive charge
of barium sulphate in suspensions.
The electrical properties of particles in suspension have been examined by
electorphoresis [13,14]. The electrophorectic mobility of particles is defined in
terms of a velocity in an applied electromagnetic field. The direction of
moment gives an indication of the electrical charge on the particles. James et al.
[13] measured the electrophorectic mobility of several commercially available
suspensions of barium sulphate at various pH values at 25°C. Their results
suggested that the suspensions could be classified into two groups: X-Opaque,
207
208
CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Electrophoretic
mobility I
10- 6
Electrophoretic mobility
'-
I
m2 S-I V-I
8.-----.,-------,-------,.----...,
~ X-Opaque
~
E-Z-HD
-*-
Barosperse
6
~
Barlop
5
-lIl- Micropaque
7
4
3
------------
------
r---~k"
2
OlF'----l-----t-----+-------l
1.5
3.2
5.9
7.5
8.3
pH (aprox)
Fig. 9.9.3. Negativ electrophoretic mobility of several commercial available barium sulphate
preparations at 25°C at various pH: pH 1.5 in 0.06 M HCl, pH 3.2-3.5 in 0.006 M HCl, pH
5.9-6.3 in dest. water, 7.5-8.0 in 0.006 M NaHC0 3 , pH 8.3-8.4 in 0.06 M NaHC0 3 (after 1.2)
E-Z-HD, and Barosperse as one (group I), with Baritop and Micropaque as the
other (group 11), both carrying a negatively charged polymer coated barium
sulphate particle. At low pH values, group I showed a decreasing electrophoretic
mobility with decreasing acidity, indicating higher negative particle charge.
Group II showed the opposite trend, suggesting a lower negative charge. Figure
9.9.3 shows the negative electrophoretic mobility of several suspensions of
commercially available barium sulphate preparations at 25°C as a function of
pH. The charge on the moving particles is probably the result of deprotonation
of the functional groups on the polymer and/or polysaccharide. In the case of
carrageenan (the polysaccharide in E-Z-HD), the sulfator (R-S0 3H+) group is
acidic and fully deprotonated, the hydroxyl groups (R-OH) may be expected to
be protonated, and the carboxyl groups (R-COOH) deprotonated.
A tentative conclusion concerning surface charge is that for particle dispersion
in suspension, barium particles should have a uniform negative surface charge.
This may be achieved by complete polymer adsorption onto the particle surface.
Coating Ability
A water soluble non-gelling and non-agglomerating polymer functioning as a
dispersion agent is crucial to formulate a high definition barium sulphate
suspension. The equilibrium between the polymer in solution and sorbed onto
the particles results in multiple layers around the particle. Neutron scattering
experiments and 1H NMR relaxation time studies showed that the polymer
chains are heavily hydrated, presumably in spaces between the polymer chain.
9.9 Visualization of the Gastrointestinal Tract
The sorbed polymer layer forms an interface with a density gradient between
particles and aqueous solution (Fig. 9.9.4).
In-vivo studies of barium sulphate preparations have revealed that high
definition images are most easily obtained using a dispersion agent that conforms to the following behaviour:
- multilayer adsorption of polymer onto the particle surface to keep particles
apart from each other and achieve homogenous dispersion,
- polymer that forms a continuous network between the particles,
- layers of polymer in the network that are able to penetrate the polymer network, resulting in a high mobility of particles. During the coating process
onto the mucosa, small particles can move into the interparticulate space
between the large particles.
The barium preparation interacts with the mucus layer. The resultant polyanion
of the polysaccharide re-orientates within the matrix of the mucus, so that the
particle sinks ultimately into the mucus layer, with the upper side of the particle
covered by polymer. Optimally, the contrast agent should be held between the
two matrices so that it mirrors the structural surface of the mucosa beneath.
transition state
matrix
Fig. 9.904- Illustrating the
'Like to like' principle for
the method by which
barium sulphate suspensions coats the mucous layer.
a diagrammatic representation, b Scanning electron
micrograph of mouse
mucosa coated with Polibar
Rapid
a
mucus matrix
b
209
210
CHAPTER 9 Clinical Use of Iodinated eM for the Visualization of Vessels and Organs
Using in vitro microscopic examination Tokita and Raju [15] found that the
typical thickness of barium sulphate coating was 0.25 - 0.3 mm on mice
jejunum mucosa. A test preparation producing an optimal coating is shown in
Fig. 9.9.5. The overall coat is thin, but with a well developed layer of densely
packed barium sulphate particles. A typical result from a commercial sample is
shown for comparison. The phantom study suggests that the test preparation
demonstrated a significant improvement in image resolution (Fig. 9.9.6).
a
b
Fig. 9.9.5 a-b. Micrograph of a fracture in the intestinal model coated with Polibar ACB preparation (each ---- represents 100 Jlm). b Micrograph of the fraction of the intestinal model
coated with a test suspension
9.9 Visualization of the Gastrointestinal Tract
Fig. 9.9.5 c. Micro-structure of the fraction of the intestinal model coated with a test suspension
a
b
Fig. 9.9.6 a, b. Phantom study. a Polibar ACB, b test suspensions coating of the intestinal
model revealing clear definition of the fine surface pattern
When
The double contrast image provides the greater sensitivity for the detection of
mucosal disease. Deformity of the bowel, such as stricturing, may be shown in
single or double contrast, but function is usually assessed only in single contrast, as the gas insufflation and smooth muscle relaxation required for double
contrast inhibits normal function.
The nature of the barium suspension and the method of examination varies
in different parts of the GI tract.
211
212
CHAPTER
9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Pharynx
It is standard practice to start with a small 5 to 10-ml bolus of either HD (250 %
wt/vol) or standard suspension (40% wt/vol) in lateral projection. The nature
of the contrast used will affect bolus transit time and upper oesophageal
opening [16]. Barium powder may be mixed with various foodstuffs such as
yoghurts, puddings, or biscuits to create different consistencies to assess how a
range of food textures is dealt with.
If there is a high suspicion of aspiration or fistula, then a non-ionic water
soluble contrast agent is recommended initially. Gastrografin is contraindicated, owing to the potential risk of pulmonary oedema.
HD suspensions are ideal for coating the mucosa of the pharynx for spot
views during "e" phonation or puffing out the cheeks to show pharyngeal
anatomy [17].
Oesophagus
With the patient standing and turned slightly to the left, rapid repeated swallowing inhibits peristalsis, allowing maximum distension of the oesophagus,
which, coupled with swallowed air, provides good double contrast views. An HD
suspension is ideal in this situation.
Assessment of oesophageal function is performed with the patient prone,
head down 10°. Single swallows only must be observed. The patient should
maintain an open mouth posture between swallows to prevent repeated swallows, as these inhibit peristalsis and prevent a clear analysis of the oesophageal
function. A standard suspension in single contrast is adequate.
Stomach
The routine examination involves a double contrast technique with gaseous
distension of the stomach and smooth muscle relaxation. About 200 - 350 ml
of gas need to be generated, usually from a combination of proprietary effervescent agents. These contain an antifoaming agent to prevent bubble formation. This can have a profound effect on coating and, if excessive, coating will be
very poor. About 150 ml of an HD suspension is recommended to obtain the
optimum mucosal definition. Either 20 mg hyoscine butylbromide or 0.5 mg
glucagon may be used to inhibit peristalsis and obtain maximum double contrast distension of the stomach and duodenal loop (Fig. 9.9.7).
The volume of water added to E-Z-HD is critical. Small changes have a
pronounced effect on viscosity and the ability to demonstrate the area gastricae
[18].
9.9 Visualization of the Gastrointestinal Tract
Fig.9.9.7. Double contrast
view of the stomach and
duodenal loop using a high
density barium suspension.
An ulcer scar (arrowhead)
with surrounding focal
gastritis is shown on the
greater curve of the antrum
Small Bowel
The standard follow-through examination (BaFT) involves the patient drinking
a large volume (400-500 ml) of dilute (70-80% wt/vol) barium suspension.
Gastric emptying should be enhanced by 20 mg oral metoclopramide, and may
be helped by laying the patient on the right side. Overhead films are taken at 10
and 30 min to assess progress of the barium column, with further fluoroscopy
and compression views of the entire small bowel as it fills.
The addition of 10 ml of Gastrografin, which is thought to release serotonin,
may enhance transit [19], as well as some effervescent agent to give a double
contrast effect. Some manufacturers also add sorbitol to barium suspensions
for small bowel examination. The problem with all these techniques is that
mucosal definition is lost in the distal small bowel, as the indrawing of water
dilutes the suspension at the mucosal interface.
Ther peroral pneumocolon is a useful supplementary technique to look at
the terminal ileum when this is difficult to view by standard compression.
Ideally, the patient should have been given bowel preparation, but this is not
essential. Gas, preferably carbon dioxide, is insufflated into the colon. A smooth
muscle relaxant is given, and the patient rotated to help reflux gas into the
terminal ileum.
213
214
CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Once achieved, a series of spot films is taken of the terminal ileum in double
contrast. Another benefit of this is that the sigmoid colon is distended, which
often lifts the terminal ileum out of the pelvis.
Intubation techniques may be considered the preferred method for
examining the small bowel. These involve placing a 10 -12 French catheter into
the distal duodenal loop or proximal jejunum. Intubation is usually via the
nasal route. When the catheter is in place, 800 -1200 ml of a 19 % wt/vol suspension is infused at 75 mllmin, with a few overhead films with spot films taken
during compression of the entire small bowel. A variation of this basic small
bowel enema (SBE) is biphasic enteroclysis. In this, 350 - 500 ml of a 50 % wt/vol
suspension are first infused to fill the small bowel in single contrast.
Compression spot views may be taken. A large volume of dilute methyl cellulose (1500 - 2500 ml of a 0.5 % suspension) is then infused at 65 - 85 ml/min. This
produces a double contrast effect, as the concentration of methylcellulose in the
solution forms a thin gel that prevents mixing with the barium suspension. The
effect of this is to leave a relatively thin layer of barium coating the mucosal surface while the lumen is distended with radiolucent fluid. The surface detail is not
as good as with true double contrast with gas distension, as the mucosal layer of
contrast is not as thin. However, the gas does create problems with overexposure
of overlapping loops, whereas the methylcellulose biphasic study gives good
transradiancy of overlapping loops without any exposure problem.
Colon and Rectum
Most examinations of the colon require full bowel preparation [20], except for
the instant enema in active colitis, or a water soluble contrast examination to
check for any leak or fistula. In colitis the affected bowel will be clear of residue
and a double contrast examination performed without the need for bowel
preparation [21].
A double contrast method is the examination of choice, using about 500 ml
of a 100 % wt/vol barium suspension, gas insufflation preferably with carbon
dioxide [22] to reduce abdominal distension post-examination, and an IV
smooth muscle relaxant. The examination consists of a series of spot films (Fig.
9.9.8) to generate a complete composite image of the colon and rectum in
double contrast with some overhead views. Decubitus views with a horizontal
X-ray beam are useful.
A single contrast examination may be used in the elderly or very immobile
or when only gross pathology is be excluded. Then, about 700 ml of a 20 %
wt/vol is used. Spot views of distended segments of bowel, with compression
views where possible, and several overhead views of the entire colon are taken.
An after evacuation fIlm is commonly taken to show the collapsed colon. This
may help diagnose polyps. To achieve good contraction, astringent agents such
as tannic acid used to be added to the barium mixture, though this is no longer
practiced, owing to hepatotoxicity.
Water soluble contrast agents, either Gastrografin diluted 1: 4 with water (if
digital imaging used, otherwise 1: 3) or Urografin 150 (Schering AG, Berlin) are
9.9 Visualization of the Gastrointestinal Tract
Fig. 9.9.8. Double contrast
barium enema showing the
transverse colon. Note the
thin smooth coating of the
mucosa, with a little pooling of barium in the haustral folds
indicated where there is any risk of perforation. Contrast is run in until an
obstruction is encountered, the colon filled, or a fistual/perforation demonstrated. The technique is of value in suspected large bowel obstruction [23]. In
the small bowel, Gastrografin draws in water, as it is hyperosmolar. This causes
loss of contrast density and mucosal definition, so that its diagnostic value in
the small bowel is very limited. Low osmolar water contrast agents will not suffer with these problems and will maintain good radiographic contrast density
and mucosal definition throughout the small bowel.
Dynamic studies of rectal evacuation require a barium paste or specialised
preparation (Anutrast, E-Z-EM Inc, Westbury, NY).
Complications
Sensitivity reactions may occur with any contrast agent, though these are extremely uncommon with barium preparations. A number of factors have been
considered: food allergy; sensitivity to latex if balloon catheters used, reactions
to glucagon, and contamination of the preparation. Barium sulphate is
extremely inert, and any reaction is more likely a reaction to an additive such as
carrageenan [24] or the preservative methyl paraben [25].
Barium sulphate outside the lumen of the GI tract is harmful. Pulmonary
aspiration of small volumes of dilute suspension seldom causes any problem,
but there is a report of fatal pulmonary inflammation following aspiration of a
HD suspension [26]. Intramural barium may lead to the formation of a granulomata [27], which may develop into polypoid masses. This may also complicate
retroperitoneal extravasation, although abscess formation or retroperitoneal
emphysema are more acute problems. Intra-peritoneal perforation produces a
severe peritonitis with serosal exudate and hypovolaemia. This may be complicated by Gram-negative endotoxic shock. Immediate fluid replacement, anti-
215
216
CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
biotics, and peritoneal lavage are essential [28]. Long-term effects are reactions
to the remaining barium particles producing dense adhesions. Removal of as
much barium as possible with careful saline lavage of peritoneum is advised to
minimise this effect.
Venous intravasation is a very rare but potentially lethal complication resulting in either hepatic or pulmonary emboli. The high density of barium
sulphate is reflected in the CT changes. Intravasation may complicate rupture of
the rectum when a balloon catheter has been overinflated or inflated normally
in a narrowed rectum, or with inadvertent vaginal insertion with rupture from
overdistension. Perforation is fortunately very rare during barium enema, and
a recent survey showed a mortality of only 1 in 56,000 [29].
Water soluble contrast agents depend largely on their osmolarity for side
effects. Gastrografin, if inhaled, may cause pulmonary oedema. Excess volumes
within the GI tract will reduce the circulating blood volume secondary to
hypertonic dehydration. This may be a significant problem in children, and can
be a problem in adults if large quantities of contrast are trapped proximal to an
obstructing lesion, drawing in fluid and over-distending the bowel. Perforation
has been reported from this [30]. Renal excretion of Gastrografin suggests
intestinal perforation with absorption of contrast and normal systemic excretion. However, it has been suggested that this may occur without frank
perforation in circumstances where there is gross ulceration, such as severe
colitis that alters permeability, so that there is direct absorption of contrast
across the diseased bowel wall [31].
Conclusion
Barium sulphate preparations remain the main contrast agent for fluoroscopic
examination of the gastrointestinal tract. The double contrast method provides
the optimum surface detail. Details of these techniques are given in specialised
texts [32]. Barium suspensions and water soluble contrast agents are also used
as bowel markers in cross sectional imaging with CT and MRI.
References
1. Krieger 1M (1972) Rheology of monodisperese lattices. Adv CoIl and Int Sci 3: 111-136
2. Everett DH (1988) Electroviscous Effects. In: Basic principles of colloid science. Royal
Society of Chemistry, Cambridge, pp 121-124
3. Soppe W (1990) Computer simulation of random packings of hard-spheres. Powder Techn
62: 189-197
4. Shuffebarger HE, Knoefel PK, Telford J, Davis LA, Pirkey EL (1953) Some factors influencing the roentgen visualization of the mucosal pattern of the gastrointestinal tract.
Radiology 61 : 801- 806
5. James WB (1978) Double Contrast Radiology in the Gastrointestinal Tract. Clinics in
Gastroenterology 7: 397 - 418
6. Gelfand DW (1978) High density, low viscosity barium for fine mucosal detail on doublecontrast upper gastrointestinal examinations. Am J Roentgenol130 : 831- 833
7. Hunt JH, Anderson IF (1976) Double contrast upper gastrointestinal studies. Clin Radiol
27:87-90
9.9 Visualization of the Gastrointestinal Tract
8. Anderson IF, Harthill JH, James WB, Montgomery D (1980) Barium sulphate preparations
for use in double contract examination of the upper gastrointestinal tract. Brit J Radiol
53: 1150 -1159
9. Briggs RW, Liebig T, Ballinger R, Ros R (1993) Mechanisms that contribute to the in vitro
relaxation and signal intensity of water in barium sulfate suspensions used as MRI contrast agents. Magn Res Imag 11 : 635 - 644
10. Morimoto T (1964) Electrokinetic potential of sparingly soluble salts. Bull Chern Soc
Japan 37: 384-39 2
11. Reyerson L, Kolthoff M, Coad K (1947) The electrokinetic potentials of precipitates. J Phys
Chern 51 :321- 332
12. Buchanan AS, Heymann E (1948) Electrokinetic potential and surface structure of barium
sulfate. Nature London 161: 649 - 691
13. James AM, Goddard GH (1972) Barium meals: A physical chemical study of the adsorption of hydrocolloids by barium sulphate. Pharmaceutica Acta Helvetia 47 : 244 - 256
14. Simmonds RJ, James AM (1976) An in vitro investigation of barium meals. Cytonios
15: 191-200
15. Tokita N, Raju MR (1988) Biological dosimetry at the tissue-barium sulphate interface: a
jejunal crypt survival assay. Brit J Radiol 61: 169 -170
16. Dantas RO, Dodds WJ, Massey BT, Kern MK (1989) The effect of high- vs low-density
barium preparations on the quantitative features of swallowing. AJR Am J Roentgenol
153: 1191-1195
17. Rubesin SE, Jones B, Donner MW (1987) Contrast pharyngography: the importance of
phonation. AJR 148: 269 - 272
18. Rubesin SE, Herlinger H (1986) The effect of barium suspension viscosity on the delineation of areae gastricae. AJR Am J Roentgenol146 : 35 - 38
19. Fraser GM, Adam RD (1988) Modifications to the gas-enhanced small bowel barium follow-through using gastrografin and compression. Clin Radiol 39 : 537 - 541
20. Bartram CI (1994) Bowel preparation - principles and practice. Clin Radiol 49: 365 - 367
21. Thomas BM (1979) The instant enema in inflammatory disease of the colon. Clin Radiol
30: 165-168
22. Bartram CI (1989) Technical note: a simple method for using carbon dioxide during
double contrast barium enema. Clin Radiol 40 : 318
23. Chapman AH, McNamara M, Porter G (1992) The acute contrast enema in suspected large
bowel obstruction: value and technique. Clin Radiol 46: 273 - 278
24. Tarlo SM, Dolovich J, Listgarten C (1995) Anaphylaxis to carrageenan: a pseudo-latex
allergy. J Allergy Clin Immunol95: 933-936
25. Schwartz EE, Glick SN, Foggs MB, Silverstein GS (1984) Hypersensitivity reactions after
barium enema examination. AJR Am J Roentgenol143: 103 -104
26. Gray C, Sivaloganathan S, Simpkins KC (1989) Aspiration of high-density barium contrast
medium causing acute pulmonary inflammation - report of two fatal cases in elderly
women with disordered swallowing. Clin Radiol 40 :397 - 400
27. Vaz SJ, Costa SC (1983) Barium 'granuloma' of the rectum. A light and electron
microscopic analysis. J Submicrosc CytOl15 : 1089 -1094
28. Grobmyer AJ, Kerlan RA, Peterson CM, Dragstedt LR (1984) Barium peritonitis. Am Surg
50(2) : 116 -120
29. Blakeborough A, Sheridan MB, Chapman AH (1997) Complications of Barium Enema
Examination: a survey of UK Consultant Radiologists 1992-4. Clin Radiol52: 142-148
30. Gelfand DW (1980) Complications of Gastrointestinal Radiologic Procedures. 1. Complications of routine fluoroscopic studies. Gastrointest Radiol 5: 293 - 315
31. Poole CA, Rowe MI (1976) Clinical evidence of intestinal absorption of Gastrografin.
Radiology 118: 151-153
32. Laufer I, Levinc MS (1992) Double contrast gastrointestinal radiology, 2nd (ed) Saunders,
Philadelphia
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
9.10
Cholezystography and Cholangiography
V. TAENZER
When? Why?
Just a few years ago, an X-ray examination of the biliary system was obligatory
for symptoms in the upper abdomen. New imaging and interventional
techniques, however, have sharply reduced the importance of cholegraphy. Oral
cholecystography as a screening method in ill-defined upper abdominal
symptoms has been replaced by sonography. Although in gallbladder visualization' the accuracy of the former is roughly as good as that of US, US diagnosis
is more reliable. Repeated examinations in cases of negative cholegraphy are
obviated. Cholegraphy can be of limited use in individual cases in documenting
the size and number of gallstones before and after litholysis.
Intravenous cholangiography/cholecystography has also decreased in
importance and is no longer used in jaundice. Endoscopic retrograde
cholangiography (ERC), percutaneous transhepatic cholangiography (PTC)
and isotope examinations have moved into the forefront here. With normal
bilirubin values in serum and normal liver function, good bile duct visualization is achieved by means of intravenous cholangiography, especially in combination with CT of the bile ducts which permits a highly accurate delineation
of bile duct abnormalities. The accuracy of roentgenographic bile duct stone
recognition, especially where the bile ducts are normal or borderline in width,
is not matched by sonography of the bile ducts.
Using intravenous cholegraphy it is possible to make an accurate, reproducible determination of gallstone size. This is very important in modern gallstone treatment since, in the chemolitholysis of gallbladder calculi, progress
checks under reproducible conditions are necessary for assessing the success of
a given therapy. Even when the procedure of gallstone lithotripsy is used, an
exact determination of size and number of gallstones is necessary preoperatively. Cholegraphy is indicated in the clarification of uncertain sonographic
findings, especially since the competitive procedure of ERC represents a comparatively high risk even in the hands of a practiced endoscopist.
Intravenous cholegraphy has experienced a rebirth due to the fast spreading of
laparoscopic cholecystectomy. The preoperative opacification of the bile ducts is
a valuable additional information for the surgeon. "Silent stones" of the choledochus are discovered in cholangiotomography in 2 to 3 % of the cases. Combined
with computerized tomography the accuracy of this procedure can be improved.
Prerequisites
As in all CM delivery, risk factors for hypersensitivity reactions should be conveyed to the radiologist. Communication of the results of US, and possibly CT,
9.10
Cholezystography and Cholangiography
are also essential. Furthermore, the request for a cholegraphic examination
must state whether there is impaired liver function or jaundice. Where bilirubin
values are elevated, an ERC is performed instead of intravenous cholangiography and cholecytography. Special risks such as hyperthyroidism or intolerance of previous administrations of CM have to be ascertained prior to
intravenous cholegraphy.
Methods/Procedures
Oral cholegraphy: A dose of 3- 6 g CM is administered perorally 12 h prior to
cholegraphy or fractionated 12 and 3 h prior to cholangiography/cholecystography. Images are taken with the patient lying and standing, 30 min after
administration to assess the contractility of the gallbladder.
2. Intravenous cholegraphy: images are taken 30 - 60 min after intravenous
infusion of 50-100 ml biliary CM, in the early phase in half-hour intervals,
in combination with CT of the bile ducts. Otherwise, the examination runs its
course as in oral cholegraphy.
3. Where insufficient information is provided by preceding noninvasive investigations in hepatocellular and obstructive jaundice, ERC is used. In cooperation with a physician experienced in endoscopy, the papilla of Vater is
probed duodenoscopically and 20 - 40 ml nonionic uroangiographic CM is
administered. ERC permits endoscopic extraction and crushing of bile
duct stones; it also allows papillotomy in papillary stenosis and the introduction of internal drainage in bile duct stenoses, whether caused by tumours or
not. Because of the possibility of direct therapeutic intervention ERC without
preceding cholegraphy is used particularly in patients with jaundice.
4. Percutaneous transhepatic cholangiography: where ERC cannot be performed, PTC is also used for temporary external biliary drainage, for example in complete stone or tumour obstruction. In PTC, after local
anaesthesia and skin puncture, a fine needle (so-called Chiba) is pushed forward with fluoroscopic assistance from the anterolateral abdominal wall to
the porta hepatis. The needle is retracted during simultaneous, slow CM
administration. As soon as the needle tip is located in a bile duct, the latter is
injected and the entire biliary tract is fIlled up with nonionic CM.
1.
Complications
1.
Method-induced complications: In standard noninvasive procedures, there
are no special, technique-associated complications. With ERC there is a risk
of pancreatitis when there is contrast-visualization of the pancreatic duct.
Moreover, the rare risk of clumsy catheterization of the papilla exists, with
duodenal perforation and subsequent retroperitoneal abscess formation.
PTC is associated with the risk of liver injury, with bleeding and bile peritonitis; in some centres, it is only carried if emergency operation facilities are
available.
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CHAPTER 9 Clinical Use of Iodinated eM for the Visualization of Vessels and Organs
2.
eM-induced complications: In intravenous CM administration, both general
and organ-specific risks exist, as described elsewhere. The general risk of a
hypersensitivity reaction with anaphylactoid shock is severalfold times as
high after injection of biliary CM as it is after the intravenous administration
of uroangiographic ionic CM.
Conclusions
US diagnosis and ERC have greatly reduced the importance of standard cholegraphic procedures. Limited indications for cholegraphy remain when the
sonographic findings are unclear, and this procedure has seen a rebirth through
laparoscopic cholecystectomy.
9.11
Intravenous Urography
P.DAwsON
In spite of the advent of new imaging modalities, the intravenous urogram
(IVU) remains the basic technique for the examination of the urinary tract and
has the advantage that it is capable of demonstrating the whole of this tract
from top to bottom.
Indications
Symptoms and signs referable to the urinary tract.
Contraindications and Precautions
A contraindication to the administration of an intravascular CM is a contrain-
dication to an IVU. The examination is relatively contraindicated in dehydrated
patients who may be at risk for CM-associated nephrotoxicity.
Impaired renal function is a relative contraindication as this is believed to be
a risk factor for CM-associated renal injury. In severe cases of renal failure the
IVU is unlikely to provide much information in any case.
Myeloma and associated conditions are sometimes claimed to be contraindications because of the alleged danger of precipitation of abnormal proteins
and CM molecules in the renal tubules.
Dehydration should be certainly avoided in these conditions if an IVU is performed. The same is true of infants in whom dehydration is dangerous and in
whom it may cause distress and crying, movement, etc, which may interfere
with the examination.
9.11
Intravenous Urography
Choice of Contrast Medium
Any iodinated water-soluble CM may, in principle, be used to obtain an intravenous urogram. A dose of iodine of some 300 mg iodine per kg of patient is
generally thought to be suitable.
A few relevant differences between the different kinds of contrast agent
should be noted: among the conventional ionic agents, sodium salts tend to
produce a lesser osmotic diuresis than meglumine salts and greater urinary
contrast concentrations are thereby achieved; the nonionic and low osmolality
ionic CM also produce a much lesser osmotic diuresis, resulting in a very
significantly increased urinary concentration and pyelographic density than do
any of the conventional high osmolality agents.
Dosage
As indicated above, the typical recommended dose is 300 mg iodine per kg for
an adult patient. Caution should be exercised in cardiac failure, impaired renal
function, in the elderly and in paediatric patients. Many radiologists prefer to
use nonionic agents in all these cases.
It is difficult to pontificate about paediatric doses but a similar dosage
regimen on a weight basis as for adults may be used. In general, doses in any
situation must always be tailored to the patient's clinical state.
Patient Preparation
Nil by mouth for 4 - 6 h prior to the examination. The aim is to achieve an
empty stomach in case of an adverse reaction rather than to dehydrate the
patient.
2. Bowel preparation is performed by some departments. It entails a risk of
dehydration and, some would argue, that with the availability of simple
tomography it is not nearly so necessary as in the past.
3. If the patient is thought to be at particular risk from an adverse reaction to
the CM but the examination must, nevertheless, proceed, the use of a nonionic agent, possibly with corticosteroid or antihistamine prophylaxis may be
considered (See Sects. 5.5, 5.6).
1.
Plain Films
1.
2.
A supine full-length anteroposterior (AP) mm of the abdomen should be
obtained. The lower border of the mm should be at the level of the symphysis pubis with the beam centered at iliac crest level.
Supine AP mms of the renal areas in inspiration and expiration may be taken
as appropriate in order to determine whether any plain mm calcifications are
likely to lie within the kidneys.
221
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
An opacity apparently in, or overlying, the kidneys may be further elucidated
by:
a) oblique views,
b) plain tomography through the kidneys or
c) inspiration and expiration views of the renal areas.
Contrast Administration
An antecubital vein is chosen for contrast adminstration and, using a 19 G needle
usually in adults but a smaller needle in children, a rapid bolus injection of the
CM (less than 1 min) is given. Care should be taken not to extravasate the CM.
Film Sequences
Immediate Nephrogram. Immediately at the end of the injection an AP fIlm is
taken of the renal areas and will demonstrate the nephrogram, which consists
principally of CM fIltered into the proximal tubules of the kidney.
Five-Minute Film. An AP fIlm is taken of the renal areas again after about 5 min.
At this point in the normal kidney excretion should be obvious in the pelvicaliceal system. Abdominal compression is usually now applied in order to produce
pelvicaliceal system distension. Compression may, however, be contraindicated
in: (a) recent abdominal or renal trauma, (b) abdominal mass, (c) recent abdominal surgery, or (d) when the 5-min fIlm has demonstrated a dilated collecting system.
Ten-Minute Film. An AP fIlm of the renal areas may again be taken to demonstrate the renal collecting system in a fully distended state.
Release Film. A supine AP abdominal fIlm is repeated and should demonstrate
the whole urinary tract with some fIlling of the bladder at some 20 min or so
after the CM injection.
Other. Specific bladder views may be obtained before and after micturition and
residual volumes assessed.
Additional Films
Like all radiological examinations, the IVU must be tailored to the patient and
modifications to the standard technique must be introduced as necessary as the
examination evolves. Thus the following may be considered in some patients:
1.
2.
Oblique views of the kidneys or bladder.
Tomography.
9.11 Intravenous Urography
3. The visualisation of the ureters may be better with the patient prone,
particularly if there is a pelvi-uteric junction (PUn obstruction.
4. If a PUJ obstruction is suspected an intravenous injection of a loop diuretic such as frusemide may be given in order to precipitate such an obstruction.
5. Delayed films may be taken in cases of an obstructive nephropathy in order
to try to see some CM excretion and to delineate the level of the obstruction.
Special Cases
Patients with significant renal impairment, in particular, must never be
dehydrated. Preliminary tomography may be necessary to determine optimal
tomography levels for the visualization of the kidneys. A higher dose than
usual of CM should be given, though the possibility that it will further impair
renal function must be borne in mind. Tomography during the early nephrographic phase should be performed. Delayed fIlms are usually necessary.
2. In hypertensive patients some radiologists like to perform very rapid intravenous bolus injection followed by a sequence of fIlms of the renal areas to
detect a discrepancy in the timing of the appearance of the pyelogram which
might indicate a renal artery stenosis. It should be noted, however, that this
technique is far from reliable in detecting a renal artery stenosis.
3. A fizzy drink may be given to infants to produce a dilated, gas-filled stomach
to act as a window through which the kidneys may be seen. The right
posterior oblique (RPO) position may be useful in visualization of the right
kidney. Tomography may be necessary, though this increases the radiation
dose.
Abdominal compression is usually avoided in very young children.
1.
Excretion of CM may be delayed in the first month of life and optimum
visualization of the urinary tract occurs at up to 3 h, which clearly dictates a
modification of the usual technique.
Cystography
A cystogram is obtained routinely in an IVU if the kidneys are functioning. It
should be noted that with the low osmolality agents the osmotic diuresis is
reduced and filling of the bladder delayed. This may lengthen the examination.
Oblique views of the bladder, tomography, and even attempts at double-contrast
cystography by the use of a lead-gloved hand bladder compression during
fluoroscopy, have all been used to seek bladder pathology. However, it should
be understood that this is usually inadequate to completely exclude bladder
pathology and if there is a serious suspicion, cystoscopy must be performed.
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
9.12
Urethrography and Micturating Cystography, Cavernosography, and Seminal Vesiculography and Vasography
D. RICKARDS
Urethrography and Micturating Cystography
Introduction
Urethrography and micturating cystography will be considered together as they
are inextricably entwined. Any suspected lower tract pathology or vesicoureteric reflux form the indications for these studies. Since the first urethrogram
performed by Cunningham in 1910 [1], many CM have been used, including
barium and Lipiodol. What is needed, according to Kaufman and Russell [2], is
an agent that is:
a) of adequate radiopacity,
b) of adequate viscosity,
c) miscible with urine and water,
d) safe in the vascular circulation and
e) sterile.
Once oily CM had been deemed dangerous because of pulmonary oil emboli
[1], manufacturers tried to fulfil the above criteria by producing specialized
agents for urethrography, e.g. Umbradil-Viscous (Astra) and Thixokon (Mallinckrodt). Both these agents were viscous enough to dilate the urethra and
were used up until 1970, when they were withdrawn because of potentially
inadequate sterility and replaced by ionic CM, e. g. Conray 280 (May and Baker)
and Urografin 310M (Schering). To increase the viscosity of these agents, they
can be mixed with sterile KY jelly, gum acacia or Lubafax (Burroughs Wellcome). Lubafax is the agent of choice, but such thickening agents are rarely
needed and are best avoided.
Micturating cystography requires a CM that has volume up to 500 ml (and
very often more is needed) is sterile and of adequate density.
In the UK, the only agent that fulfils these criteria is Urografin 150 (Schering
AG) which is supplied in 2so-ml and soo-ml bottles.
Technique
Full assessment of the urethra involves both an ascending and descending
urethrogram. The patient should be questioned about his present drug
regimen, allergies and any previous contrast examination. No preparation is
required unless the patient is very nervous or has a history of an autonomic
disorder, in which circumstances it is advisable to administer 0.6 mg atropine
prior to the procedure.
9.12
Urethrography and Micturating Cystography, Cavernosonography
Ascending Urethrography. There are many commercially available penile
clamps that are used to instil CM into the external meatus, e. g. Cunningham,
Knutsen. Individual choice determines which one is suitable. The use of a Foley
catheter, the balloon of which is partially inflated in the navicular fossa of the
anterior urethra to provide a water-tight seal, is to be avoided because
a) it is more than likely that the balloon will be blown up in the anterior urethra
and not the navicular fossa,
b) it is painful and
c) the balloon causes urethral trauma.
Before the study, the patient should try and empty his bladder, preferably
combined with uroflowmetry. Once in place, contrast is instilled slowly under
fluoroscopic control with the patient in the supine oblique position and relevant
films of the anterior urethra exposed. Adequate distension of the anterior
urethra can be obtained without thickening agents by injecting CM more rapidly. In ascending urethrography, resistance to retrograde injection will be
afforded by the distal sphincter or constricting anterior urethral pathology, e. g.
stricture. Overdistension should be avoided because of pain and the possibility
of intravasation. Ideally, CM should pass proximal to the distal sphincter to outline the posterior urethra. Contrast may not pass proximally into the bladder
because
a) of obstructing anterior urethral pathology,
b) of spasm of the distal sphincter mechanism,
c) obstructing posterior urethral pathology or
d) bladder neck spasm or stenosis.
If there is no suprapubic catheter in situ through which the bladder can be
filled, the examination is ended. Distal sphincter spasm may pass with time, but
the administration of muscle relaxants is worthless.
Descending Micturating Cystourethrography. Contrast has to be instilled into
the bladder either by
a) retrograde filling via the penile clamp in males,
b) via a suprapubic catheter or
c) via a urethral catheter.
Suprapubic and urethral catheters have the advantage of being able to drain the
bladder before filling, thus accurately assessing the amount of residual urine
and avoiding dilution of any contrast instilled into the bladder that would
diminish anatomical detail. In order for the patient to initiate micturition, the
bladder has to be adequately filled and what volume is required is dependent
upon the patient's urodynamic status. The normal adult bladder is capable of
containing 500 ml without difficulty, but the patient that has been on suprapubic catheter drainage for more than 7 days or has detrusor instability is likely to tolerate only a much lower volume. During filling, the bladder anatomy is
noted on fluoroscopy and relevant films exposed. When a male feels full, but not
overfull (such a situation is likely to inhibit micturition), he voids either supine
225
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
(male) or erect in the prone oblique position and spot fl1ms of the posterior
urethra are exposed. Females void into a specially designed funnel held between
their upper thighs while standing and films are exposed in the anteroposterior
position. Whilst under direct fluoroscopy, the patient is asked to voluntarily
stop micturition at any stage before complete bladder emptying. In males and
under normal circumstances, the distal sphincter should immediately shut and
the small amount of CM within the posterior urethra will be milked back into
the bladder through the bladder neck. In addition, the anterior urethra should
empty completely. Any CM left in any part of the urethra either during the "stop
test" or at the end of micturition is abnormal. In females, the distal sphincter
should close, but emptying of the urethra with milk back into the bladder is the
exception rather than the rule. The female bladder neck is often incompetent in
nulliparous young females and it is not a structure that is essential to urinary
continence.
Combined anterior and descending micturating urethrography provides the
following information:
1.
2.
3.
4.
5.
6.
7.
8.
Anatomy of the urethra.
Bladder capacity.
Bladder anatomy.
Presence or abscence of vesicoureteric reflux.
Competence of the bladder neck.
Competence of the distal sphincter.
Presence or absence of intraprostatic reflux.
Residual urine volume.
Complications
Pain. Adequate distension of the anterior urethra is associated with pain
which can be eliminated by the administration of lignocaine jelly prior to the
study. However, lignocaine jelly is very viscous and when injected into the
urethra causes a lot of distension of it and, consequently, pain. Lignocaine jelly
also reduces the quality of the radiographs by causing filling defects in the urethra.
Haemorrhage. In some patients, especially those with urethral pathology,
distension causes small mucosal capillary tears and subsequent haemorrhage
and does not detract from the quality of the study.
Intravasation. Intravasation is due either to:
a) the intraurethral part of the delivery system used impinging upon the distal
anterior urethral mucosa - this is faulty technique - or
b) overdistension in the presence of urethral pathology.
In either event, the procedure must be terminated and the patient given prophylactic antibiotics. Intravasation is associated with heavy postprocedural
haemorrhage which is usually self-limiting.
9.12
Urethrography and Micturating Cystography, Cavernosonography
Reactions to Contrast Media. Reactions to CM are less likely to occur than with
intravenous contrast administrations and more likely if intravasation occurs.
Ionic CM are usually used for luminal studies because of cost considerations.
Should the patient have any allergic history, nonionic agents should be considered, but to fill the bladder with 500 ml of nonionic contrast is expensive. In the
author's clinical practice, nonionic CM have not been used for any urethral study.
Infection. Any instrumentation of the lower urinary tract is liable to be complicated by infection, especially if there is a urodynamic abnormality, e. g.
incomplete bladder emptying. Antibiotics should be considered in those patients who leave large bladder residuals, are known to have an urinary tract
infection and in whom bleeding occurs as a result of the study.
Cavernosography
Cavernosography involves the direct administration of CM directly into the
corpora cavernosa. The indications are: impotence, painful or deviant erection,
or, following suspected penile fracture.
Different CM requirements are to be met, depending upon the indication for
the study which must be considered as an intravascular procedure. For
anatomical depiction of the corpora (indications 1 and 2), the CM needs to be
of adequate radioopacity sterile, and nontoxic in the subcutaneous tissues.
These requirements are met by a nonionic medium. In our practice, Omnipaque 150 in 150 ml bottles is used.
In the investigation of impotence, cavernosography is performed as part of a
penile pressure study to assess the response of erectile tissue to muscle relaxants, e. g. Caverjet (prostaglandin E'), and perfusion of CM at known rates. CM
requirements are: adequate radiopacity, viscosity and volume and that it is
sterile and nontoxic in the subcutaneous space.
Up to 500 ml may be used, but in 90 % of studies 200 ml is sufficient. The CM
is injected via a pressure pump at a rate of initially 100 mllmin until erection
occurs. In our practice, the ideal medium is Omnipaque 150 (Nycomed).
Technique
Cavernosography. A single 21-gauge butterfly needle is inserted into either
corpus as distally as possible, preferably just proximal to the glans penis. Under
fluoroscopic control, CM is slowly injected and both copora are opacified. Up to
40 ml CM will be needed to opacify both corpora, which freely intercommunicate. Spot films in the relevant degree of obliquity are exposed.
The needle is withdrawn and the site of puncture compressed until no
bleeding can be identified. The following information can be gained: anatomy
of the corpora and normal venous drainage.
Pharmacocavernometrography. Pharmacocavernometrography involves both
corpora being punctured with 21-gauge butterfly needles as distally in the
227
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CHAPTER
9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
corpora as possible. Through one needle, continuous pressure measurements
are recorded by connecting it to a pressure transducer. Through the other,
muscle relaxants and CM are injected at a rate sufficient to produce an intercavernosal pressure of 100 mm Hg. Whilst CM is being injected, the patient
should be turned supine oblique so that the whole length of the corpora can be
seen fluoroscopically and the draining veins at the base of the corpora identified. Spot fIlms of the relevant anatomy are exposed. The information gained is:
corporal dynamics, corporal anatomy and anatomy of the draining veins.
Complications
Extravasation. Contrast which is injected into the pericorporal tissues is
associated with instant localized pain and the needle must be repositioned.
Extravasation is easily identified on fluoroscopy as the CM will not flow away
from the tip of the needle on injection.
Contrast Reactions. A full allergy history must be taken. However, the use of
ionic CM should be avoided as they are more toxic in the extravascular space.
Priapism. Priapism is a complication of the muscle relaxants given to achieve
erection rather than the CM used.
Corporal Rupture. This is a complication of poor technique. If the corpora are
overdistended by too rapid a rate of injection, rupture is possible and serious
because it is itself a cause of impotence.
Infection. Infection is rare as long as aseptic measures are taken.
Seminal Vesiculography and Vasography
Seminal vesiculography and vasography are part of the investigation of
obstructive infertility and involve the direct administration of CM into the vas
deferens and/or seminal vesicles. Transrectal US has partly replaced these
procedures, but where that fails to identify the level of obstruction, contrast
studies are indicated. The CM should be of adequate radioopacity, nonirritant
to the mucosa of the vas deferens, of low viscosity and sterile. Many agents fulfil
these criteria. In our practice, Omnipaque 240 (Nycomed) is used.
Technique
Vasography is usually performed in theatre immediately prior to corrective
surgery to any obstructing lesion that may be identified. The vas is surgically
exposed in the scrotum and cannulated. CM is injected under image intensification control until either there is flow of CM seen into the posterior urethra,
which excludes an obstructing lesion, or there is hold-up of CM despite
adequate injection pressure, which indicates the level of an obstructing lesion.
9.13 Visualization of the Kidneys and Adrenal Glands
Seminal vesiculography aims to identify the patency of the seminal vesicle
ducts. This can be done by (a) cannulating the ejaculatory ducts at urethroscopy - this will also provide opacification of the vas deferens - or (b) puncturing
the seminal vesicles via a perineal approach under transrectal US control. This
is likely to give information about the seminal vesicle and ejaculatory ducts
only.
In either approach, sufficient contrast is injected until the relevant anatomy
has been detailed and spot films exposed.
Complications
Infection. As with any invasive procedure, infection is a possible complication
but this is rare as a sterile procedure is easily attained.
Haemospermia. Though alarming to the patient, this is an important finding as
it indicates patency of the ejaculatory ducts.
Pain. Overdistension of the seminal vesicles causes perineal pain.
References
Cunningham JR (1990) The diagnosis of stricture of the urethra by the roentgen rays.
Trans Amer Assoc Genitourinary Surgeons 5: 369
2. Kaufmann JJ, Russell M (1959) Cystourethrography: clinical experience with newer
contrast agents. Am J Roentgenol 75 : 884
1.
9.13
Visualization of the Kidneys and Adrenal Glands
G.P. KRESTIN
Computed Tomography of the Kidneys and Adrenal Glands
Why?
Shortly after the introduction of CT as a noninvasive imaging technique, its
importance for the routine diagnosis of pathological changes in the retroperitoneum became clear. Already by 1980, a cost reduction of more than 30 %
vis-a.-vis 1973 could be achieved through the use of CT for the clarification of
renal masses. As regards this question, CT has to compete today effectively only
with US, whereas standard X-ray procedures are primarily employed for the
assessment of the urinary tract.
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
For detecting adrenal mass lesions, CT clearly represents the technique of
first choice. Its outstanding importance has been in no way diminished in
recent years by the use of MRI. In the renal region, MRI can at best be used as a
supplementary technique, especially in patients who demonstrate a known
intolerance to iodinated CM. In adrenal gland imaging, a more reliable differentiation of pathological processes is possible with MRI, but CT still remains
the recommended method of detection due to its better spatial resolution.
One advantage of CT over US consists in the possibility of using CM. Not
only are organ blood flow and pathological changes made visible in this way,
but kidney excretion can also be visualized. Dynamic sequences may permit a
semi-quantitative estimation of renal function.
When?
Spiral CT examination is increasingly being employed to detect masses. It is
already competing with established procedures such as abdominal imaging,
intravenous urography and US in connection with pain in the side. CT is, however, today usually used as a supplementary technique to US. Here it is often a
question of confirming or characterizing an already detected pathological
lesion or of confirming or excluding suspected change.
CT is rarely used for clarifying the nature of inflammatory renal disorders; if
at all, it is performed in cases of abscesses or xanthogranulomatous pyelonephritis as well as acute pyelonephritis, for which late images are very reliable.
Cysts are usually identified sonographically; if uncertainties remain, CT can
provide further information and better differentiate between "simple" and
"complicated" cysts. All uncharacterized cysts and cystic and solid masses can
be identified using CT. In some cases, this yields an aetiological classification
(e.g. angiomyolipoma) and after CM administration usually a precise localization and determination of the extent of the pathological change. For the preoperative staging of renal cell carcinoma, CT is the technique of choice. AngioCT, just recently introduced, can image the renal arteries and has already been
successfully employed for the preoperative evaluation of kidney donors.
In the adrenal gland region, it is a question of recording pathological
changes: CT is here the best "screening" procedure for detecting or excluding
adrenal gland metastases as well as benign adrenal gland enlargements (hyperplasia, adenoma). It even often provides information about the etiology of the
illness. When CM is administered it is possible to differentiate between welldeveloped and less well-developed vascular lesions. Late images after CM are
better suited to clarify the aetiology.
The indications for CM administration in CT examination of the renal and
adrenal gland region have been summarized in Table 9.13.1.
How?
Incremental CT is preferable to spiral CT, and the thinnest slices possible should
be attained. The volume to be studied must be taken into account in determining the collimation. The length of the data that can be described can be calcu-
9.13 Visualization of the Kidneys and Adrenal Glands
Table 9.13.1. Use of CM in CT diagnosis in the kidneys and adrenal glands
CMuse
Kidneys
ot necessary
Helpful
Diagnostic
Adrenal glands
ot necessary
Helpful
Diagno tic
Indications
Detection of stones. angiomyolipoma. hydronephrosis, large cysts
Thmour detection, turnour differentiation
Abscesses, assessment of function, infarct
Hyperplasia. exclusion of tumour, tumour differentiation
For better differentiation and detection of the tumour's composition
(necroses, cystic parts)
Differentiation of hyperva cuJarized lesion (pheochromocytomas,
carcinomas)
lated on the basis of the slice thickness, the pitch (the table rate [mm/s]Jspeed
of rotation [sJ. x slice thickness [mm]), the collimation and the maximum time
of data acquisition, which depends on the time the patient can hold their breath.
For the diagnosis of perirenal and pararenal masses, investigating more
extensive inflammation, or for excluding the possibility of a local residuum
after tumour nephrectomy, peroral contrast enhancement of the upper gastrointestinal tract is also required. For this, 500 - 800 ml of a 4 % solution of a water
solvent CM are used.
All known renal and adrenal masses should be examined with and without
CM to determine the increase in concentration in the pathologic lesion. The
native image can be obtained with either spiral CT or sequential data acquisition. A total of 80 -120 ml CM must be given. Bolus injection is preferable to an
infusion; the rate of administration is secondary in imaging of the parenchyma.
Using spiral CT. CM images can be obtained at different phases. Early postcontrast images provide good cortico-medullary differentiation and optimal
presentation of perfused kidney cortex. In the subsequent nephrographic phase
(90 -120 S after CM administration), even the smallest slightly perfused lesions
can be detected in the homogenously coloured parenchyma. Finally, in the
excretion phase (4- 5 min after CM administration). the excretion into the renal
pelvis and in the urethra can be viewed. Thin-slice images (2- 5 mm) should be
used to precisely determine the increase in concentration in smaller lesions;
this usually prevents inaccurate measurements caused by the partial volume
effect.
CT Angiography. Images of renal arteries are made using spiral CT. Typically
one administers 90 -120 ml CM at a flow of 3- 5 mlls. Data acquisition is then
initiated 20 - 25 s after starting the CM bolus. Slices should be 5- 8 mm thick.
Contrast-Enhanced Images. Adequate visualization of the kidneys and adrenal
glands is typically reached 5 -10 min after rapid administration of 100 ml CM.
The kidneys can be examined with 8-1O-mm contiguous slices and the adrenal
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glands with s-mm slices. In the case of a pathological finding, especially if its
diameter is under 1.5 cm, thin-slice images (2-4-mm slices) should be carried
out in order to record precisely the size of the lesion. In this way, distortions in
the measurement due to partial volume effects can usually be avoided. If the
patients are incapable of cooperating very much and, due to variable inspiration the changes to be visualized can only be recorded poorly or not at all, it is
advisable to take 5-mm slices, with 3-mm table shifts. Here it has to be taken
into account that CT is often the last diagnostic examination before surgery and
it should be conducted as carefully as possible.
Complications
Complications in renal CT can be caused by systemic effects of the CM itself
(see Chapters 3 and 4), by the route and rate of CM administration and by the
possibly diseased condition of the organ of interest (renal functional disorder).
Slight side effects from CM administration such as feeling sick, hot or
nauseous, frequently occur at high administration rates. For this reason, it is not
uncommon after bolus administration to have to interrupt the examination for
a short period, ultimately leading to a suboptimal examination. Bolus administration of CM should, therefore, not always be used, but only in unequivocal indications.
The nephrotoxic effect of iodinated CM is greater in patients with previously impaired renal function (e. g. chronic glomerulonephritis, diabetic nephropathy). Pre-existing dehydration increases the risk of nephrotoxicity. Another
form of nephrotoxicity is caused by pathological protein (Tamm-Horsfall
mucoprotein and Bence Jones protein) precipitates and uric acid precipitates.
The incidence of serious renal functional disorder following intravenous CM
administration can be markedly reduced by sufficient hydration of the patients
prior to testing. Hence, a longer fasting before renal CT examination should be
avoided in all patients.
Conclusion
The use of CM plays an essential role in renal and adrenal gland CT imaging.
Aside from the distinction between nonvascular, poorly vascular, and highly
vascular lesions, it is also possible to attain a semi-quantitative assessment of
renal function. The type of data acquisition must be determined with regard to
the specific clinical issue, expecially when spiral CT is employed.
Renal and Adrenal Gland Angiograms
Why?
Renal vessels can be visualized directly following intraarterial contrast injection or, indirectly, by intravenous CM administration (indirect intravenous
digital subtraction angiography). The renal veins can be enhanced indirectly
9.13 Visualization of the Kidneys and Adrenal Glands
after intraarterial CM injection or, in a retrograde manner, by means of direct
intravenous CM injection. For the visualization of adrenal gland arteries, selective arterial CM injection is required.
In recent years numerous noninvasive techniques have been developed for
imaging the renal arteries. In particular, duplex or colour Doppler US are
increasingly being used for screening. CT and MRI angiography have also
achieved greater significance, but are still in a phase of continuous development,
the consequence of which is that they cannot yet fully replace catheter angiography. Possible multiple feeders, pathological vascular structures or damage to
the intima following trauma can be delineated only on an angiogram.
When?
Angiograms are by nature invasive examinations and thus represent considerable stress on patients and angiography is only justified given a clear
indication, i. e. if there is a high probability of influencing therapy as a result.
Absolute indications for angiography are the suspicion of renal artery stenosis
and the clarification of possible rena). vessel injury. The diagnosis of renal and
adrenal gland tumours is today at best only an occasional indication for angiography, which is indicated principally for pre-operative visualization of
vascularity. Renal and adrenal gland pWebography is carried out only in exceptional cases.
How?
For most questions posed today, digital subtraction angiography (DSA) has
replaced standard (cut-film) angiography. The DSA technique also has the
advantage of indirect vascular visualization following intravenous CM administration. The indications for intravenous DSA of the renal arteries have to
be clearly distinguished from those requiring intraarterial DSA.
Intravenous DSA of the Renal Arteries. This procedure has diminished greatly
in importance. It is only used for orientation in patients with Leriche syndroma
or when there are contraindications to intra-arterial techniques.
The examination is carried out after introducing a central venous high-pressure catheter via the basilic vein with intestinal hypotonia (40 mg Buscopan
i. v.) and, if at all possible, using ECG triggering. On average, two to three series
of films are taken sagittally as well as at a 20° left obligue or a 30° - 45° right
oblique. Per series, 35 - 40 ml of a 60 % CM are administered with a flow rate of
20 mlls. With this technique, the examination is diagnostic in 95% of cases
(accuracy, 90 %; sensitivity, 86 %; specificity, 92 %).
Intra-arterial DSA of the Renal Arteries. Diagnostic angiography is increasingly being replaced by noninvasive techniques. Intraarterial DSA is
primarily employed before or during percutaneous angioplasty. There are other
relative indications for kidney transplant study (rejection or stenosis), preoperatively for the clarification of vascularity or of venous involvement, or in
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the kidney donor, in cases of suspected renal vein thrombosis and in suspected
traumatic vascular lesions.
In the examination of the renal arteries a pigtail catheter is first introduced
as a rule via the femoral artery. This permits a survey study of the abdominal
aorta with the administration of 25 ml of a 60 % CM (flow rate 15 - 20 mllmin).
For selective angiography, a special catheter (renal, cobra or side-winder catheter) is substituted. One or more series are taken sagittally or obliquely after
administeration of 20 ml CM (at a flow rate of 8 mlls) per series.
Cut-Film Angiography of the Renal Arteries. Cut-film angiography is still
indicated for noncompliant patients, for extremely obese patients and before
transluminal angioplasty in order to determine the exact diameter of the vessel.
The same examination technique is used as in intra-arterial DSA but about
35 - 40 ml CM are administered per series. Sharpness of detail can be increased
by using magnification techniques. The intraarterial administration of vasodilators or vasoconstrictors (pharmacoangiography) may facilitate tumour
diagnosis.
Renal Phlebography. Renal phlebography is only used in exceptional cases. It
can be combined with venous blood sampling. It is, however no longer
indicated for the diagnosis of tumour thrombosis. DSA is used in the renal
phlebographic examination after catheterization of the femoral vein.
Adrenal Gland Angiography. Today there are hardly any indications for the
visualization of adrenal gland vessels. This examination is carried out, if at all,
primarily with intraarterial DSA technique, and cut-fIlm angiography is only
used on noncompliant or extremely obese patients. Flush abdominal aortography is first performed in order to determine the vascularity of large adrenal
or extra-adrenal tumours. Selective angiography is performed by catheterization of the renal vessels or by selective catheterization of the adrenal gland
arteries. Pinpoint diagnosis can be obtained by means of magnification techniques. 5 -10 ml CM are manually administered superselectively.
Adrenal Gland Phlebography. Selective adrenal gland phlebography is performed by catheterization of the veins with special catheters. Retrograde
visualization of the entire adrenal gland can be achieved by manual CM injection. The phlebography of adrenal gland veins is usually only carried out
today in selective venous blood sampling in hormonal overproduction.
Complications
Alongside the general complications already described arising from the actual
administration of CM (see renal and adrenal gland CT), arteriography is subject
to a variety of complications. Local complications at the site of the puncture
frequently occur when higher-calibre catheters are used or catheters are
frequently changed. In the. selective catheterization of renal vessels, intimal
dissection or thromboembolism, though rare, may occur. This can induce an
9.14 Contrast Media in Gynaecology
acute increase in blood pressure. In selective renal angiography, vasoconstriction and vasospasm are observed frequently, above all in the segmental arteries,
as compared to other vessels. They usually resolve spontaneously or can be
abolished by medication. There is a naturally higher frequency of complications
in the course of renal artery interventions.
In adrenal gland angiography, if a phaeochromocytoma is present, hypertensive crises can be triggered. Thus, given a known or suspected phaeochromocytoma, long-term prophylaxis with alpha (or alpha and beta) receptor
blockers should be undertaken prior to planned angiography. In selective
adrenal gland phlebography, the administration of CM at high pressure can
easily lead to extravasation, haematoma or infarct.
Conclusions
The main indication for renal angiography today is the elucidation of renovascular hypertension. In contrast, diagnostic angiography for the diagnosis of
renal masses is only rarely justified, whereas adrenal gland angiography has
practically been abandoned. With careful execution and selection of procedure,
and the careful use of CM, even this invasive imaging technique is associated
only rarely with complications.
9.14
Contrast Media in Gynaecology
H.J. MAURER and J.G. HEEP
Hysterosalpingography
Why?
The indications for hysterosalpingography (HSG) have only been reduced in
part by ultrasound (US), which avoids the use of ionizing radiations. The extent
to which magnetic resonance imaging (MRI) will also further limit the use of
HSG depends upon its spatial resolution. US can generally demonstrate the
uterus and ovaries precisely enough, but its spatial resolving power is not (yet)
sufficient to image the fallopian tubes. Here, however, the incorporation of US
CM into US practice could lead to an increase in the range of its indications.
1.
2.
Today, HSG is primarily used to examine variants and malformations of the
internal female genitalia, especially with regard to tubal patency and possible
obstruction; the form and extent of pathological changes in the ovarian
fimbria can also be better demonstrated with HSG than US.
HSG is also indicated for examining the tubes before and after their ligation
or before and after reconstruction operations.
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9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
3. Some centres perform HSG prior to intracavitary radiotherapy in cases of
uterine body or cervical carcinoma in order to gain a precise image of the
location and extent of the carcinoma. This procedure, however, is largely
being replaced by US and hysteroscopy.
When?
Since HSG is an invasive technique using ionizing radiation, it should follow all
non-invasive examination procedures; for example, in fertility tests, it should
only be used after the endocrinological and andrological tests have been completed. The only exception is if a malformation or pathological change, such as
sactosalpinx, has already been detected clinically or by US and requires further
clarification. HSG should be performed, following clinical and US exams, if possible, in the first 14 days following menstruation.
How?
The instrumentation used for performing HSG is well known. Increasingly, use
is being made of the suction technique, which does not injure the portio
cervicalis. Only in very rare cases does the cervical canal have to be dilated.
Whether HSG should be performed (a) under local anaesthesia or (b) while
holding the cervical os depends upon the examiner or the anatomical situation.
General anaesthesia has its own risks and is only necessary in atypical
situations in which the patient is under emotional stress or frightened. A genital
infection has to be excluded or cleared up prior to HSG.
HSG has to be performed under locally sterile conditions in order to prevent
the introduction of organisms into the cervix and corpus uteri. The nonionic,
iodinated eM (20 ml, 300 mg IIml) is administered under fluoroscopic control.
The required images should be in medium format (100 mm) with an image
intensifier in order to use the smallest possible dose of radiation, ca. 20 % of a
standard image.
Complications
Technique-Related Complications. As the instrument is inserted, injuries to the
cervical wall, though very rare, or perforations of it, though even rarer, can
occur. This may happen if the cervical wall has been softened by inflammation
or (very rarely) by tumour.
During or after HSG, bleeding can occur as a result of injury to a blood vessel
of the ostium uteri, as in the case of a small, submucosal, invisible haemangioma, or injury to the cervical mucous membrane. This can also occur if a
(previously unknown) coagulopathy exists. Such bleeding can usually be
stopped locally.
X-Ray Contrast Media-Related Complications. Even in a properly performed
HSG, a small amount of the X-ray CM can be absorbed by the mucous
membrane. In spite of fluoroscopic monitoring, occasionally too much CM is
9.14 Contrast Media in Gynaecology
injected, especially in cases of a completely closed cervical canal or fallopian
tubes closed on one or both sides. Even with normal injection pressure,
CM may penetrate the uterine wall and intravasate to veins and/or lymphatic
vessels.
In patent tubes, a greater or lesser amount of the X-ray CM makes its way into
the abdominal cavity. Here it is quickly absorbed. Peritoneal irritation and
general side effects caused by systemic X-ray CM effects after absorption are
rare. Nonionic, low-osmolar X-ray CM and the isotonic X-ray CM iotrolan have
proven to be especially well tolerated.
Lymphography of the Groin, Pelvic and Paravertebral Area
Why?
Imaging of the lymphatic vessels and nodes primarily serves for the detection
of metastases. The sensitive imaging methods of US, CT and MRI have largely
reduced the need for lymphography, especially since the specificity of the last is
insufficient to fulfIl all expectations. Moreover, the further development of
radio- and chemotherapy has now made the precision formerly required in
lymph-node assessment superfluous.
When?
If in suspected lymph node metastases the imaging procedures just cited have
not provided adequate information, lymphography can aid diagnosis by
detecting changes characteristic of metastases in normal-sized lymphnodes
themselves or in lymphatic vessels in the pelvic or paravertebral area.
How?
See the section on lymphography.
Complications
See the section on lymphography.
Lymphography of the Breast
Why?
Despite many efforts, a satisfactory technique for the lymphography of the
breast has not yet been successfully developed, especially one that would permit
the axillary, supraclavicular and parasternal lymph nodes to be adequately
demonstrated too.
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When?
If at all, lymphography of the breast should be performed at the end of the diagnostic process, in order to aid in treatment decisions.
Phlebography
Why?
In signs of swelling of one or both of the lower extremities, phlebography can
help to make the diagnosis: thrombosis of the external and/or common iliac
veins and its cranial spread (inferior vena cava); or, compression caused by
tumour or lymph nodes.
The imaging of the uterine plexus and the deep pelvic veins to exclude
postpartum thrombosis without operation is not possible by means of persymphyseal or pertrochanteric injection or through peruterine CM injection in
the two cornua corpus uteri. This question may be resolved using US or by MRI
if their spatial resolving power proves sufficient.
When?
Phlebography of the pelvic veins is indicated if clinical examination, Doppler
US, CT and/or MRI have not yielded an unequivocal explanation of the cause of
swelling of one or both of the lower extremities and lymphoedema has been
excluded. The technique of phlebography, its complications and their treatment
are discussed in the section on phlebography (Sect. 9.4).
Arteriography of the Internal Genitalia
Why?
Though many efforts have been made to expand diagnostic accuracy with the
help of arteriography, the procedure has failed to become established. The
arteriographic findings were not characteristic enough to contribute to definitive diagnosis. Only in cases of hydatid mole/choriocarcinoma is it possible,
on the basis of an angiographic roadmap to make the staging classification that
is crucial for treatment decisions.
When?
Arteriography of the internal genitalia is not used until all other diagnostic
imaging procedures have been tried, unless there are special reasons in
individual cases requiring a change in this sequence (US ~ CT/MRI ~
arteriography).
9.15 Arthography
How?
Examination is always carried out using the Seldinger technique. A pigtail
catheter is used for the aortography, whereas an appropriately preformed
catheter is employed for selective examinations (see also Sect. 9.3, 9.7).
Arteriography of the Breast
Why?
Basically, the same holds for the arteriography of the breast as for the internal
genitalia. The findings are largely nonspecific and are, thus, seldom of decisive
significance.
When?
Arteriography of the mammary vessels is generally employed as the last of the
imaging procedures (US -7 mammography -7 MRI -7 arteriography).
How?
Arteriography is performed transfemorally using the Seldinger technique. An
appropriately preformed catheter is inserted into the internal thoracic (mammary) artery.
Complications and their treatment are discussed in the chapter on arteriography. (See Sect. 9.3.)
9.15
Arthrography
V. PAPASSOTIRIOU
Why?
Arthrography continues to be a valuable examination technique in the imaging of
joint disorders in spite of the introduction and spread of endoscopy and modern
imaging techniques such as US, CT and MRI. It provides comprehensive data on
the condition of the menisci and discs, the thickness of, and changes in, articular
cartilage, lesions of the ligamentous apparatus and the size, form, contents and
parietal contours of the capsules and their bursae and recesses.
As a low-risk technique, arthrography is associated with no sequelae and
thus can usually be performed on outpatients. It can be used on children and
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elderly patients without reservation. Arthrography is a very easy technique to
perform and requires no special equipment. It can be carried out in any
practice possessing standard equipment. For this reason, it is less costly than CT
or MRI.
A very important advantage of the technique is its great diagnostic power
and accuracy. In the hands of experienced users and with careful technique,
arthrography may attain a diagnostic accuracy of 90%-95% [1,9].
The use of standard tomography and CT after the administration of X-ray
CM, or X-ray CM and air or gas (oxygen, carbon dioxide) markedly extends the
range of possibilities provided by the technique to address specific diagnostic
questions.
When?
Arthrography should always be preceded by a careful clinical examination of
the joint and its function. The clinical examination provides the indispensable
basis for deciding which special diagnostic procedures are subsequently indicated.
It is also absolutely necessary first to obtain conventional films of the joints.
This may reveal the following causes of clinical symptoms: osseous lesions following trauma, inflammation of bone and joint, degenerative processes, aseptic
necroses, loose radiopaque intra-articular bodies, calcification of the menisci
and articular cartilage, and tumours.
Accordingly, arthrography should be employed largely to clarify the suspected clinical diagnosis, i. e. to confirm or exclude it and to secure support for
further therapeutic measures.
The indications for arthrography vary somewhat for different joints:
Arthrography of the knee joint is performed most frequently. Data on its
frequency, however, vary considerably. According to Hall [4], it accounts for 55 %
of all arthrographic examinations, according to Dalinka [2] and my own
statistics, 80 % - 90 %.
The indications for knee-joint arthrography are: acute trauma; sport- and
work-related accidents with articular distortion (Fig. 9.15.1); unexplained
recurring haematomas with and without trauma; chronic, nonspecific joint
symptoms; persisting symptoms following endoscopic intervention or arthrotomy; articular "locking" due to meniscallesions or loose bodies in the joint,
mostly in osteochondritis dissecans; nonspecific swelling in the posterior
articular space and along the calf muscles; and articular instability and
meniscal injuries in atWetes and patients subject to occupationally related
strains (e.g. floor tilers, gardeners, etc.). Another important area in which
arthrography of the knee joint is indicated arises when expert opinion is
needed, especially in cases of doubt involving work-related accidents or
previous interventions.
The following are held to be the most important indications for arthrography
of the shoulder: impact trauma and arm distortion with delayed mobilisation
and shoulder symptoms with restriction of function that cannot be further
9.15 Arthography
Fig.9.15-1. Positive single-contrast arthrography of the knee joint (10 ml Iotrolan 300) in a
25-year-old patient after a sports accident. Diagnosis: longitudinal rupture of the medial
meniscus near the capsule
clarified by clinical examination or plain X-rays. Those affected usually display
the so-called impingement syndrome with chronic shoulder pain (painful arc),
which is usually the result of rupture of the rotator cuff (Fig. 9.15.2) or of
chronic inflammatory or degenerative processes of the articular soft tissues.
Incomplete rupture of the rotator cuff unfortunately often eludes standard
arthrographic demonstration. Loose bodies in the joint and adhesive capsulitis
can, however, be clearly demonstrated arthrographically.
Chronic pain and restriction of movement in post-traumatic states in both
growing and mature patients can be largely clarified by means of arthrography
of the elbow joint. Examination of this joint is also indicated for demonstrating
loose bodies, mostly in osteochondritis dissecans with corresponding symptoms of "locking".
Injuries to the distal radioulnar articular cartilage ("triangular ligament")
that result from radial fractures or from falling on the joint with a hyperextended hand often lead to painful conditions following immobilization,
especially when the wrist is rotated. With arthrography of the wrist, rupture of
the ligament can be superbly demonstrated (Fig. 9.15.3). Arthrography is also
very useful in clarifying symptoms following chronic overuse of the wrist.
The primary indication for arthrography of the ankle joint (in almost 90 %
of cases) is acute trauma with deformity of the joint (Fig. 9.15-4). Capsular ligament ruptures without bone trauma can almost always be demonstrated in the acute stage. However, the fJ1rns, for which the patient must remain
in a flxed position, are often inconclusive. Due to the considerable pain, the
examination cannot always be performed properly, and the risk of completely
severing an already partially torn ligament through movement must not be
forgotten.
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Fig.9.15.2. Positive single-contrast arthrography of the shoulder joint (15 rnl Iotrolan 300) in
a 50-year-old patient after physical overexertion. Diagnosis: complete rupture of the rotator
cuff with contrast outlining the subacromial bursa and the subdeltoid bursa
For clarification of the condition of cartilage and bone in osteochondritis
dissecans and in inflammatory, degenerative and post-traumatic articular
changes with recurrent swelling, arthrography can be helpful.
In many paediatric radiology and paediatric orthopaedic centres, arthrography of the hip joint is used in hip dysplasia and Perthes' disease. The
examination is less often performed on adults, however, there has been increasing success recently in clarifying cases of prosthesis loosening following
endoprosthetic operations. Further important indications are coxitis and
osteochondritis dissecans.
The arthrography of smaller joints is less frequent and only performed when
a very specific problem is being investigated.
In summary, arthrography is the technique of choice in acute trauma or posttraumatic states, in inflammatory or degenerative processes of the articular soft
tissues, in osteochondritis dissecans with or without loose bodies in the joint,
and in the diagnosis of articular tumours.
9.15 Arthography
Fig. 9.15.3. Positive single-contrast arthrography of the wrist (5 ml Iotrolan 300) in a
26-year-old patient following gymnastics.
Diagnosis: rupture of the distal radioulnar
articular disc ("triangular ligament") with
contrast imaging of the distal radioulnar
joint
Fig.9.15.4. Positive single-contrast arthrography of the ankle joint (5 ml Iotrolan 300)
in a 33-year-old patient after a sports accident. Diagnosis: rupture of the deltoid
ligament; spreading of the eM medially
Which Contrast Medium?
Arthrography makes unavoidable demands not only on the examiner's experience, competence and technique but also on the quality of the CM.
There are important requirements that an ideal X-ray CM should satisfy. In
assessing CM quality, the most important criteria are: good and artefact-free
contrast, optimal sharpness in outlining the various articular structures, good
local tissue compatibility and general tolerability and slow absorption.
In historical terms, the development of orthographic technique since 1905
has been closely related to research and further development of CM. In the
course of time, negative CM such as oxygen, carbon dioxide, air and positive
oily and water-soluble X-ray CM were introduced in conjunction with single
contrast and double-contrast technique.
The chemotoxicity of X-ray CM, the complications arising from negative or
positive X-ray CM and from incorrect or careless administration, put a considerable burden on the method and hindered widespread clinical acceptance.
It was not until the 1930S that radiologists had better tolerated water-soluble,
ionic, tri-iodinated and X-ray CM at their disposal; these CM have adequately
proven their reliability for over half a century.
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The nonionic, monomeric, X-ray CM developed in the 1970S proved beneficial to arthrography, at a time when it was becoming an increasingly popular
technique. The development of a dimeric, hexaiodinated, nonionic and watersoluble CM, Iotrolan 300, represents a significant further achievement in CM
research; for over 7 years now, it has been the arthrographic CM preferred by
many radiologists. This X-ray CM clearly permits a better and longer-lasting
detailed demonstration of structures with very good contrast density and excellent image sharpness; it thus fulfils to a great extent the criteria listed above
with excellent local and systemic tolerability [8]. The principal source of the
superb qualities of this X-ray CM is its isotonicity with blood and body fluid.
This minimizes the loss of contrast caused by the osmotically induced influx of
fluid into the articular space.
Which Method?
Pneumarthrography, the single-contrast technique with negative CM, such as
air, carbon dioxide or oxygen, is hardly ever still practiced, since the diagnostic
quality is inadequate when compared to that of other techniques. It is performed, if at all, on patients with a known allergic diathesis [2].
Given the superb quality and tolerability of the nonionic X-ray CM available
today and the effectiveness of prophylactic measures using H 1 - and Hzreceptor blockers against undesirable side effects, little stands in the way of
using positive X-ray CM for single contrast or double-contrast arthrography,
even on patients theoretically at risk.
Approximately 20 % of all arthrographies are performed with single-contrast
technique and positive X-ray CM. With this technique, the amount of CM appropriate to the given joint is administered free of air bubbles, intra-articularly
and under fluoroscopic control. In the arthrography of smaller joints, 2 - 5 ml
CM is given and in shoulder and knee-joint arthrography, ca. 10 ml or, in individual cases, more.
When the X-ray CM iotrolan is used as an arthrographic medium,joints have
to be moved for a longer period of time to optimally distribute the administered
CM and avoid misinterpretation (Fig. 9.15.5). Iotrolan has a higher viscosity
than the other X-ray CM and thus requires correspondingly more time in order
to outline natural or pathological folds, fissures and tears.
The most important advantages of the positive single-contrast technique are
held to be its very good artefact-free sharpness of detail and high accuracy
combined with an almost complete lack of impairment of joint function.
Double-contrast arthrography is the technique of choice of most examiners.
It has proven its outstanding reliability particularly in the investigation of the
shoulder and knee joint.
It is performed after controlled administration of positive X-ray CM under
fluoroscopic control followed by gas/air insufflation. The amount of X-ray CM
and gas varies considerably with both the joint and examiner involved. For the
examination of the knee joint, 4-8 ml X-ray CM and 40-60 cm 3 air, carbon
9.15 Arthography
Fig. 9.15.5 a, b. Positive single-contrast arthrography of the right knee joint (10 rnl Iotrolan
300) in a 46-year-old patient with joint effusion following severe strain. Diagnosis immediately after CM administration without movement exercises, no lesion visible (a). A
rupture of the meniscus is clearly depicted 10 -15 min after CM administration and movement exercises (b)
dioxide or oxygen are used. In shoulder arthrography, 3-5 ml X-ray CM and
cm 3 air or gas are quite sufficient.
The popularity of the double-contrast technique springs from its remarkably
sharp contour definition and its "plastic" depiction of the individual articular
structures. The disadvantages of the technique appear to be an increase in the
risk of infection, greater irritation of the articular capsule, overshadowing effects
due to foaming and an impairment of articular function after the examination.
10 -15
General Rules Applicable to All Arthrographic Techniques.
The following is a list of general rules that hold for all arthrographic procedures:
- Disinfect thoroughly, best by spraying and amply wetting the skin around the
joint.
- Shorten any troublesome hair growth at the point of injection with scissors,
since shaving can injure the skin.
- Cover the joint with a sterile slit towel.
- Use sterile gloves.
- Use sterile one-way syringes and cannulae.
- Draw up the CM and the local anaesthetic into the syringe immediately prior
to injection.
- Avoid injecting at places where there are skin abrasions or inflammations.
- Inflltration of anaesthetic is not obligatory in puncture of a joint. However,
local anaesthesia is often appreciated by anxious patients.
- Existing joint effusions should be largely drained (punctured) prior to CM
administration if at all possible.
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9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
- The intra-articular administration of CM and air should always occur
under fluoroscopic control. Irritating CM extravasation into the articular
soft tissues and consequent overshadowing effects can be avoided in this
way.
- Application of an adhesive absorbent dressing and/or compression bandage
is required to protect the site of injection.
- Thoroughly distribute the X-ray CM in the articular space by means of active
and passive joint movements.
- Take all films under fluoroscopic control.
- Take concluding survey films of the entire joint. If necessary also obtain
tomograms or computed tomograms.
Complications
Arthrography is quite a low-risk technique.
Local skin irritation caused by the disinfectant and sensitivity reactions to
the local anaesthesia can occur, but they are relatively rare and not specific to
this technique. An unpleasant "bubbling" sensation occurs only with the
double-contrast technique, it is felt to be variably unpleasant by patients and
can last up to 36 h (J].
Soft tissue emphysema following faulty gas insufflation can be painful and
last up to 2 days. Very unusual complications such as pneumomediastinum and
air embolism are described in the literature. They may be viewed as special and
isolated cases related to faulty technique on the part of the operator.
Small reactive effusions and accompanying feelings of articular tension or
worsening of existing symptoms and synovial irritation are difficult to explain
aetiologically. On the one hand, they can be taken to be reactions to the X-ray
CM; this appears improbable, however, given the good local tolerability of
modern nonionic X-ray CM. On the other hand, they could be induced by the
intensive stress manoeuvres during the examination.
Local infection and bacterial arthritis should not occur if the rules of cleanliness and asepsis are strictly followed. Lindblom [5] mentions two cases of
arthritis out of 4000 cases, Wirth et al. [10], one incident of staphylococcal
arthritis in a diabetic, whereas we did not experience a single case of articular
infection in our total test group of 14000 arthrographies.
Occurrence of systemic allergic reactions, such as urticaria with itching,
oedema of the eyelids, feelings of unease, and circulatory instability may be
associated with the use of ionic and nonionic X-ray CM. In ca. 2000 arthrographies with the dimeric, hexaiodinated, nonionic, X-ray CM Iotrolan 300,
eight patients complained of similar symptoms 8 h after the examination. With
oral antiliistamines, symptoms were quickly terminated. Only in one case were
corticosteroids also administered. It is worth noting that in some of these cases
CM hypersensitivity was known to exist.
Fatal complications have not been described as yet in the literature. Newberg
et al. in a statistical summary of 126,000 cases [6] noted 317 local and systemic
complications, but not a single fatality following arthrography.
9.15 Arthography
Fig. 9.15.6. Positive single-contrast arthrography of the left knee joint (10 rnl Iotrolan 300) in
a 52-year-old patient who had already suffered long-term symptoms and undergone arthroscopy without findings. Diagnosis: old horizontal rupture of the medial posterior horn with
1nt ...-::ar"lln"nl"ll1" CT"llnlTlinn
Fig. 9.15.7 a, b. Positive single-contrast arthrography of the left knee joint (10 rnl Iotrolan
300) in a 41-year-old patient after a sports accident and CT without fmdings (a). Diagnosis:
vertical longitudinal rupture of the medial posterior horn (b)
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Prospects
Arthrography - due to its diagnostic power and its high rate of accuracy retains its status as one of the most important techniques for the study of joints.
Incomprehensibly, in many places, especially in the United States, arthroscopy
has resulted in a marked decline in arthrographic examinations. Responsible
orthopaedic surgeons and trauma specialists, however, are aware of the limits of
arthroscopy as a diagnostic technique and employ endoscopic techniques
almost solely for therapeutic purposes. In our own experience, most patients
who come for arthrography have been referred by precisely those physicians
who themselves perform arthroscopic procedures. Nonspecific postoperative
symptoms are also monitored primarily arthrographically.
Neither arthroscopy (Fig. 9.15.6) nor CT (Fig. 9.15-7) and US, when viewed
critically and objectively, can completely replace arthrography. Only MRI can be
seen as representing a truly competitive technique; however, MRI is timeconsuming and costly and cannot be employed in· routine examinations in
every institution [4].
References
1.
2.
3.
4.
5.
6.
Annewanter G (1984) Die MeniscusHision dargestellt irn Arthrogramm und ihre Korrelation zum Operationspraparat. Inaugural dissertation, Free University of Berlin
Dalinka MK (1980) Arthrography. Springer, Berlin Heidelberg New York
Freiberger RH, Killoran PI, Gardona G (1966) Arthrography of the knee by double contrast method. Am I Roentgenol 97: 736 -747
Hall FM (1987) Arthrography, past, present and future. AIR 149: 561- 562
Lindblom K (1948) Arthrography of the knee, a roentgenographic and anatomical study.
Acta Radiol Suppl 74 (Stockh)
Newberg AH, Munn CS, Robbins AH (1985) Complications of arthrography. Radiology
155: 605 - 606
7. Richlin P, Riittirnann A, Del Buono MS (1971) Meniscus lesions. Practical Problems of
clinical diagnosis - Arthrography and Therapy. Grune and Stratton, New York
8. Schmidt M, Papassotiriou V (1989) Arthrography with iotrolan. In: Taenzer V, Wende S
(eds) Recent developments in nonionic contrast media. Thieme, Stuttgart, pp 182-189
9. Scholz I, Weyrauch U (1981) Korrelation zwischen Arthrographie und Operationsbefund
bei Meniscuslasionen. Z Orthop 119: 177 -181
10. Wirth W, Mihicic I (1989) Arthrographie. In: Schinz (ed) Radiologische Diagnostik in
Klinik und Praxis, VIIt. Thieme, Stuttgart, p 293
9.16 Contrast Media for Paediatric Patients
9.16
Contrast Media for Paediatric Patients
J. TROGER
Introduction
Water-soluble, biliary X-ray contrast media (CM) ceased being used in
paediatric radiology several years ago. Their administration for the visualisation
of the biliary tract was replaced entirely by sonography, endoscopic retrograde
cholangiopancreatography (ERCP) and, increasingly, by MR cholangiography.
Water-soluble renal CM are administered for cholangiography performed
intraoperatively, perioperatively, percutaneously or during ERCP.
Regardless of the type of contrast material, allergic and allergoid (including
idiosyncratic) reactions are rare in childhood [1]. On the other hand, the
osmolality of a CM is of crucial importance on intravascular administration [2].
Any hyperosmolality of a CM compared to blood will lead to a shift of fluid
towards the hyperosmolar CM [3]. The younger the child is, the more pronounced these disturbances of water and electrolytes will be. Moreover, hyperosmolar solutions cause pain on paravascular or paracavitary administration
(e.g. voiding Cysto-urethrogram per bladder puncture) and, consequently, can
reduce the child's willingness to co-operate. It was for these reasons that the use
of high-osmolar, ionic CM in children - particularly in neonates, babies and
infants - was replaced very early on by low-osmolar, non-ionic CM.
Intravenous Administration
Ionic CM may no longer be used in neonates, babies and infants. The increase
of osmolality leads to an influx of water into the vessel with a consequent shift
of electrolytes [4]. As a general recommendation, low-osmolar, non-ionic CM
should be used in all children and juveniles.
Another reason for the now widely accepted use of low-osmolar, non-ionic
CM is the much smaller number of allergic/idiosyncratic reactions compared
to the use of ionic CM [5]. On top of this, reducing the number and severity
of subjective side effects felt during the injection or immediately afterwards
(e.g. a sensation of warmth) produces better examination conditions and
results, since a calm and co-operative child is easier to examine. A further
benefit is the better image quality of low-osmolar CM compared to highosmolar agents [6].
Regardless of the type of contrast medium, all iodinated CM lead to an
excess supply of iodine to the thyroid and can provoke a thyrotoxic crisis in
hyperthyroid patients. In contrast, hypothyroidism develops in premature
babies, neonates and babies 4 to 10 days after intravascular CM administration. The increase in the supply of iodide leads to inhibition of T3 and T4
249
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
synthesis and, hence, to transient hypothyroidism which sometimes requires
treatment.
The excess availability of iodide after intravenous CM administration is due
on the one hand to unavoidable free iodine and, on the other, to molecular
degradation in the body. Improper storage of contrast media (high temperature, exposure to light, exposure to X-rays, long storage time) increases the
proportion of free iodide.
The replacement of ionic, high-osmolar CM by non-ionic, low-osmolar
agents led to a substantial improvement of the tolerance together with better
image quality [6]. Because water and electrolyte shifts were a particularly
feared event in paediatric radiology - particularly in patients only a few months
or years old -, the non-ionic, dimeric blood-isotonic contrast media represented a further step towards better tolerance from a theoretical point of
view [7]. In our own and in co-operative studies we have not seen the late reactions observed in adult radiology. Because non-ionic dimeric CM are more expensive, we use non-ionic monomeric agents in the overwhelming majority of
cases, reserving the dimeric non-ionic CM for high-risk patients or special
indications (e. g. premature babies, bronchography).
Excretory urography
The performance of excretory urography has become much less frequent in
recent years (in our department it has fallen to 10 % of the level of 12 years ago,
i. e. 33 cases in 1997 compared to 367 in 1985) as the use of sonography has
increased. Most such examinations are now carried out prior to surgery or to
lithotripsy and, occasionally, to clarify a complex pathomorphology.
We use exclusively non-ionic CM, which we administer as an intravenous
bolus after a fasting period of 12 to 15 hours and no fluids for 2 hours. Under no
circumstances should the child be deprived of fluids for longer than this.
The dose of CM per kg body weight is much higher in neonates, babies and
infants than in older children and adults because of the higher total water content and, in neonates, because of immaturity of the kidneys.
The dosage is shown in Table 9.16.1.
Computerised Tomography
The contrast medium dose should not usually exceed 1.5 ml per kg body weight
for computerised tomography using the spiral technique. The delay must be
Table 9.16.1. Contrast medium dosage for excretory urography
1st year of life
3 ml per kg body weight
minimum 20 mI
2nd to 3rd year of life 1.5 mI per kg body weight
minimum 20 ml, maximum 30 ml
1.0 mI per kg body weight
minimum 20 ml, maximum 50 ml
From 3rd year of life
(up to a maximum of 70 ml in considerably overweight patients)
9.16 Contrast Media for Paediatric Patients
adjusted with reference to the age of the child and the nature of the examination. As a rule of thumb: the younger the child, the shorter the circulatory time
and, hence, the shorter the delay (usually between 20 and 30 seconds).
Excessively high doses should also be avoided for computerised tomography.
It must again be pointed out that non-ionic, monomeric contrast media are
twice as hypertonic as blood and, consequently, can lead to disturbances of the
water and electrolyte balance if given in extreme dosage.
Angiography and Angiocardiography
At least for the high doses of angiocardiography including interventional
procedures, the difference in osmolality between monomeric, non-ionic (twice
as hypertonic as blood) and dimeric non-ionic (blood-isotonic) CM must be
borne in mind particularly when examining neonates and babies. The excessively high doses used during an interventional cardiological procedures might
lead to water and electrolyte shifts which could be as severe as those under ionic
CM.
Bronchography
The indications for bronchography have decreased markedly through the use of
endoscopy, computerised tomography and magnetic resonance imaging. Contrast media with special approval for bronchography are no longer available.
Bronchoscopy is virtually obsolete at our hospital.
Non-ionic CM are eminently suitable for unusual indications (e.g. simultaneous bronchography during angiocardiography in highly complicated anatomical situations). Sufficiently high contrast density and definition with an
acceptable duration of opacification (about 30 seconds) lead to high-yield
images [8]. Obviously, the image quality of the blood-isotonic, non-ionic,
dimeric CM is better than that of the non-ionic, monomeric CM, since the
higher osmolality of the latter leads to dilution of the contrast material in the
bronchus.
Voiding Cysto-Urethrography
We use exclusively non-ionic, monomeric CM. AI: 1 dilution with warmed
physiological saline solution reduces the costs while keeping the contrast
density sufficiently high.
Ionic CM can, of course, also be used for the examination of a pre-filled bladder. Because the hyperosmolar solution is diluted through the fluid in the bladder, urothelial irritation is also unlikely. Strong competition for the demonstration of vesico-uretero-renal reflux is currently developing in the form of
sonographic echosignal-enhanced reflux examinations [9].
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Gastrointestinal Tract
The osmolality of the CM is also of crucial importance for examinations of the
gastrointestinal tract. The administration of a CM which is hyperosmolar compared to blood leads to the influx of water into the lumen of the bowel. This
reduces the fluid volume of the blood. There have been isolated reports of
clinically relevant hypertensive hypovolaemia due to the use of an ionic highosmolar CM. The increased volume of the bowel contents caused by the influx
of water into the lumen increases the transit speed of the CM and reduces the
contrast density and definition.
Ionic high-osmolar CM should, therefore, no longer be used for examinations of the gastrointestinal tract. The non-ionic CM, particularly non-ionic
dimeric, blood-isotonic CM meet the requirements of very good image quality
and minimal or no effect on the water and electrolyte balance. We use nonionic, dimeric CM when examining premature babies and non-ionic, monomeric CM for the other age groups if the use of barium sulphate is contraindicated.
Oral Gastrointestinal Transit
Ionic, high-osmolar CM may no longer be used in neonates, babies and infants
because of the influx of water. These high-osmolar contrast media are no longer
available in our department. If barium sulphate is contraindicated, non-ionic
CM must be used. An additional advantage of non-ionic CM is their high image
quality on oral administration as well. In this indication, too, our own studies
have shown an advantage of dimeric, non-ionic CM over their monomeric
counterparts [10]. With the exception of high-risk patients, we always use
monomeric CM for reasons of cost. A further advantage of water-soluble CM
over barium sulphate is their faster transit, which means that urgent diagnoses
can be made with less loss of time.
The dosage depends on body weight and the diagnostic question.
Contrast Enema
In cases in which barium sulphate is contraindicated, a non-ionic CM should be
employed at least in babies, infants and high-risk patients. A substantial influx
of water into the bowel lumen is again likely if a high-osmolar, ionic CM is used
particularly in stenoses, in which the CM can remain in front of the stenosis for
a long time, this represents a substantial risk to babies, who are highly sensitive
to fluid shifts.
A contrast enema with CM is used in neonates to dissolve a meconium plug
or for the treatment of meconium ileus and, less frequently, in children (e. g. dissolution of a meconium equivalent in mucoviscidosis). We reject high-osmolar,
ionic CM in this situation as well - particularly as they can also cause mucosal
irritation - and use exclusively monomeric, non-ionic CM, which are twice the
9.17 What Is the Role of Newer Contrast Media in Interventional Radiology?
osmolality of blood. We help the meconium to slide by means of an addition to
the enema solution (e.g. Fluimucil®, a mucus liquifacient) which, together with
the increasing volume caused by the influx of water, often results in evacuation
of the meconium plug or meconium pearls.
References
Goodling CA, Berdon WE, Brodeur AE, Raven M (1975) Adverse reactions to intravenous
pyelography in children. Am J Roentgenol123: 802 - 804
2. Wood BP, Smith WL (1981) Pulmonary edema in infants following injection of contrast
medium for urography. Radiology 139 :377 - 379
3. Trager J (1988) Vergleichende Untersuchung zum Einfluss der Kontrastmittel-Osmolalitat
auf den Wasser- und Elektrolythaushalt sowie auch die Kontrastdichte des harnableitenden Systems - tierexperimentelle Studie. In Eickenberg HU, Engelmann UH (1988) UroImaging '88. Schnetztor, Konstanz
4. Schofer 0, Trager J (1986) Vergleichende Untersuchungen nierengangiger Kontrastmittel
verschiedener Osmomalitat; tierexperimentelle Untersuchungen. In Kaufann HJ Mediz.wissenschaftl. Buchreihe. Schering, Berlin
5. Nybonde T, Wahigren H, Brekke 0, Kristofferssen OT, Mortensson W (1994) Image quality
and safety in paediatric urography using an ionic and non-ionic iodinated contrast agent.
Pediatr Radiol 24 : 107 -110
6. Trager J (1986) Rantgen-Kontrastmittel in der Ausscheidungsurographie bei Neugeborenen, Sauglingen und Kleinkindern. In Melchior H (?) Bildgebende Systeme der Urologie.
Karger, Basel
7. Trager J, Wenzel-Hora BI, Darge K (1995) Iotrolan in paediatric examinations. Eur Radiol
5 (suppI2): 69-73
8. Thompson 1M, Whittlesey GC, Slovis TL et al. (1997) Evaluation of contrast media for
bronchography. Pediatr Radiol 27 : 598 - 605
9. Darge K, Diitting T, Mahring K, Rohrschneider W, Trager J (1998) Diagnostik des
vesikouteralen Refluxes mit der echoverstarkten Miktionsurosonographie. Radiologe
38: 405-409
10. Trager J, Wenzel-Hora BI (1989) Gastrointestinal diagnosis with iotrolan: Experience in
paediatric radiology. In TaenzerV, Wende S (1989) Recent developments in non-ionic contrast media. Thieme, Stuttgart New York
1.
9.17
What Is the Role of Newer Contrast Media
in Interventional Radiology?
P.DAWSON
CM are used in most fluoroscopically guided interventional procedures. Such
procedures may be categorized in two groups vascular and nonvascular. In the
nonvascular procedures, such as hepatobiliary, urogenital, etc., though large
total doses may be used, intravasation is slow and most of the CM will be passed
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out via the gut or the bladder. High dose toxicity is very rarely a problem,
therefore. It is true that anaphylactoid reactions may occasionally occur in such
procedures but these are rare. Nevertheless, there is a case for using nonionic
agents to reduce this risk even further in such patients with significantly increased risk factors but this case is weaker than when CM is administered intravascularly.
Angiographic interventional procedures are a different matter because the
CM enters the circulation immediately. Nonionic agents should be used in
patients with definable risk factors as in any diagnostic procedure. Considerable total doses may be used in complex angiographic interventional procedures and it is in this context that the nonionic agents come into their
own. Low osmolalities, low chemotoxicities and zero sodium content make
them most suitable for use in procedures anticipated to entail a high total
dose [1].
There has been some debate about the ideal CM for use in the specific case
of angioplasty. Low osmolality media (ionic or nonionic) have generally been
used to minimize pain of the concomitant angiography and, it has also been
argued, to minimize endothelial injury. This last point seems unconvincing
since the endothelial injury caused by any CM is likely to be swamped by the
gross mechanical or thermal injury caused by the procedure itself.
Some are now arguing that nonionic low osmolality agents should not be
used because they have weak anticoagulant and antiplatelet properties as compared with the ionic agents [2]. This also seems a rather spurious argument in
this context because any "anticoagulant" injected locally will have only a very
transient effect. Much more important is likely to be the patient's state of
systemic anticoagulation. The use of adequate systemic heparinization seems
likely, therefore, to be much more important [2]. In coronary angioplasty, in
particular, it would seem a pity to throwaway the advantage of a proven,
distinctly low cardiotoxicity, as offered by nonionic agents, in order to chase a
theoretical anticoagulant gain.
.
All this being said, no clinical trial comparing the outcome of angioplasty,
short or longer term, with different CM has, as yet, been reported, so it must be
said that the jury is still out.
References
Dawson P, Hemingway AP (1987) Contrast agent doses in interventional radiology. JIntervent Radiol2: 145 -146
2. Dawson P, Strickland NH (1991) Thromboembolic phenomena in clinical angiography.
Role of materials and technique. J Vasc Intervent Radiol 2: 125 -135
1.
9.18 Computer Tomography Angiography (CTA)
9.18
Computer Tomography Angiography (CTA)
S.c. RANKIN
Introduction
The development of spiral computed tomography has renewed interest in the
non-invasive imaging of the vascular tree using CT [1]. Spiral technology allows
the rapid acquisition of a volume of data during a single breath-hold with no
respiratory misregistration at peak vascular enhancement following a peripheral intravenous injection of contrast medium. From the data set, multiple
overlapping images can be reconstructed with no increase in patient dose and
superb 2D and 3D images generated.
Technique
Technique must be meticulous if good quality images are to be obtained [2]. In
spiral CT, the variables which can be controlled are the following.
1. Slice Thickness (Collimation)
The collimation affects both the spatial resolution and the signal: noise. Imaging small vessels running in plane requires 2- or 3-mm collimation; however,
if the patient is very large, s-mm collimation may be required to improve the
signal:noise ratio and the quality of the image. Large vessels which run through
the length of the volume can be imaged using s-mm collimation.
2. Duration of the Scan (Breath-hold)
Most patients can hold their breath for 30-40 seconds if they are hyperventilated prior to the scan; suspended respiration is used for the chest and
abdomen. In the pelvis, suspended respiration is not required, and for the
carotid arteries the patient may breathe but should not swallow.
3. Pitch
The pitch is the ratio between the table feed speed and the collimation; a pitch
of 1 is ideal, as this produces minimal z-axis blur.
Pitch =
Table speed (mm/s)
11"
. Gantry rotation in seconds
Co ImatlOn mm
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
4. Table Feed Speed
Distance in mm
Table speed mmls = - - - - - - - Tolerable breath-hold
For example, if the distance to be covered is 250 mm and the patient can hold his
or her breath for 25 seconds, the table speed is 10 mm/second. Using a gantry
rotation of 1 second, the collimation could be 10 mm, giving a pitch of 1, or for
better spatial resolution a 5-mm collimation could be used, requiring a pitch of 2.
Z-axis Blur. In spiral technology, interpolation algorithms convert spiral data to
axial sections and new lBo-degree interpolations decrease the degree of z-axis
blur, so there is very little increase in effective slice thickness with a pitch of 1;
even with a pitch of 2, the effective slice thickness is only increased by a factor
of 1.3. Using 5-mm collimation and a pitch of 1(5-mm slice, table speed 5 mm/s)
with lBo-degree interpolation gives an effective slice thickness of 5.1 mm. If
3-mm collimation is used with a pitch of 1.7 (3-mm slice, table speed 5 mm/s),
the effective slice thickness would be 3.6 mm. The distance covered in a given
time in both protocols is the same, but with improved spatial resolution using
the 3-mm slice.
5. Intravenous Contrast
The amount and timing of the contrast injection is vital. Many centres use nonionic contrast at a concentration of 300 mglml, and this may be decreased to
150 - 240 mglml for the pulmonary arteries. For vascular imaging, the length of
the bolus should equal the scan duration to maximise contrast levels. The
volume to be injected is calculated by multiplying the injection rate by the scan
duration, using an injection rate of between 2.5 and 6 mlls.
6. Timing
The delay between the start of the injection of contrast and the beginning of
data acquisition should be optimised, particularly if high injection rates are to
be used to maximise contrast in small vessels running in plane (e. g. renal arteries), but it is less important if lower injection rates are used for larger vessels
which run through the plane (e.g. the aorta). For the vast majority of patients,
a delay of 25 - 30 seconds will give good opacification of the aorta and its
branches. If the patient is thought to have a poor cardiac output or the timing
of the bolus is critical, the delay should be tailored to the patient. Many of the
manufacturers now have computer software which will begin the scan when the
enhancement within the vessel reaches a pre-set threshold; alternatively, the
delay can be customised by using a test injection to produce a rough approximation of a cardiac output estimate.
Cardiac Output Estimate. A 5-mm slice at the level of interest is selected, and a
dynamic multi-slice technique with no table movement is used. 10 -15 ml of
9.18 Computer Tomography Angiography (CTA)
contrast medium is injected at the same rate as for the final injection. An
8-second delay is programmed in, and a scan every 3 seconds (i.e. 2 seconds
interscan delay) is performed for 30-40 seconds. A low mA and kV are used to
minimise patient dose and reduce the heat loading on the tube. Either by using
a region of interest and generating time/density curves of the enhancement of
the aorta or by "eyeballing" the images, the scan with the maximum enhancement is identified to work out the delay (time to maximum enhancement + 8 s).
Some authors recommend adding 3- 5 seconds to allow for the larger volume of
contrast medium used for the diagnostic images.
7. Field of View
Use a decreased field of view, as the decrease in the size of pixel will increase the
resolution. A low noise reconstruction kernel (smooth) may be better for 2D
and 3D imaging.
8. Reconstruction
In spiral CT the scans can be reconstructed anywhere along the volume to
produce overlapping slices with no increase in radiation dose to the patient.
Longitudinal resolution improves when the reconstruction interval is less than
the collimation, but only to a certain level; reconstructing two images per
rotation is recommended to improve lesion detection, and reconstructing three
images per rotation will produce better 3D images.
9. Post-processing of the Data
The main programs used to produce 2D and 3D images are curved or linear
multiplanar reconstruction (MPR), surface shaded display (SSD), maximum
intensity projections (MIP), and volume rendering (not available on all workstations).
Curved Multiplanar Reformats (MPRs). These are single voxel tomograms
drawn through the centre of the vessel on the axial, coronal, or sagittal images
and extended through the data set. They are very quick to perform but are
operator-dependent, and inaccurate drawing may imply lesions that are not
present. The grey scale reflects the attenuation values, calcification can be
separated from the contrast medium, and intra-luminal stents are clearly
visualised.
Surface Shaded Display (SSD). A binary image is generated based on a pre-set
threshold, and contiguous voxels above this threshold are modelled as a single
structure with excellent anatomical detail; however, the relative attenuation
values are lost, and the contrast medium cannot be differentiated from calcification. Extensive editing is required to produce high-quality images, and the
incorrect setting of a threshold may imply or remove lesions.
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9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Maximum Intensity Projection (MIP). This is ray tracing at a preselected angle
through the volume of data. The maximum value encountered in each ray is
encoded into a 2D display. The grey scale of axial CT is preserved and differentiation of calcification, stents, and contrast maintained.
Volume Rendering. A voxel intensity histogram is generated, and each voxel is
mapped for opacity and brightness. Relative voxel attenuation is preserved
using a grey scale in the final image. All the data set is used, and the final image
can project vessels, organs, or both. There is now the possibility, using the CT
data set and computer software, to view the interior of vessels and fly through
them using virtual reality.
Application
Carotid Arteries
Identification of internal carotid artery stenosis is important, as endarterectomy may be beneficial if the stenosis is greater than 70 %. Carotid angiography
is the gold standard but carries a risk of stroke. Duplex ultrasound is usually
performed with a reported accuracy, compared to angiography, of between 95
and 98 %. Grading errors may occur, particularly if there is very high-grade stenosis, severe contralateral disease, or extensive calcification, and there will be
some technical failures because of the position of the bifurcation. Magnetic
resonance angiography (MRA) has a sensitivity similar to Doppler ultrasound
and angiography, but there are well-known contra-indications to MRI.
CT angiography has several advantages over MRA l31. It is very quick and the
MR contra-indications do not apply. The image is dependant on the volume of
contrast medium rather than on the rate of flow, and it may be superior for highgrade stenosis. CTA is not a screening method, but rather a problem-solving tool
when the duplex ultrasound is sub-optimal and if MRA cannot be performed.
The results from CTA correlate well with duplex ultrasound and angiography, with an accuracy of 92 % comparing SSD and angiography; using MIPs
there is an 89 % correlation for all grades, increasing to 100 % for severe stenosis
and occlusion.
Technique
With a 2-mm collimation use a pitch of 1.5 - 2, or a 3-mm collimation with a
pitch of 1, scan from C 6 -7 to skull base. Patient must not swallow. Use 100 rnl
non-ionic contrast medium 2-3-mlls, with a 20-second delay or timed delay.
Reconstruct every 1 mm. Pre-edit images and then use MIPs and SSD with a
threshold of 100 HU.
Thoracic Aorta
The aorta is well demonstrated on conventional CT, but spiral CT offers several
advantages. Depending on the collimation and pitch used, the entire aorta can
9.18 Computer Tomography Angiography (CTA)
be imaged on a single spiral to allow assessment of the full extent of aortic dissections (Fig. 9.18.1). Complex anatomy can be resolved using 3D reconstruction, and the addition of multiplanar reconstruction aids the diagnosis and may
help in surgical management [4].
In aortic dissection the addition of MPRs may help in the identification of
the intimal flap. In many centres, trans-oesophageal ultrasound is used, as the
initial investigation for dissection and the reported sensitivity of trans-
a
b
Fig.9.18.1. a Axial CT of a type 111 aortic dissection demonstrating the intimal flap (arrow);
b MPR of the same data showing full extent of the dissection
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9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
oesophageal ultrasound, spiral CT, and MR angiography are the same (100%),
although CT is better than the other two at identifying branch dissections [5].
Motion artefact in the ascending aorta can be a significant problem and may
mimic dissection.
Angiography, which may not identify the false lumen if contrast medium
does not flow through it, is good at assessing involvement of the aortic valve and
the coronary arteries.
Technique
With 3-mm collimation, use a pitch of 1.5 - 2, reconstructing every 2 mm, or with
5-mm slice with pitch of 1, reconstructing every 3 mm. Use 90 -120 ml contrast
medium at 3-4 mI/s,with a delay of 20 seconds; in suspected aortic dissection,
use a cardiac output estimate. Use overlapping axial images, MPRs, and MIPs to
assess the true and false lumen and to classify the dissection type. Inject via the
right arm to decrease the artefact from the dense contrast medium projected
across the mediastinum.
Pulmonary Arteries
Spiral CT is an excellent non-invasive method of diagnosing pulmonary emboli
in the central and segmental pulmonary arteries, with a sensitivity of 91 % and
a specificity of 78 % when compared with angiography (Fig. 9.18.2) [6]. The use
of MPRs may improve visualisation. CTA can be used in patients with indeterminate isotope ventilation/perfusion scans. The limitation of the technique is
that spiral CT cannot detect thrombi in subsegmental vessels, and thus small
pulmonary emboli will be missed.
Technique
Employ suspended respiration if possible.With a 3-mm slice, use a pitch of
1.6 - 2, or a 5-mm slice with a pitch of 1. Use a pitch of 2 if the patient is very
breathless. Reconstruct every 2 mm. Scan from the inferior pulmonary veins to
the top of the arch of the aorta. Use 100-140 mI non-ionic contrast medium,
150-240 mg/ml at 4-5 mlls to ensure that the bolus length corresponds to the
duration of the scan. Employ a delay of 10 -15 seconds or based on cardiac output estimate if the patient's condition suggests a poor cardiac output.
Aorto-lliac Disease
CT can be used in the preoperative assessment of aortic aneurysms. It is less
invasive than angiography and more accurate in defining the size of the
aneurysm. Use of thin section spiral CT with overlapping reconstruction and
multiplanar reformats has improved the assessment of the relationship of the
aneurysm to the renal arteries [7] and also the extension into the iliac vessels.
9.18 Computer Tomography Angiography (CTA)
a
b
Fig.9.18.2. a Axial scan of an embolus in the left upper lobe artery (arrows); b MPR of
same data showing involvement of the basal arteries (arrows)
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
Fig. 9.18.3. MIP of an aortic aneurysm showing its relationship to the renal arteries and iliac
vessels, prior to stent insertion
Any associated abnormality in the renal or visceral arteries can also be
identified. CTA will provide all the pre-operative information required for
aortic stent insertion (Fig. 9.18.3) and will identify the post-operative complications, including continuing leaks, deformity of the stent, and patency of the
inferior mesenteric artery [8,9].
Technique
Use a low-dose, low-resolution scan precontrast to practice the prolonged
breath-hold, localise renal arteries, and assess required distance to be covered
by the spiral to include the full extent of the aneurysm.
For the diagnostic scan, with a 2-mm collimation, use a pitch of 1.5 - 2, or a
3-mm slice with pitch of 1 for the origins of the renal arteries. Scan from the
level of the coeliac axis for 30 rotations. Below this, change to 5-mm collimation
with a pitch of 1- 2 to cover the required distance. Continue to suspend respiration while changing from one protocol to the other. The patient can breathe out
gently for the pelvis.
For the delay, use cardiac output estimate, or if using a slow injection rate of
2- 3 mlls, an empirical delay of 30 seconds can be used. The volume of the contrast medium must be sufficient to last the duration of the scan. Use an injection
rate of 2.5-6 mlls.
9.18 Computer Tomography Angiography (CTA)
Renal Arteries
Hypertension is a common condition, but less than 5% of patients will have a
renovascular cause. Nevertheless, this is a potentially curable group, and it is
important to diagnose significant renal artery stenosis. The gold standard for
diagnosis is angiography, and response to treatment is the defmitive proof.
Captopril renal scintigraphy may suggest the diagnosis, and Doppler ultrasound can be used. This may identify significant stenosis, but a negative result
does not exclude it. Magnetic resonance angiography may well be the most
appropriate screening test, but it is not widely available and is costly. CT angiography is a potential screening test which is both sensitive and specific (Fig.
9·18-4).
Galanski et al. [10 1, comparing CTA with angiography, reported that CTA had
an overall sensitivity of 95 %, but was 100 % sensitive and 92 % specific for
significant (> 50%) stenosis. The axial images were the most useful for identifying accessory arteries, but axial images combined with MPRs improved
visualisation of stenoses, and MIPs were helpful for ostial stenosis. SSDs were
unhelpful, as calcification could not be identified.
Technique
With a 2-mm slice, use a pitch of 1.5 - 2, or a 3-mm slice with a pitch of I,
reconstructing every 1mm. Scan from the superior mesenteric artery to L3.
Employ a delay based on cardiac output estimate. If using a lower injection rate,
an empirical delay of 30 seconds will usually be successful. Use a contrast
Fig.9.18.4. MIP of renal arteries. No evidence of renal artery stenosis
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CHAPTER 9 Clinical Use of Iodinated CM for the Visualization of Vessels and Organs
medium of 100 -150 ml at 2.5 - 6 mIls. Use curved MPRs and MIPs rather than
SSDs for further assessment of renal artery stenosis.
Peripheral Vascular Disease
Doppler ultrasound is the usual non-invasive investigation for the femoral
arteries, but an assessment of the iliac vessels may be difficult. CT angiography
can be used, and in a study comparing CTA and angiography for iliac disease,
there was complete agreement in 90 % of the cases, with CT underestimating
the degree of stenosis in 4 %; however, for clinically significant stenosis
(> 85 %), CT was 93 % sensitive with an accuracy of 95 % [11]. Rieker et al. [12]
found CTA was 100% sensitive for femoral and popliteal artery occlusion and
94 % sensitive for tibial artery occlusion, but the results in high-grade stenosis
(75 - 99 %) were not quite as good, with a sensitivity of 88 % for femoral disease
and 73 % for popliteal stenosis. Although CTA is a quick examination, it does
require the use of a large volume of contrast medium, which will probably limit
its use to patients where the result of Doppler ultrasound is unclear.
Technique
For the iliac artery, with a 5-mm collimation, use a pitch of 1- 2. Inject at
2-3 mIls, with a 30-second delaY. If using a higher injection rate, use cardiac
output estimate for the delay. For a lower limb, with a 5-mm slice use a pitch of
1. Scan from inguinal ligament to proximal calf, using two spirals. Employ a
timed delay. This requires 200 ml dilute contrast medium.
Advantages and Limitations of (1 Angiography
CT angiography offers several advantages as a method of investigating the arterial system. It is a non-invasive technique, and no arterial injection is required,
with a consequent decrease in patient morbidity, physician time, and cost. The
disadvantages are limited z-axis coverage at a suitable mA, which limits spatial
resolution, and small vessels less than 2 mm will not be identified. Stenoses will
be overestimated if there is low subject contrast between the vessel and background, which occurs either because of a poor bolus injection of contrast
medium or if the vessel diameter is less than the effective slice thickness. A
stenotic vessel may be called occluded if the subject contrast falls below the low
contrast resolution of the scanner. Volume averaging will cause an underestimate of stenosis, as it leads to vessel blurring, which is greater for stenotic
than for normal vessels, so the stenosis will appear less marked. This effect is
most marked in longitudinal reformats, as longitudinal resolution is worse than
transverse resolution.
Further disadvantages are that 3D imaging may be time-consuming, and
there is no contrast saving, as large volumes of intravenous contrast medium
may be required, which may limit the use in patients with poor renal function.
9.19 Magnetic Resonance Angiography (MRA)
References
1.
2.
3.
4.
5.
6.
Rubin GD, Dake MD, Semba CP (1995) Current status of three-dimensional spiral CT
scanning for imaging the vasculature. Radiologic Clinics of North America 33 : 51-70
Brink JA (1995) Technical aspects of helical (spiral) CT. Radiologic Clinics of North
America 33 : 825 - 841
Link J, Brossmann J, Penselin V et al. (1997) Common carotid artery bifurcation: preliminary results of CT angiography and color-coded duplex sonography compared with
digital subtraction angiography. American Journal of Roentgenology 168 : 361- 365
Quint LE, Francis IR, Williams DM et al. (1996) Evaluation of thoracic aortic disease with
the use of helical CT and multiplanar reconstructions: comparison with surgical findings.
Radiology 201 : 37 - 41
Somner T, Fehske W, Holzknecht N et al. (1996) Aortic dissection: a comparative study of
diagnosis with spiral CT, multiplanar transesophageal echocardiography, and MR
imaging. Radiology 199 :347-52
Remy-Jardin M, Remy J, Deschildre F et al. (1996) Diagnosis of pulmonary embolism with
spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology
200: 699 -706
7. van Hoe L, Baert AL, Gryspeerdt S et al. (1996) Supra- and juxtarenal aneurysms of the
abdominal aorta: preoperative assessment with thin-section spiral CT. Radiology
198: 443-448
8. Moritz JD, Rotermund S, Keating DP, Oestmann JW (1996) Infrarenal abdominal aortic
aneurysms: implications of CT evaluation of size and configuration for placement of
endovascular aortic grafts. Radiology 198: 463-466
9. Rozenbilt A, Martin LM, Veitch FJ, Cynamon J, Wahl SI, Bakal CW (1995) Endovascular
repair of abdominal aortic aneurysms: value of postoperative follow-up with helical CT.
American Journal of Roentgenology 165 : 1473 -1479
10. Galanski M, Prokop M, Chavan A, Schaefer C, Jandeleit K, Olbricht C (1994) Accuracy of
CT imaging in the diagnosis of renal artery stenosis. ROFO 161: 519 - 524
11. Raptopoulos V, Rosen MP, Kent KC et al. (1996) Sequential helical CT angiography of
aortoiliac disease. American Journal of Roentgenology. 1996; 166 : 1347 -1354
12. Rieker 0, Duber C, Schmiedt et al. (1996) Prospective comparison of CT angiography of
the legs with intraarterial subtraction angiography. American Journal of Roentgenology
166: 269 - 276
9.19
Magnetic Resonance Angiography (MRA)
I.EM. MEANEY
Paramagnetic contrast agents shorten the Tl relaxation time of spins in the
immediate vicinity of the contrast agent in direct proportion to the concentration. Contrast-enhanced MRA exploits this feature and by relying exclusively
on T 1 shortening, generation of intravascular signal is completely dependent on
exogenous contrast material. As blood contrast no longer depends on "inflow"
effects, images can be acquired in any plane thus increasing anatomical
coverage for any combination of field of view and slice thickness. Flow artefacts
seen with TOF imaging are effectively eliminated.
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With most modern scanners, a 3-D data-set that covers the arterial anatomy
at sufficiently high resolution can be acquired in approximately 20 - 30 seconds
by exploiting fast gradient technology. For all anatomies, the volume of tissue
that must be imaged is dictated by the patient's anatomy, and the demand for
adequate spatial resolution dictates the slice thickness, and therefore the
number of slices required. Because of the predominant supero-inferior orientation of the blood vessels, the coronal plane, which gives the maximum
anatomical coverage for any combination of field-of-view and slice thickness
for almost all territories, can be used with comprehensive coverage of large
anatomical regions-of-interest. Unlike CTA there are many operator defined
scan options (reduced number of phase-encoding steps, use of rectangular field
of view, increased bandwidth) which can be exploited to give shorter scan times
on MR.
Technique
An intravenous cannula is placed into a peripheral vein, usually in the upper
extremity. After appropriate placement of the imaging volume, a pre-contrast
image set may be acquired. The first data set is inspected to ensure appropriate
placement of the imaging volume and to check for excessive "wrap-around"
artefact, which is minimized by crossing the arms over the chest or, preferably,
by extending them above the head for imaging of the chest or abdomen. The
first image set may also be used for subtraction purposes should this prove
advantageous.
As arteries within the chest and abdomen move with respiration, it is essential that the patients suspends respiration during the scan in order to ensure
images free of respiratory motion artifact. The patient is instructed to take
several deep breaths to improve blood oxygenation and increase breath-holding
ability, and the contrast injection started. After an appropriate interval, the
patient is instructed to suspend respiration (typically easiest on full inspiration) and imaging is commenced. The aim is to acquire data during the first
pass of the gadolinium bolus, in order to produce the highest possible intravascular signal (blood T 1 will be shortest during the first pass owing to it's high
concentration) at a time when venous enhancement will be absent or minimal.
Immediately on completion of the 3-D acquisition, the patient is allowed to
breath normally and a further acquisition is performed. This second postcontrast acquisition is useful in the rare event of the contrast being missed on
the "arterial" phase images. In most instances this image set shows both arterial
and venous anatomy.
Contrast Dose and Injection Rate
The aim of CE-MRA is to make the blood brighter than background tissues. To
achieve a blood Tl substantially shorter than that of the brightest background
tissue, fat (Tl 270 msec at 1.5 T), total gadolinium dose must be at least
9.19 Magnetic Resonance Angiography (MRA)
0.2 mmollKg (assuming a relaxivity of 4.5 mollsec, typical of commercially
available gadolinium chelates). An injection rate approximately equal to the
scan duration is appropriate, given the fact that the intravenously injected bolus
will "stretch-out" on passing through the lung filter, thus giving some margin
for error with acquisition timing. Therefore, an injection rate of 1.5 mlIsec over
20 seconds for a scan time of 20 seconds will give an imaging window of approximately 40 seconds for acquisition of the arterial anatomy. In order to
ensure delivery of the total dose of injected agent a 20 ml saline "flush" is
advised to prevent stagnation of gadolinium chelate in a kinked arm vein. Although hand injection is effective, use of an automated MR compatible pump
(MEDRAD) simplifies the process and is used for all studies in our department.
Timing of the Gadolinium Infusion
Accurate timing of the gadolinium bolus is important to ensure high quality
CE-MRA. Arterial signal is proportional to contrast-induced Tl shortening
which is proportional to the concentration of gadolinium chelate. Blood concentration depends on the injection volume, contrast injection rate and cardiac
output. As the highest arterial contrast concentration is achieved during the
first pass of the gadolinium bolus, synchronization of data collection, especially the contrast-defining central lines of k-space with the first pass is desired, to
ensure optimal intravascular signal and absence of venous enhancement as
venous enhancement rapidly follows arterial enhancement. The following
options are available to ensure imaging during the first pass of the bolus:
- Best-guess technique: This technique is based on the assumption that the cir-
culation time from arm to aorta lies within a predictable range in most
patients. Although patient's circulation times may vary widely, sound clinical
experience has shown that by using a scan delay time of 10 - 20 seconds, and
an imaging time of 10 - 30 seconds, selective arterial imaging is possible in
the vast majority of cases. With shorter scan time a longer scan delay time is
used.
- Test-dose: A 1- 2 ml bolus of gadolinium is injected followed by a saline chaser,
and imaging of a single slice in the region of interest is performed. Contrast arrival, determined by either visual inspection or ROI determination,
dictates the scan delay time for the 3-D acquisition according to the formula:
Scan delay time = arrival time +
injection time
2
scan time
+---2
- Bolus-detection: This can be performed using either a "black box" technique
(e. g. GE SMARTPREP) in which a pulse sequence automatically detects the
arrival of contrast agent in the aorta and synchronizes the 3-D acquisition
with arrival of the bolus. An alternative method is to use MR fluoroscopy
(Philips BolusTrak) in which the operator watches for the arrival of contrast
agent into the imaging field and initiates the 3-D acquisition at the ap-
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propriate time. With both of these methods immediate sampling of the contrast-defining central lines of k-space at the start of the scan is performed to
ensure optimal intravascular signal and absence of venous enhancement.
Nature of the MR Data
For CE-MRA the image data is acquired in a 3-D volume. An array of data
represents the Fourier transform of the object (k-space), in which different
parts of the data represent features of the image. For example, the low spatial
frequencies dominate image contrast (center of k-space) and the high spatial
frequencies (periphery of k-space) dominate image resolution. This unique
feature of the MR data, which has no parallel in CT imaging can be exploited to
enhance image quality on CE-MRA and decrease the occurrence of venous
enhancement.
Temporal Order of K-Space Sampling
Because of the relatively short artery-to-vein transit time for most vascular
territories (30 seconds for abdominal imaging) compared to the scan time, it is
advantageous to sample the contrast-defining lines of k-space early during the
acquisition before venous enhancement occurs. Artery-to-vein circulation times
vary widely throughout the body and although it is possible to selectively
perform arterial imaging of the abdominal aorta and renal arteries in most patients with a best guess technique, it is much more difficult to selectively image
the carotid arteries because venous enhancement lags behind arterial enhancement by 8 -12 seconds only. For all vascular territories, however, acquisition of
the central lines of k-space early during the arterial bolus is advantageous as this
will minimize venous signal. If this approach is employed, it is essential to know
that contrast agent has arrived in the imaging field at the start of imaging, therefore this approach of sampling of the central line of k-space at the start of the
scan should always be used in association with some form of bolus-detection.
Differences Between TOF Imaging and CE-MRA
With TOF imaging, images must be acquired perpendicular to the direction of
blood flow to optimize "inflow" effects. A saturation pulse can be placed on
either side of the imaging slice thus completely eliminating flow from one
direction only and thus generating either pure arterial of pure venous images.
With contrast-enhanced MRA, flow from one direction cannot be eliminated by
use of a saturation pulse because of the very short blood T 1 values. Therefore,
imaging must be performed during the relatively short temporal window
between peak arterial enhancement and onset of venous enhancement to
ensure selective arterial imaging.
For TOF imaging, ultra-short TR's cannot be exploited as the rate limiting
step is the time required for "inflow" of fully relaxed spins from outside the
9.19 Magnetic Resonance Angiography (MRA)
Fig.9.19.1. Whole volume
maximum intensity projection of a 20 second
breath-hold 3D abdominal
MRA acquired during the
arterial phase following
injection of a 30 rnl bolus of
contrast agent with an automated injector. There is
excellent depiction of the
aorto-iliac arteries and side
branches with both good
resolution and excellent
signal-to-noise
imaging slice and TR's of the order of 25 - 35 msec must be used. For CE-MRA,
ultra-short TR's (5-7 msecs) can be exploited without sacrificing intravascular
signal. As the acquisition time is proportional to the TR x Py (no. of phase
encoding steps) x NEX (no. of excitations - always 1 for CE MRA), scan times
for CE MRA are 5 -7 times faster than TOF MRA's for a given number of slices
and resolution.
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Fig.9.19.2. Whole volume
maximum intensity projection of a 12 second
breath-hold 3D MRA of the
aortic arch and great vessels
to the level of the circle of
Willis following injection of
a 30 rnl bolus of contrast
agent with an automated
injector
The Importance of Speed
There are four important advantages offered by the fast acquisition allowed by
CE-MRA:
1.
2.
For applications within the chest and abdomen, generation of high quality
MRA's artefact free images relies on suspension of respiration for the
duration of the scan. Therefore, faster acquisitions are preferable and the
acquisition time can be matched to the patients breath-holding ability with
scan times of 10 seconds easily achievable.
For any contrast dose, the greatest arterial gadolinium concentration (and
therefore vascular signal) will be achieved by rapid injection of contrast
material. For shorter (breath-hold) acquisitions rapid injection, extremely
rapid injection (20-30 ml over 10-20 seconds) gives highest contrast-tonoise ratios.
9.19 Magnetic Resonance Angiography (MRA)
3. Because CE-MRA is non-selective (contrast-material passes rapidly from the
arteries into the veins) imaging must be performed during a relatively narrow imaging "window" in order to ensure pure arterial imaging. Therefore,
data acquisition which is shorter than the mean artery-to-vein transit time
facilitates pure arterial imaging, providing the bolus is timed appropriately.
4. Another important feature of the ability to acquire data rapidly is the
resultant short examination time. If the examination is confined to acquisition of a CE-MRA only, then total imaging time including localisers is of
the order of 2-3 minutes, and total examination time less than 15 minutes.
Although the extremely rapid acquisition time results in a cheap examination
in terms of magnet time, this is offset by the considerable cost of the contrast
agent. Nonetheless, taking into account savings on X-ray consumable costs
(e.g. catheter & contrast material), X-ray personnel and bed occupancy (for
arteriography), any cost-effective analysis is likely to favor MRA providing
accuracy is high.
Current Clinical Applications
The success of contrast-enhanced MRA is largely related to its ability to
generate images with high resolution, high contrast-to-noise without the risks
of arterial catheterisation or nephrotoxic contrast agents. The earliest application of contrast-enhanced MRA was in the evaluation of the aorta and renal
arteries, however, scan times were long (4 minutes) and accurate delineation of
the visceral (e.g. renal arteries) was poor. With the development of faster
gradient technology imaging of a sufficient number of slices with sufficient
resolution to cover the arterial anatomy within a breath-hold became a clinical
reality, and with it, the introduction of fast contrast-enhanced MRA into routine
clinical practice. The greatest experience with 3-D CE MRA is in the evaluation
of the renal arteries in patients with suspected renal artery stenosis. Sensitivities and specificities of greater than 90 % have been reported by most
authors. All but the smallest accessory renal arteries can be depicted. Imaging
of the mesenteric arteries in patients with suspected mesenteric arteries has
also been reported, as has successful imaging of abdominal aortic aneurysms.
Within the thorax, 3-D CE-MRA has been shown to be accurate for evaluation of a wide spectrum of disorders affecting the thoracic aorta. Additionally,
high accuracy compared to conventional catheter arteriography has been
reported in patients with suspected pulmonary embolism, although experience
with MRA in this area is limited.
Experience with CE-MRA of the peripheral arteries is still limited. Assessment of the aorto-iliac arteries is standard in patients undergoing CE-MRA for
suspected renal artery stenosis. Using the same approach, the aorto-iliac
segments can be evaluated in patients with suspected arterial disease from midabdominal aorta to mid thigh because of the large field-of-view capabilities. A
new approach is to use a "stepping-table" approach (as initially exploited for
conventional X-ray "bolus-chase" arteriography) with successive imaging over
the aorto-iliac system, thighs and legs during a slow infusion of contrast agent.
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Using this technique, independent researchers have shown high accuracy compared to catheter arteriography.
Venous Imaging With Contrast Agents
It is possible to demonstrate venous anatomy and pathology by repeating the
acquisition at least once after passage of the bolus through the arteries and into
the veins. This type of venous imaging is useful for assessing all venous territories, but especially the portal vein, intracranial venous sinuses, and other
sites where contrast agent cannot be directly injected. It is well known that concentrated gadolinium chelates (e. g. at the concentrations achieved in the arm
veins during injection) generates a signal void on 3-D MRA images because of
T 2 * effects. However, by using a dilute solution of contrast agent (1- 2 %) direct
injection into arm or leg veins produces high contrast MR venograms for a total
dose of 1- 2 ml of gadolinium chelate. This type of imaging, direct MR venography, is only applicable in instances where contrast agent can be directly
injected immediately downstream of the region-of-interest but offers an exciting alternative to upper and lower limb X-ray venography.
Blood Pool Agents
The gadolinium chelates currently available are "extracellular agents" that are
rapidly distributed through the extravascular space following injection. Several
manufacturers are currently evaluating agents that remain in the blood stream
after injection, called "blood pool" agents. The advantage of these agents is the
relatively long imaging window offered by virtue of the long time the agent
stays in the circulation, thus allowing images to be acquired without breathholding and with cardiac and respiratory triggering. A significant disadvantage
is the longer post-processing time required to eliminate venous structures, as
imaging is not performed during the arterial phase. Although these agents are
potentially applicable to any vascular territory, the greatest application may be
for imaging the pulmonary circulation and coronary arteries although hard
data is still lacking.
Future Prospects
The use of CE-MRA for demonstration of vascular anatomy and pathology
without recourse to arterial puncture and without use of nephrotoxic iodinated
contrast material is likely to increase. In the relatively short time-period since
it's introduction, the applications for CE-MRA have expanded to encompass
almost all vascular territories, and are likely to increase further. The development of newer contrast agents, faster gradients, new coils, and newer pulse
sequences will herald further expansion within the field probably with anticipated rapid incorporation into clinical practice.
9.20 Carbon Dioxide Angiography
References
1. Prince MR (1994) Gadolinium-enhanced MR aortography. Radiology 191: 325
Prince MR, Narasimham DL, Stanley JC, Chenevert TL, Williams OM, Marx MV, Cho KJ
(1995) Breath-hold gadolinium-enhanced MR angiography of the abdominal aorta and its
major branches. Radiology 197: 785 - 671
3. Meaney JFM, Weg JG, Chenevert TL, Stafford-Johnson OS, Hamilton BH, Prince MR (1997)
Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med
2.
336: 1422 -1427
4. Meaney JFM (1997) Evaluation of chronic mesenteric ischemia with gadolinium-enhanced
magnetic resonance angiography. JMRI 5 : 32 - 37
5. Prince MR, Chenevert TL, Foo TK, FJ Londy, JS Ward, JH Maki (1997) Contrast-enhanced
abdominal MR angiography: Optimization of imaging delay time by automating the
detection of contrast material arrival in the aorta. Radiology 203 : 109 -114
6. Holsinger AE, Wright RC, Riederer SJ, Farzaneh F, Grimm RC, Maier JK (1990) Real-time
interactive magnetic resonance imaging. Magn Reson Med 14: 547 - 553
7. Prince MR, Narasimham DL, Jacoby WT (1996) Three-dimensional gadolinium-enhanced
MR angiography of the thoracic aorta. AJR 166 : 1387 -1394
8. Meaney, JFM, Ridgway JP, Smith MA (in press) Stepping-Table Gadolinium-Enhanced
Digital-Subtraction Magnetic Resonance Angiography Of The Aorta And Lower Extremity
Arteries: Preliminary Experience. Radiology
9.20
Carbon Dioxide Angiography
S. HASHIMOTO and K. HIRAMATSU
Introduction
Carbon dioxide was initially used in the imaging of retroperitoneal, mediastinal
and other structures. CO 2 was first applied to the cardiovascular system for the
diagnosis of pericardial effusion in the 1950S. However, owing to the poor contrast, it was not until the advent of digital subtraction angiography (DSA) that
CO 2 was utilized in the angiographic diagnosis of visceral and peripheral
arteries [1]. CO 2 is now also used for the visualization of venous structures in
DSA. We have recently found that CO 2 DSA is sensitive in detecting minute
arteriovenous shunt [2] and minute haemorrhage [3].
Properties of CO2
CO 2 is a colourless, odourless gas. Its concentration is about 0.03 % in air. When
injected, it produces a negative contrast because of its lower atomic number and
lower density in relation to the surrounding tissues. CO 2 is buoyant and floats
above blood or other body fluids. The gas is cleared by the lungs rather than by
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the kidneys and is not considered to impair renal function, even with selective
injections. It almost never causes hypersensitivity reactions and can be administered to patients who are allergic to iodinated contrast media (ICM). CO 2
has a much lower viscosity than ICM. Because of the low viscosity, CO 2 DSA can
be performed through smaller-calibre catheters or needles. According to
Poiseuille's law, CO 2 thus has the potential to pass through the small arterial
stump, the tiny hole in the wall, or through minute arteriovenous fistula much
faster and more easily than do ICM. When CO 2 extravasates out of the high
pressure arterial system, it expands and becomes much more readily discernible in the lower pressure extravascular space. This never happens when
aqueous ICM are used. CO 2 is highly soluble in serum and is not considered to
reach the capillary circulation in gaseous form. This explains why no parenchymal stain is obtained in CO 2 DSA that can camouflage the extravasation. Once
the ICM extravasates out of the vessel, it may either be diluted by the non-clotted blood or camouflaged by the tissue staining, making it hard to detect.
Method
A digital subtraction angiographic unit of good quality is a must in CO 2 DSA.
CO 2 DSA is performed by manually injecting 10 - 60 ml of medical-grade CO 2
gas in a disposable syringe. The use of a gas-priming technique allows a controlled and less sudden delivery in manual injection. A specialized, automatic
injector that enables a reliable, gradual CO 2 delivery is available in some countries. The images are obtained at 3.1 to 12.5 frames per seconds in CO 2 DSA. In
peripheral CO 2 DSA, it is recommended elevating the feet 10 to 15 degrees to
achieve optimal fIlling.
Every effort should be made to minimize misregistration artefacts. If there is
a large amount of gas overlying the abdomen and pelvis in visceral CO 2 DSA,
butyl scopolamine is administered to reduce peristalsis of the bowel over the
region of interest. The patient is kept under restraint, if necessary, to eliminate
involuntary movement. When the patient is unconscious or his/her respiratory
function has deteriorated, he/she is kept breathing freely, and as many masks in
various respiratory phases as possible are taken before the injection of the gas.
An adequate mask is selected in the post-processing stage. Averaging or
"stacking" of both mask and live images is also performed to suppress noise and
summate images.
CO2 Versus Iodinated Contrast Media (lCM)
ICM angiography continues to be the primary and gold-standard vascular
imaging technique. It has, however, some limitations in emergency. It is not difficult to detect extravasation on ICM angiography if the bleeding is brisk
enough. Slower haemorrhage is usually undetectable with ICM. On the other
hand, CO 2 DSA detects much slower haemorrhage because of its lower viscosity, compressibility and high solubility. Thus, ICM and CO 2 work closely to-
9.20 Carbon Dioxide Angiography
gether; whereas ICM angiography provides the most detailed vascular roadmap
and arterial, parenchymal, or venous pathology, CO 2 DSA provides valuable information on the specific site of obscure arterial bleeding. Aside from the
emergency situation, when the renal function is impaired or the patient is
highly allergic to ICM, CO 2 is used instead of ICM both in visceral and
peripheral angiography.
To date, the safety of CO 2 is not guaranteed for its use in areas above the
diaphragm, and the gas should not thus be administered into these areas until
its safety has been firmly established.
CO 2 is nearly 1110 as dense as most of the commonly used ICM. CO 2 DSA
images have poorer CNR than ICM DSA do and are extremely susceptible to
misregistration artefacts.
Summary
Excessive amounts of CO 2 may cause a green house effect. Judicious use of small
amounts of CO 2 , however, reduces angiographers' frustration and saves many
exsanguinating patients in an emergency. CO 2 is also helpful in patients with
poor renal function and an allergy to ICM.
References
1. Hawkins IF (1982) Carbon dioxide digital subtraction arteriography. AJR 139: 19 - 24
2. Takeda T et al. (1988) Intraarterial digital subtraction angiography with carbon dioxide:
superior detectability of arteriovenous shunting. Cardiovasc Intervent Radiolll :101-107
3. Hashimoto S et al. (1997) CO2 as an intra-arterial digital subtraction angiography (IADSA) agent in the management of trauma. Semin Intervent Radiol14 :163 -173
275
CHAPTER 10
Contrast Media for Clinical Magnetic Resonance
Imaging and Ultrasound
10.1
Contrast Media for Clinical Magnetic Resonance Imaging
H. P. NIENDORF, T. WELS and V. GEENS
Introduction
A major feature of magnetic resonance imaging (MRI) is the great variation
possible in the choice of suitable scanning sequences to obtain optimal image
contrast and the desired tissue differentiation. As with any other procedure, the
sensitivity and specificity of MRI and, hence, its accuracy can be enhanced
through the use of contrast media (CM). Despite the use of appropriate imaging
techniques, more exact conclusions about the tissue integrity, function and
perfusion of certain organ systems can, in most cases, only be drawn with the
help of CM. Their use can also simplify the examination procedure itself or
obviate other diagnostic methods. Wide-spread clinical use had demonstrated
definite advantages of contrast-enhanced MRI over the plain examination. At
present, contrast media are used world-wide in more than 25 % of all MR examinations, depending on the indication and clinical experience.
There are several parameters which determine the image content and, hence,
the diagnostic yield of the MR tomogram. The signal intensity (51) of a tissue is
determined on the one hand by the tissue parameters T 1, T 2, proton density,
susceptibility, flow effects and chemical shift and, on the other, by the equipment
parameters magnetic field strength, gradient fields and the measuring
sequences (TR, TE, flip angle, measuring time, pixel size). Tl-, T2-, Ti- or
proton-weighted scans are obtained by appropriate choice of the equipment
parameters.
The tissue parameters can be modified by substances introduced into the
body from outside. Pharmacological compounds of paramagnetic and superparamagnetic substances suitable for this can be regarded in the widest sense
as potential CM for MRI. Common to both substance groups is an ability to
shorten the tissue-specific relaxation times. This shortening of the relaxation
10.1
Contrast Media for Clinical Magnetic Resonance Imaging
times has a distinct influence on the signals when appropriate imaging sequences are chosen.
At the end of the '70S and beginning of the '80S, Lauterbur et al. were the first
to report on the possible benefits of paramagnetic ions (heavy metals from the
group of rare earths such as gadolinium and dysprosium) as shorteners of the
relaxation time [1,2]. However, it was not until these otherwise poorly tolerated
heavy metals with their usually unsuitable pharmacological properties were
complexed that the way was opened for their development as contrast media for
clinical use.
The different components of an MR contrast medium (e.g. Gd-DTPA) must be
mentioned in this connection. First comes the heavy metal ion, the paramagnetic
properties of which affect the tissue parameters in such a way as to alter the signal
intensities. The chelating agent must be viewed separately from the heavy metal
ion; it determines important pharmacological properties of the contrast medium
and, as a result, permits incorporation of the heavy metal into the human organism. It is the pharmacokinetic properties of a contrast medium such as its solubility in water, distribution in the organism, tissue affinity and excretory pathway
from the body which are of most importance to its diagnostic effect and tolerance. In the case of Gd-DTPA the important factor is the pharmacokinetic properties of the chelating agent and not those of the heavy metal.
The first paramagnetic metal chelate, gadopentate dimeglumine (Gd-DTPA,
tradename Magnevist®) was introduced onto the market by Schering AG in
1988. Since then, it has been used throughout the world in more than 20 million
MRI examinations [15].
The first gadolinium complexes developed disperse in the extracellular
compartment after intravenous administration; The term "extracellular
contrast media" (extracellular fluid space marker [ECFSMj) was coined to
describe this property. The substances currently undergoing clinical development, e.g. Gd-EOB-DTPA, which have an early extracellular and a later intracellular phase, are termed "tissue-specific" or "intracellular" contrast media.
This contribution to the book is intended to provide a brief overview of the
contrast media currently used in the MR technique and of their possible applications.
Mode of Action of the Contrast Medium Substance Groups
Paramagnetic Substances
A paramagnetic substance is characterised by the presence of at least one
unpaired charge. The general rule is: The more unpaired electrons a substance
displays, the greater is its magnetic moment. Paramagnetic substances display
positive magnetic susceptibility. On application of a magnetic field of induction
Bo, the substance aligns itself in the direction of the field. The magnetisation
induced in the substance itself adds to the already existing magnetic field of
induction Bo• Thus, in the presence of paramagnetic substances, a local increase
of the field strength occurs in their immediate vicinity. After removal of the
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and illtrasound
external magnetic field, paramagnetic substances return to their original
unorganised state.
What has just been said applies equally to the hydrogen protons of the body
and to the paramagnetic and superparamagnetic contrast media. As a result of
the transfer of energy between the unpaired electrons of paramagnetic substances administered from outside, e. g. gadolinium or manganese, and the
nuclear spin of the hydrogen protons of the human organism, the nuclear spin
system - deflected after a single high-frequency impulse - returns more quickly to its original state of equilibrium than is the case without the contrast
medium. The result is a shortening of the tissue-specific TI-relaxation time,
whereby the relaxation of the nuclear spin can be described roughly as a dipoledipole interaction between the nuclei. Thus, in an external magnetic field,
paramagnetic substances exert an effect with the help of their own strong but
short-range local magnetic fields which increases the relaxation rate of hydrogen protons in their vicinity.
Over and above this, magnetic fields of paramagnetic atoms or molecules in
their immediate vicinity cause additional inhomogeneities of the external
magnetic field. As a consequence, the precession frequencies of the protons display local differences. This phase-incoherence shortens the relaxation time T2 •
Thus, paramagnetic substances influence the signal intensity by shortening the
T1- and T2 -relaxation times, although the influence on T1 relaxation predominates. Shortening T1 within a normal imaging technique leads to an increase of
the signal intensity. Consequently, paramagnetic substances are described as
"positive" CM. T2 shortening, on the other hand, leads to a loss of signal intensity. The effect of T1 shortening on the signal intensity decreases more and more
as the contrast medium concentration of paramagnetic substances is increased,
since the protons can then relax almost completely within the repetition time.
Further increases of the contrast medium concentrations lead to a marked
decrease of the signal intensity via T2 shortening. Thus, a maximum dose exists
for physical reasons regardless of the tolerance of a contrast medium which
should not be exceeded if an optimal contrast effect is to be achieved.
Superparamagnetic Substances
Superparamagnetic substances (e. g. iron oxide particles) are what are known as
single-domain particles. This means that they can be completely magnetised
even at low field strengths and do not retain any residual magnetisation after
the field has been switched off. Consequently, there is also no clumping or
aggregation of the particles as a result of reciprocal attraction. Overall, the
magnetic susceptibility of superparamagnetic compounds is similar to that of
paramagnetic compounds, although the magnetisation induced by an external
field is much stronger.
Superparamagnetic CM shorten the T2 time selectively, without affecting the
T1 time to any significant extent. They lead dose-dependently to a reduction of
the signal intensity or to signal extinction without displaying the dose-dependently biphasic pattern typical of paramagnetic substances. They can be described as "negative" CM.
10.1
Contrast Media for Clinical Magnetic Resonance Imaging
The mechanism ofT2shortening is fundamentally different from the mechanism which leads to the T1 shortening under paramagnetic CM. The superparamagnetic substances can be described as T2-relaxation centres or, more
accurately, as "interference fields". These interference fields affect the homogeneity of the externally applied magnetic field. The result is an increasing
phase shift of the protons in the x-y plane and shortening of the transverse relaxation time T2. This is not simply a local interaction, but a longer-range effect
of these field inhomogeneities produced by the large magnetic moment of the
superparamagnets. Because virtually no parts of the frequency coincide with
the Larmor frequency of protons, dipole-dipole interactions are rare. As a
result, there is only a minimal influence on T1 relaxation.
The T2-relaxation rate is proportional to the particle count and inversely
proportional to the particle radius. Consequently, smaller particles are more
effective superparamagnetic CM. Because of the strong induced magnetic field,
superparamagnetic substances affect the signal intensity even in very low substance amounts (50 % decrease of the signal intensity with a dose of 3 Jlg Fe/g
liver tissue).
Substances used for MRI are the ferrites (iron oxide particles:
Fe~+O~-M2+02- with M = manganese, copper, zinc or iron) and magnetites
(mixture of 1/3 Fe 2+oxide and 213 Fe 3+ oxide present in an inverse Spinell structure) in different formulations.
There are at present two classes of superparamagnetic CM: Larger particles
(SPIOs, size 60-180 nm) with a shorter plasma half-life (e.g. Endorem®,
Guerbet and Resovist®, Schering AG) and ultra-small particles (USPIOs, size
< 20 nm) with a distinctly prolonged plasma half-life (e.g. AMI 227). Unlike
paramagnetic CM, they are not available in aqueous solution, but are applied as
suspensions, the particles of which after intravascular administration are
phagocytised by the cells of the monocytic macrophage system (formerly also:
reticuloendothelial system (RES» in the liver, spleen, lymph nodes and bone
marrow and are then subject to physiological iron metabolism.
Extracellular Contrast Media
The extracellular paramagnetic chelates currently available for clinical use are
all gadolinium complexes. They disperse quickly in the extracellular space. No
evidence is available that they enter the intracellular space to any significant
extent. The complexes cannot cross an intact blood-brain barrier (BBB) because
of the size of their molecules and their pronounced hydrophilicity.
What are known as "tight junctions" of the capillary endothelium are
nowadays regarded as an important morphological substrate of the BBB (Jl.
However, not all intracerebral structures are protected by the BBB. The falx, the
pituitary, the chorioid plexus and other structures display an increase of signal
intensity after CM administration even under physiological conditions.
An SI increase or contrast enhancement in the CNS area occurs everywhere
where either no BBB function exists from the start or where it has been permanently damaged. The extent of the SI increase in the different parts of a lesion
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and Ultrasound
depends on its degree of vascularity (CM supply), the degree of capillary permeability and the size of the interstitial space, i. e. the water content. In general,
the latter is bigger in tumour tissue and in inflamed tissue than in healthy tissue.
The conditions for all causes of contrast enhancement subsumed under the
term "BBB disturbance" are many and various. In general, metastases as well as
durosarcomas, neurinomas and adenomas display the capillary structure of the
original tissue. These are, therefore, mass lesions whose capillary bed does not
have a BBB function from the very start. The interstitial space of a tumour is,
therefore, freely accessible to gadolinium chelates.
Although glioblastomas originate from actual cerebral tissue, the malignant
tumour tissue with a tumour-typical capillary bed takes the place of the normal
cerebral parenchyma with its BBB function. These cases, therefore, constitute more
displacement of the normal tissue equipped with a BBB function than actual
damage to an existing BBB. Cellular units of malignant cells without a tumour-specific capillary supply adjacent to vital tumour tissue do not display contrast enhancement and, consequently, can be demonstrated only by pathophysiology.
In the case of inflammatory changes and acute MS lesions, in acute vascular
occlusions, in trauma and in radiation damage, on the other hand, actual
damage to the BBB is present. Other possible causes of usually only slight
and/or short-lasting impairment of BBB function are: Chronic hypertension
(> 200 mm Hg), toxic influences (e.g. lead poisoning) or the intravascular injection of highly hypertonic solutions (e. g. mannitol).
Virtually all relevant anatomical structures of the body and tumour staging
can now be claimed as extracranial indications. As mentioned above, the
magnitude of the SI increase in inflamed or tumorous tissue depends on the
degree of vascularity, the degree of capillary permeability and the size of the
interstitial space outside the CNS as well. Contrast medium-enhanced MRI also
has its place in functional examinations. Good examples are the assessment of
kidney function and voiding cystourethrography.
MR angiography (MRA) is now a routine examination for many questions.
The introduction of paramagnetic gadolinium chelates has greatly advanced its
development. The contrast effect on use of MR contrast media results primarily
from the change in the relaxation times, so that the quality of the angiograms is
largely independent of the course of the vessels and venous vessels with a low
flow rate or stasis are more readily demonstrable than with other techniques.
Extracellular contrast media normally permit demonstration of the arterial
blood flow over a period of up to 30 seconds. A longer-lasting contrast effect is,
however, desirable for many uses, e. g. coronary MRA, myocardial perfusion, the
high resolution imaging technique and interventional procedures. This could,
for example, be achieved with a contrast medium that remains strictly within
the intravascular space for a longer period of time.
Table 10.1.1 provides an overview of the gadolinium complexes currently in
use for clinical MRI. In the case of Gd-DTPA, 0.1 mmoUkg body weight is regarded as the adequate dose in the majority of cases. In many countries, however,
a dose of up to 0.3 mmollkg body weight is permitted; This is administered in
particular when the indication is the exclusion of disease or the demonstration
of singular metastases and smaller lesions.
10.1
Contrast Media for Clinical Magnetic Resonance Imaging
Pharmacodynamics
Stable binding of the heavy metal gadolinium to a chelating agent is very important for pharmacodynamic and pharmacokinetic reasons. The gadolinium
ions are firmly bound to polycarboxylic acids in these complexes. The complexes can be divided into open-chained and macrocydic complexes (Table
10.1.1). These compounds are so stable that no significant amounts of the metal
ion are released in vitro or in vivo.
The complexing of the metal ions leads to a distinct improvement of the
pharmacodynamic and pharmacokinetic properties compared to the metal
chlorides. In the form of the respective sodium or meglumine salts, the metal
complexes are readily soluble in water and very well tolerated. As regards their
acute toxicity (LD so ) all substances display a high therapeutic spectrum (Table
10.1.2) compared to the diagnostic doses (0.1- 0.3 mmollkg body weight).
The cardiovascular tolerance of the gadolinium complexes must also be
described as good. In a population of 12 subjects, Kashanian et al. demonstrated
the tolerance of a bolus injection of Gd-DTPA at a rate of 10 ml/ls s
Table 10.1.1. Gadolinium complexes currently in clinical use and their characteristics. Some
substances are not licensed in all countries. The osmolality of Gadovist~ is so low that it is
offered in a concentration of 1 mol!l
Generic name
Trade name
Ligand
Osmolality
(0.5 molll)
[osmollkgl
Stability
constant
log (uff)
Gadopentate
Gd-OTPA
Gadoterate
Gd-OOTA
Gadodiamide
Gd-OTPA-BMA
Gadoteridol
Gd-D03A
Gadobutrol
Gd-Butrol
Magnevist*
Schering
Ootarem e
Guerbet
Omniscane
Nycomed
ProHance*
Bracco
Open-chained
1.96
22.2
Macrocyclic
1.35
24.7
Open-chained
0.79
16.9
Macrocyclic
0.63
23.8
Macrocyclic
0.56
21.8
Gadovist*
Schering
Table 10.1.2.
Intravenous toxicity (estimated LO so ) of various contrast media in rats [4,51
Generic name
LD 50
(mmollkg)
GdCI,
Gadopentate
Gadoterate
Gadodiamide
Gadoteridol
Gadobutrol
0.5
8
18
approx. 25
< 15
approx. 25
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and ffitrasound
(0.1 mmollkg body weight) in comparison to placebo injection [6]. Kanal et al.
demonstrated in a larger prospective clinical study with 4,260 patients that
bolus injections of Gd-DTPA (dose: 0.1 mmollkg body weight) do not pose any
additional risks to the patients [7].
Pharmacokinetics
Gadolinium complexes are highly hydrophilic and, therefore, readily soluble in
water. They are quickly excreted again via the kidneys after intravenous
administration [8]. The excretion rate depends on the distribution in the extracellular space and on the glomerular filtration rate. In subjects with normal
kidneys, the half-life in the body is about 1.5 hours. Within the first 24 hours
after administration, more than 98 % of the dose is excreted with the urine,
while less than 1% is excreted extrarenally. The percentage of extrarenal
excretion does not increase significantly even in patients with impaired kidney
function [9]. No particular differences were observed between the different
gadolinium chelates in this respect [10-13].
In a study with haemodialysis patients, a mean plasma half-life of 1.87 hours
was found for Gd-DTPA (membrane: Fresenius F60, blood flow: 250 mllmin).
More than 9iYo of the amount of contrast material administered had been
eliminated after only 3 dialysis sessions each of 3 hours' duration. After a
diagnostic contrast medium dose of 0.1 mmollkg body weight Gd-DTPA
recommended for dialysis patients as well, excretion was very similar to that in
subjects with normal kidney function [14].
Tolerance and Safety
Gd-DTPA, which was approved by the Federal Institute of Health in 1988 as the
world's first contrast medium for MRI, is estimated to have been used to date in
more than 20 million examinations. Because the most extensive experience has
been gained with Gd-DTPA thanks to this high frequency of use, special
attention is paid to it in the following as regards the assessment of the safety of
gadolinium-containing extracellular CM. The data so far available on other
gadolinium-containing CM indicate that they are comparable to Gd-DTPA as
regards the spectrum and incidence of adverse events.
The quality of adverse events of MR contrast media does not differ fundamentally from that after the administration of iodinated non-ionic CM. The
overall incidence of adverse events, however, is lower than that of iodinated CM.
If the results of "The Japanese Committee on Safety of Contrast Media" after
intravenous injection of non-ionic monomeric CM is used as the reference, the
overall rate of adverse events of gadopentate, for example is 2- 3 times lower
[15]. As regards idiosyncratic reactions as well, the spectrum is qualitatively
comparable to that with iodinated CM. However, the incidence of idiosyncratic
reactions is about 8 times lower than that under non-ionic X-ray CM.
Since the market launch of Gd-DTPA, a total of 8,591 adverse events (AEs)
in 4,630 patients has been reported to the department Corporate Drug Safety of Schering AG within the framework of postmarketing surveillance (PMS)
10.1 Contrast Media for Clinical Magnetic Resonance Imaging
Table 10.1.3.
Postmarketing surveillance
(PMS) after more than
20 million uses of Gd-DTPA:
8,591 adverse events were
reported in 4,630 patients
(as at 31. 12. 1997)
Type of adverse event
Number
Subjective symptoms
Injection site reactions
Vomiting
Cardiovascular reactions
Rash
Urticaria
Mucosal reactions
Oedema of the larynx
Angiooedema
Dyspnea
Lung oedema
Anaphylactoid shock
Visual disturbances
Convulsions
Deaths - not drug-related
Deaths - possibly drug-related
Circumstances of death unknown
3,247
203
1,090
866
344
1,077
990
80
14
473
10
55
24
66
39
9
4
(Table 10.1.3). Referred to the more than 20 million doses used, this results in a
rate of adverse events of < 0.02 %. The reporting rate of AEs has stabilised at this
value in the last few years.
Of the AEs reported 52 were deaths. A possible association with contrast
medium administration was assumed in 9 of these deaths, all of which were
secondary to anaphylactoid shock. Of these 9 patients, 3 had asthma, 2 were
allergics and 1 had previously shown an allergic reaction to an iodinated CM.
39 deaths were not regarded as contrast medium-related. The majority of the
patients concerned were in an advanced stage of illness. According to the attending doctors, the cause of death was the underlying disease and not the use
of the contrast medium. Five deaths in a clinical study with an observation
period of 1 year in patients with cerebral metastases are mentioned by way of
example. The deaths occurred within a period of 3 -14 weeks after contrast
medium administration. The circumstances of death were unknown in 4 further cases.
PMS is a voluntary reporting system of adverse events. It is a generally
known fact that mild and moderate adverse events are reported less frequently
within the framework of the PMS. Consequently, their actual frequency cannot
be reliably established. It can, however, be assumed that they are 10 times more
frequent than would be assumed from the number of adverse events actually
reported. On the other hand, severe adverse events (oedema of the glottis, anaphylactoid shock, death) are probably reported very much more completely
than mild and moderate events. It is this low rate of severe adverse events more
than anything else that confirms the good safety profile of Gd-DTPA.
Apart from the chemotoxic and possible idiosyncratic effect of a contrast
medium, attention must be paid in particular to the total osmotic load as
regards local adverse events at the injection site and the burden on the cardio-
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and Ultrasound
Table 10.1.4. Calculation of the total osmotic load on use of different contrast medium
Substance
Diatrizoate (370 mg iodine/ml)
Iohexol (350 mg iodine/ml)
Iopromide (300 mg iodine/ml)
Gadopentate
Low-osmolar Gd complex
Osmolality
(mOsmoU
kg RIO)
Injection
volume
(ml)
Total osmotic
load
(mOsmol)
2,100
150
150
150
14
14
315
123
820
610
1,960
approx.700
92
27
10
vascular system. Although the in-vitro osmolality of Gd-DTPA of 1,960 mOsmollkg is similar to that of ionic X-ray contrast media, the total in-vivo value
of 27 mOsmol must be regarded as low (Table 10.1.4). This is due to the fact
that the diagnostic dose in MRI is 5 -10 times lower in relation to the injection
volume than in examinations with X-rays.
As ever, the primary excretory organ, the kidney, is a critical factor in the
use of contrast media. Negative effects on kidney function are well documented
for iodinated X-ray contrast media in particular. There is no evidence of such
effects with the gadolinium chelate contrast media, of which gadopentate is
again the most widely tested preparation. No relevant kidney function damage
caused by administration of the contrast medium has been observed during
clinical studies and follow-up observations. This is also true for patients with
a creatinine clearance of less than 20 mllmin. However, because the plasma
half-life of gadopentate increases considerably in such cases, subsequent
haemodialysis must be considered [16].
The safety proflle in children and juveniles between 0 and 18 years of age is
also very good. Data on the tolerance of gadopentate documented in clinical
studies in Europe and the USA and reported in the literature have been
gathered for a total of 826 neonates, children and juveniles. Cranial or spinal
MRI was performed in 680 patients and whole-body MRI in 146. Ten patients
(1.21 %) exhibited mild to moderate adverse events, although the examiners
considered them to be possibly associated with the contrast medium in only
one case. The same body weight-related standard dose (0.1 mmollkg) as for
adults is also recommended for neonates and babies [17]. The lower glomerular
flltration rate of the small patients is compensated for by the almost twice as big
extracellular volume. This also explains the longer time span which can be used
for contrast medium-enhanced imaging in neonates compared to adults.
Special Formulations
Although the above-described gadolinium chelates can be administered not
only via the intravascular route, it should be mentioned here from the start that
no approved commercial peparations are available for most of the indications
dealt with below.
10.1
Contrast Media for Clinical Magnetic Resonance Imaging
Direct arthrography with Gd-DTPA is a good example. A formulation of GdDTPA (2 mmolll) suitable for intraarticular injection can be produced by
diluting Magnevist ® with physiological saline solution. The intraarticular
application of Gd-DTPA leads to an increase of the signal intensity of the joint
fluid and, consequently, can improve the indirect demonstration of chronic
changes to the articular cartilage in rheumatic diseases. Clinical studies have
shown that even small defects in the cartilage (> 2 mm) can be visualised.
Another special formulation "Magnevist® enteral" (1 mmollGd-DTPA and
15 g mannitol per litre) is available as a commercial preparation for oral or
rectal application. It allows better differentiation of intraabdominal organs and
pathological lesions which cannot otherwise always be sufficiently demarcated
from bowel loops. This formulation always shows a positive contrast effect even
on use of T2 -weighted sequences, making adequate demarcation possible
between bowel loops and adjacent fatty tissue a feat which is otherwise difficult
with the homogeneous signal intensities resulting from contrast medium
administration.
Adverse events such as flatulence and watery stools occurred in about 6 % of
the patients observed in a suitably designed study. The flatulence is attributable
to the bacterial break-down of mannitol, while the watery stools can be ascribed
to the osmotic effect of the portion of mannitol that is not broken down.
Tissue-Specific Contrast Media
A limitation of the currently available (extracellular) contrast media is their
relatively non-specific distribution in the extracellular space of the body.
Parenchymal organs such as the liver and spleen, for example, display a
temporary, generalised and non-specific increase of the 51. This can lead in MRI
to a situation already known from computerised tomography (CT): Focal
lesions - particularly of the liver - are more difficult to diagnose a few minutes
after CM administration than before its injection. Although dynamic examination techniques can provide differential-diagnostic indications of the type of
lesion, the detection of lesions is not improved.
The diagnostic potential could be improved through the development of
organ-specific contrast media; These would keep the systemic load as low as
possible through a reduced systemic dose while in the region of interest
providing a concentration of the CM high enough to increase the detection rate
of lesions and improve the diagnostic assessment. Of main interest here apart
from a reduction of the dose would be possible improvement of diagnostic tissue and structure differentiation and visualisation of organ functions.
Liver-Specific (Intracellular) Contrast Media
With increasing clinical experience and continuous technical improvement,
MRI of the abdomen has achieved high diagnostic value in many indications.
The contribution of MRI to the diagnostic work-up of the abdomen consists
primarily in tumour screening and typing.
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and illtrasound
The demonstration and characterisation of focal lesions is the most important indication for MRI of the liver in western industrial countries. In comparison to other imaging procedures, MRI permits better differential-diagnostic assessment of an already known focal lesion and, with the liver-specific
contrast media now being developed, displays high sensitivity in the detection
of lesions.
Extracellular CM administered as an intravenous bolus are used for dynamic
scanning sequences of known intrahepatic tumours to improve the differential
diagnosis as well as in the search for tumorous lesions of the pancreas and
spleen. The administration of extracellular CM has not led to any improvements
of the sensitivity as regards the demonstration of smaller lesions « 1 cm) of the
liver in particular compared to plain MRI [18].
Contrast enhancement with tissue-specific CM has, however, led to a distinct
improvement of the detection of focal liver lesions. This was achieved with
substances which are taken up by liver-specific cells such as hepatocytes and
Kupffer's cells. Depending on the origin of the tissue or the degree of dedifferentiation of lesions, liver-specific cells which take up the contrast media are
either absent or present only in reduced number. The fewer liver-specific cells
are present in a lesion, the greater is the difference in contrast to the surrounding liver parenchyma.
Various substances with different magnetic properties have so far been
clinically tested, and two of them have already been introduced onto the
market. They are essentially either paramagnetic chelates, which are excreted
via the hepatobiliary route, or superparamagnetic iron particles, which accumulate in the monocyte-macrophage system (Table 10.1.5).
The derivative Gd-EOB-DTPA of the extracellular gadolinium compound
Gd-DTPA displays very good properties. The ethoxybenzyl part of Echovist®
leads to vehicle-mediated transport of the complex through the sinusoidal
plasma membrane of the hepatocytes. After crossing the membrane, the
gadolinium chelate is excreted unchanged in the bile. High hydrophilicity and
relatively weak protein binding are responsible for the good tolerance. Echovist ®is excreted completely in roughly equal proportions via the hepatobiliary
Table 10.1.5. Overview of some liver-specific contrast media
Generic name
li'adename
Company
Water-soluble, paramagnetic chelates with hepatobiliary uptake
Mangafodipir
Mn-DPDP
TeslascanGadobenate·
Gd-BOPTA
MultiHanceGd-EOB-DTPA
Echovist e
Gadoxetate·
Nycomed
Bracco
Schering
Superparamagnetic iron particles. taken up by the RES
AMl-2S
Feridex e
Endorem e
SH U SSSA·
Resovist e
Berlex
Guerbet
Schering
* Not yet commercially available.
10.1
Contrast Media for Clinical Magnetic Resonance Imaging
and renal routes. The dynamic increase of contrast shortly after the bolus injection is comparable to that of the extracellular substances. The high signal
intensity of the healthy liver parenchyma during the hepatobiliary phase, which
lasts about 2 hours, can distinctly improve the diagnosis of focal lesions with no
or only very few healthy hepatocytes such as metastases, dedifferentiated
hepatocellular carcinomas or haemangiomas. Within the framework of clinical
studies, good lesion detection and differentiation were achieved in dynamic
examinations with a dose of 25 pmol Echovist® per kg body weight.
Mangafodipir (Teslascan®) is the first manganese complex to be used as a
contrast medium in clinical studies and to gain market approval in Europe.
With its 5 unpaired electrons, the manganese ion distinctly reduces T1 relaxation. Excretion is both biliary and renal. Mangafodipir is proving itself to be a
positive and very effective marker of liver cell tissue in MRI. Maximum signal
intensity lasting several hours is reached about 15 minutes after administration.
Only small amounts (5 pmollkg body weight) are required because of the
pronounced contrast effect. The difference in contrast between healthy liver
parenchyma and focal lesions is marked [19]. It is too early to assess the
tolerance of mangafodipir. The contrast-giving effect is based on free
manganese ions, which are known to accumulate in hepatocytes. Pharmacokinetic studies have shown that Mn 2 + is released in plasma shortly after
injection and that the paramagnetic ion accumulates in the liver as well as in
other tissues such as the pancreas and myocardium [20].
Superparamagnetic iron oxides (SPIOs) are polysaccharide-coated iron
particles. After intravenous administration, they are taken up by phagocytising
Kupffer's cells, but not by hepatocytes or metastases. Depending on the degree
of dedifferentiation, Kupffer's cells are also present in hepatocellular carcinomas, their number decreasing with increasing dedifferentiation. Focal nodular
hyperplasia also contains Kupffer's cells and, consequently, displays uptake of
SPIOs. The iron oxides are marked by pronounced shortening of T2 relaxation
[21]. These contrast media have also led to a distinct improvement in the detection of focal hepatic lesions and have reduced to < 1 cm the threshold at which
lesions can be demonstrated [22,23]. The iron oxides are converted in the liver
within a few days to a non-superparamagnetic form of iron which then
becomes part of the body's normal iron pool.
The first preparation to be approved, AMI-25 (Feridex®, Endorem®), can be
administered only as an infusion. Thanks to galenic improvements, SH U 555 A
(Resovist®) is also suitable for bolus injection and, therefore, for dynamic
imaging sequences. Although the newer formulations of SPIOs now display
virtually no clinically relevant adverse events, they are still the subject of particularly critical discussion because of cardiovascular side effects of earlier
preparations.
Intravascular Contrast Media
The development of intravascular CM has two basic diagnostic aims. One is to
be able to visualise vessels including those with a diameter < 1mm - over a
longer time span (up to an hour). The extracellular CM currently available
287
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and Ultrasound
permit contrasting of the arterial blood flow for only about 30 seconds. The
second diagnostic aim is the use of intravascular CM as markers of pathologically increased capillary permeability or of a histopathologically altered capillary structure. The ability to visualise the emergence of the CM from the
peripheral vascular and capillary bed in relation to its functional state would be
ideal. By analogy to the behaviour of extracellular CM within the CNS - a
disturbance of the BBB can be concluded from CM extravasation -, the emergence of intravascular CM in the periphery of the body might indicate damage
to the endothelia of the vessels and/or capillaries. This initially non-specific
process could be followed by an attempt at morphological characterisation of
the vascular region affected - pointers to traumatic, inflammatory or tumourspecific vascular changes.
To ensure that an extracellular contrast medium cannot escape into the interstitial space from normal blood vessels without barriers such as the bloodbrain barrier, molecules are required which have a diameter greater than that of
the previously described gadolinium chelates. This can be achieved, for
example, by binding gadopentate to albumin, dextran, polylysin or new kinds of
polymers [24]. Various substances are currently undergoing preclinical and
clinical development.
MS-325 (Epix, Cambridge, USA), a low-molecular gadolinium-DTPA derivative, is bound specifically to albumin, the quantitatively most important protein
in the blood. The indications from preliminary clinical studies are that the
safety and efficacy are acceptable.
Polymers of gadolinium complexes have been investigated intensively. These
large molecules can diffuse only very slowly from the intravascular into the
interstitial space. Moreover, slower glomerular excretion provides for delayed
elimination from the vascular lumen.
Just recently, ultra-small superparamagnetic iron oxides (USPIOs) have been
employed as highly effective TI contrast media in preliminary clinical studies
with volunteers. These particles display an improved TilT 2 ratio and, thus,
a weaker T2 effect. Very good contrast enhancement of the vascular system
is achieved on use of heavily TI-weighted sequences with a dose of 1- 3 mg
(15 - 0 p.mol) Felkg body weight [25]. An example is the substance AMI-227 from
Guerbet, France. The USPIOs survive longer in the blood stream because they
are not phagocytised by liver-specific cells as quickly as the SPIOs, but are
absorbed much more slowly by other cells of the monocytic macrophage
system in, among others, the spleen, lymph nodes and bone marrow.
The TI-shortening effect and the high intravascular half-life lead to improved
visualisation of the vascular anatomy with 3-D gradient-echo sequences. Very
short echo times must be used if signal losses due to the T -shortening effect
are to be avoided.
Like macrophage-specific superparamagnetic iron oxides (SPIOs), the iron
oxides are broken down intraceliularlY and added to the body's iron pool.
r
10.1 Contrast Media for Clinical Magnetic Resonance Imaging
Summary
Extracellular paramagnetic contrast media are now an indispensable component of MRI and MRA. Tissue-specific paramagnetic - e.g. Gd-EOB-DTPA
and superparamagnetic contrast media - e.g. AMI-25 and Resovist@ (SPIO)
will improve the diagnosis of hepatic lesions to a decisive extent. Despite the
very good safety profile, however, the indication for the use of an MRI contrast
medium must be carefully reviewed in each individual case.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Lauterbur PC, Mendonca-Dias MH, Rudin AM (1978) Augmentation of tissue water
proton spin-lattice relaxation rates by in-vivo addition of paramagnetic ions. Front Med
BioI Eng 1: 752 -759
Mendonca-Dias MH, Gaggelli E, Lauterbur PC (1983) Paramagnetic Contrast Agents in
Nuclear Magnetic Resonance Medical Imaging. Seminars in Nuclear Medicine
13 :364-376
Sage MR (1982) Blood-brain barrier: Phenomenon of increasing importance to the
imaging clinican. AJR 138 : 887 - 898
Weinmann H-J, Press W-R, Gries H (1990) Tolerance of extracellular contrast agents for
MRI. Invest Radiol 25 : S 49 - S50
Vogler H, Platzek J, Schuhmann-Giampieri G et al. (1995) Preclinical evaluation of
gadobutrol: a new, neutral, extracellular contrast agent for MRI. Eur J Radiol 21 : 1-10
Kashanian FK, Goldstein HA, Blumetti RF et al. (1990) Rapid bolus injection of gadopentate dimeglumine: Absence of side effects in normal volunteers. AJNR Am J Neuroradiol
11: 853-856
Kanal E, Applegate GR, Gillen CP (1990) Review of adverse reactions including anaphylaxisin 4260 intravenous bolus injections (Abstract 434). Radiology 177 (suppl):l59
Weinmann H-J, Brasch RC, Press WR, Wesbey GE (1984) Characteristics of gadoliniumDTPA complex: a potential NMR contrast agent. Am J Roentgenol142 (3) : 619 - 624
Schuhmann-Giampieri G, Krestin G (1991) Pharmacokinetics of Gd-DTPA in Patients
with chronic renal failure. Invest Radiol 26 (11) : 975 - 979
Weinmann H-J, Laniado M, Mtitzel W (1984) Pharmacokinetics of GdDTPAIdimeglumine
after intravenous injection into healthy volunteers. Physiol Chern Phys Med NMR
16: 167-172
Le Mignon MM, Chambon C, Warrington S, Davies R, Bonnemain B (1990) GD-DOTA.
Pharmacokinetics and tolerability after intravenous injection into healthy volunteers.
Inves Radiol 25 (8) : 933 - 937
Mc Lachlan SJ, Eaton S, De Simone DN (1992) Pharmacokinetic behavior of gadoteridol
injection. Invest Radiol 27 (1) : 12 -15
Van Wagoner M, Worah D (1993) Gadodiarnide injection. First human experience with the
nonionic magnetic resonance imaging enhancement agent. Invest Radiol28 (1): 44-48
Lackner K, Krahe T, Gatz R, Haustein J (1990) The dialysability of Gd-DTPA. Bydder G et
al., (eds) Contrast Media in MRI, Bussum: Medicom Europe: 321- 326
Niendorf HP,Alhassan A, Balzer T, ClauB W, Geens V (1998) Sicherheit und Risiken von GdDTPA:Klinische Erfahrungen nach tiber 20 Millionen Anwendungen. In: Magnevist-Eine
Monographie, Hrsg. Felix R, Heshiki A, Blackwell Wissenschaftsverlag, 3. Auflage, S 27- 38
Niendorf HP, Brasch RC (1993) Gd-DTPA Tolerance and Clinical Safety. In: MRI Contrast
Enhancement in the CNS: A Case Study Approach, Hrsg. Brasch RC, Raven Press, Ltd., New
York,S 18
Elster AD (1990) Cranial MR imaging with Gd-DTPA in neonates and young infants:
preliminary experience. Radiology 176 : 225 - 230
289
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and IDtrasound
18. Hamm B, Wolf KJ, Felix R (1987) Conventional und rapid MR imaging of the liver with
Gd-DTPA. Radiology 164: 313 - 320
19. Rofsky NM, Earls JP (1996) A contrast agent for abdominal MR imaging. Magn Reson
Imaging Clin N Am 4(1):73-85
20. Gallez B, Bacic G, Swartz HM (1996) Evidence for the dissociation of the hepatobiliary
MRI contrast agent Mn-DPDP. Magn Reson Med 1996 35 (1): 14-19
21. Halm PF, Stark DD, Weissleder R et al. (1990) Clinical application of superparamagnetic
iron oxide to MR imaging of tissue perfusion in vascular liver tumors. Radiol 174
(2): 361- 366
22. Chachuat A, Bonnemain B (1995) European clinical experience with Endorem. A new contrast agent fur liver MRI in 1000 patients. Radiologe 35 (11 SuppI2): 274- 276
23. Reimer P, RUDlmeny EJ, Daldrup HE et al. (1995) Clinical results with Resovist: a phase
2 clinical trial. Radiology 195 (2) : 489 - 496
24. Adam G, Miihler A, Spuntrup E et al. (1996) Differentiation of spontaneous canine breast
tumors using dynamic MR imaging with 24-Gadolinium-DTPA-cascade-polymer, a new
blood-pool contrast agent for MR angiography. Experimental study in rabits. Invest
Radiol 31 (5) : 267 - 274
25. Anzai Y, Prince MR, Chenevert TL et al. (1997) MR angiography with an ultrasmall superparamagnetic iron oxide blood-pool agent. J Magn Reson Imaging 7 (1) : 209 - 214
10.2
Ultrasonographic Contrast Media
A. BAUER, R. SCHLIEF and H. P. NIENDORF
Introduction
Ultrasound contrast agents have recently proven to be clinically useful in many
different body areas, together with different ultrasound modalities. Ultrasound
contrast agents are based on microbubbles with a diameter of a few micrometers, and their efficacy depends on their gaseous content. Unlike X-ray contrast media, where iodine atoms are the direct atomic basis of increased
radiodensity, and in MR, where the paramagnetic properties of the gadolinium
atom change relaxation times, the microbubbles in ultrasound are the relatively
large (microscopic) active principle of contrast. Depending on the size of the
microbubbles and the gaseous contents, the efficacy for backscattering ultrasound is determined. The size of the microbubbles also determines whether
they can pass the lung capillaries after IV injection and so be useful as wholebody echo-enhancing agents. All microbubbles that are in clinical use today are
confined to the vascular bed and may therefore be seen as true bloodpool contrast agents. Unlike X-ray and MR contrast agents, the microbubbles cannot
leak out into the extravascular space, since microbubbles are destroyed by this
process.
The history of the clinical use of ultrasound contrast media started as early
as the early 1960s, when Gramiak and Shaw [1] saw enhanced signals after the
10.2
IDtrasonographic Contrast Media
injection of dyes in the ultrasound M-mode of the aortic valve. Since then, different methods for "home-brew" contrast media have been tried, including
shaken saline and the generation of microbubbles by sonication. However, most
of these methods result in quite large microbubbles with indeterminate size
distribution. An overview of these agitated, injected solutions is given by Ophir
and Parker [2].
Basic Physics and Pharmacology
The dominating physical effect utilized by ultrasonic contrast media is the
increase in sound backscatter. Due to the presence of microbubbles, part of the
incoming ultrasound wave is returned, and the returning echo is registered by
the transducer. Since ultrasound wavelengths are around 1 rom, and the diameter of the microbubbles (]lm) is quite small compared to the wavelength, this
process is described as "scattering". This term is used in physics to describe a
process in which the wavelength of an incoming wave is greater than the size of
an interacting structure, for example, the scattering of light by the molecules of
the earth's atmosphere. The microbubbles give rise to an increase in the backscatter cross-section for the ultrasound waves. The underlying parameters that
are important for the contrast effects of ultrasound contrast media are the differences in compressibility and density between the microbubbles' gaseous
contents and the surrounding structures (liquid). For a given microbubble, the
number and size of the microbubbles determine the intensity of the backscattered echo. In conventional fluid media such as water, only a few microbubbles
are needed to increase the backscatter dramatically. In principle, a larger microbubble will increase backscatter more than a smaller one. However, to allow
undisturbed capillary passage, the ideal, diagnostically usable microbubbles
should be smaller than 10 ]lm in size.
The usual theory of free, gas-filled microbubbles does not consider the most
dominant problem in the manufacture of ultrasonic contrast agents: stability.
The microbubbles have to be stabilized so that they can survive long enough in
the circulatory system to be diagnostically useful. They should be stable enough
to pass through the lungs after IV injection and then to increase the echogenicity of the blood in all body areas. Suspensions of free microbubbles made by
shaking solutions of saline are associated with a lot of indeterminate factors,
such as gas solubility, surface tension and viscosity that are not under the control of the user. Most pharmaceutical preparations thus contain a protecting
shield against the loss of gas, or contain a perfluorocarbon gas with very low
blood solubility. A very subtle solution to this problem was created by the use of
saccharide microparticles that generate and carry the gas microbubbles, thereby forming stabilizing sites. The saccharide microparticles dissolve after injection into the blood, while liberating stable echogenic gas bubbles.
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and Ultrasound
Commercial Ultrasound Contrast Media
Echovist® (SH U 454, Schering AG)
Echovist@ is the first commercially available ultrasound contrast medium. The
first preclinical results were obtained in 1984, when the use of this medium as a
right-heart contrast agent was demonstrated. Echovist@ is based on specially
manufactured galactose granules. Before injection, galactose solution is added,
and the vial is shaken until a homogenous suspension is formed. This process
determines a size distribution of microbubbles that has more than 97% with a
diameter of less than 7 JIm [3]. After IV injection and dissolution of the
galactose, free microbubbles are formed.
The use of Echovist@ in cardiology is only as a right-heart contrast agent,
since the microbubbles do not traverse the lungs. This enables the diagnosis of
haemodynamically relevant shunts: the microbubbles are only seen in the left
heart and systemic circulatory system if an open foramen ovale enables a circumvention of the lung passage.
Another important application area of Echovist ® is in the diagnosis of tubal
patency during the investigation of infertility [4]. The presence of Echovist@ as
an echogenic marker gives a clear image of the Fallopian tubes and demonstrates their patency without any risk of radiation and anaesthesia.
Albunex 8 and FS069 (Molecular Biosystems)
Microbubbles of Albunex@ are surrounded by an albumin shell of 30 - 50 nm.
These encapsulated bubbles of Albunex@ are less effective as ultrasound scatters than free gas bubbles of the same size, but they are much more stable. The
mean size of the microbubbles is about 4 Jlffi; 95 % of the microbubbles are less
than 10 JIm [5]. The albumin encapsulation allows the pulmonary passage, with
a plasma half-life of about 1 min. Albunex· has been approved in the USA for
right and left side cardiac imaging.
A recent modification, FSO 69, contains a low-solubility perfluorocarbon gas
instead of air [6]. This enables a longer persistence in the circulation. FSO 69 has
been shown to improve endocardial border definition in more than 90 % of
patients, while only 59 % of those patients exhibited improvement with the use
of Albunex@in a recent phase-III study.
Levovist 8 (SH U 508 A, Schering AG)
Similarly to Echovist@, Levovist@ is based on galactose microparticles, generating microbubbles of well-controlled size distribution. Levovist@ contains an
additive, palmitic acid, a naturally occurring fatty acid that covers the microbubbles as a thin coating. This palmitic acid coating enables undisturbed
passage of the lungs by the microbubbles and stabilization in the vascular bed.
The signal in Doppler applications lasts up to 25 dB with and the duration of enhancement increases up to 5 min [7]. With more than 5,000 patients in clinical
10.2
Ultrasonographic Contrast Media
trials, Levovist I» has shown an excellent safety profile as a result of its natural
constituents. Levovist I» is available for whole-body Doppler-signal enhancement in Europe.
New formulations of microbubbles, based on perfluorocarbon gases or on
polymer-encapsulated microbubbles, are currently in development and in the
phase of clinical trials, and a considerable number of new microbubble
preparations are expected to reach approval in the next few years.
Clinical Indications and Application Areas
Contrast Echocardiography
Ultrasound contrast agents are used in echocardiography to distinguish
between the blood-filled cavity and the myocardial structures and for the identification of haemodynamic phenomena. Intracardial thrombi, septal defects,
altered wall movement and stress echocardiography as well as valve diseases
can be diagnosed with the use of echogenic contrast media [8]. The use of contrast media, especially in colour Doppler echocardiography, increases the sensitivity of the detection of subtle blood flow and blood flow alterations. Thus,
especially in patients with poor Doppler signal-to-noise ratios, improvement of
imaging of shunts and valve incompetence is achieved.
Contrast-Enhanced Hysterosalpingosonography (HyCoSy)
With the introduction of the first echogenic contrast medium, Echovist 1», it was
possible in conjunction with transvaginal examination techniques to develop a
sonographic alternative to X-ray Hysterosalpingography. Aside from the
diagnosis of uterine anomalies, tubal patency can be demonstrated sonographically by the transcervical administration of Echovist 1». The advantage of
this method over conventional procedures such as HSG or laparoscopy consists
in the elimination of radiation exposure, allergic contrast media reactions and
operative risks. It allows the patient to observe the examination and to witness
the results along with the physician. Clinical studies have shown a specificity of
100 % and a sensitivity of 88 % for HyCoSy in comparison to conventional
diagnostic methods [4].
Contrast-Enhanced Doppler Sonography
Very often in routine clinical work, the Doppler technique suffers from a poor
signal-to-noise ratio, the Doppler signal being not loud enough to be clearly
captured by the system. This situation occurs, depending on the anatomical
area, in 5- 30 % the patients. In obese patients, in transcranial Doppler, and for
imaging of deep-lying vessels, this frequently represents a clinical problem [9].
The recently-introduced class of transpulmonary, stable ultrasound contrast
media such as Levovistl» have been shown to be useful in these circumstances.
Transcranial ultrasound, carotid ultrasound, cardiac imaging, imaging of the
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and ffitrasound
Fig. 10.2.1.
Without echo-enhancement,
the internal carotid artery is
not clearly visualized. After
Levovist@, the origin of the
internal carotid artery is
imaged, and a kinking of the
internal carotid is seen
(image kindly provided by
Dr Meents)
renal artery and the liver and peripheral vessels have been shown to be specially important applications for transpulmonary echo enhancers.
Transcranial Doppler Sonography
Besides the widely used one-dimensional transcranial Doppler (TCD),
transcranial Duplex Doppler and colour sonography are gaining wider acceptance. Because of the ultrasonic barrier of the skull bone, a complete
transcranial examination of the cerebral circulation may quite often require the
use of ultrasound contrast media. With Levovist®, complete delineation of the
large intracerebral vessels is achieved; without contrast use, about 15 % of the
studies do not achieve a conclusive diagnosis [10]. The detection of low and
slow flow enables a complete examination of the arterial and venous circulations transcranially, allowing the diagnosis of thrombosis and intracerebral
tumour, as well as any stenosis in the Circle of Willis.
Extracranial Carotid Artery
A frequent clinical problem is the assessment of high-grade carotid stenosis
with ultrasound. A heterogeneous vessel wall, plaque calcification and small
residual lumen give rise to problems in performing an adequate ultrasound
examination. The quantification of high-grade stenosis is therefore very often
problematic. This situation is resolved by the use of a transpulmonary echo
enhancer such as Levovist® [11]. The diagnosis of a complete occlusion should
certainly include the use of ultrasound contrast media. An example of a carotid
scan before and after Levovist ®is given in Figure 10.2.1.
Renal Artery Doppler Sonography
The renal artery is very often a problematic region and the origin of the renal
artery is often hard to find. The exclusion of a renal artery stenosis in patients
with hypertension as well as the measurement of renal indices, can be significantly facilitated by the use of ultrasound contrast media. It has been shown
that the use of Levovist ® results in the shortening of the examination time
needed [12]. An inconclusive examination turned into a diagnostic examination
by the use of Levovist® is shown in Figure 10.2.2.
10.2
illtrasonographic Contrast Media
Fig. 10.2.2. The origin of the renal artery from the abdominal aorta is only visualized after IV
administration of Levovist® due to obesity in this patient. A renal artery stenosis could be
excluded in this normal renal artery (image kindly provided by Dr Bonhof)
Peripheral Vascular System
Usually, colour Doppler sonography of the peripheral arteries is less problematic than in other parts of the body. However, a small percentage of some 10 -15 %
of patients present signal problems and consequently indeterminate diagnosis,
or grading of a stenosis without the use of echo enhancers. In iliac arteries and
calf arteries, especially, an increased diagnostic yield has been found with the
use of Levovist® [13].
Peripheral Venous Imaging
Colour Doppler of the venous system is still not very widely used. The use of IV
echo-enhancing agents produces signal enhancement in the venous system as
well, since the microbubbles survive secondary capillary passage. This enables
diagnosis of venous thrombosis, especially in the parts of the body where signal
problems are typically found, such as in transcranial imaging of the venous
sinus [14]. However, even in conventional venous imaging, the procedure of
colour Doppler of the venous system is facilitated by the use of ultrasound contrast media.
Tumour Vascularity Imaging
The study of the vascularity of tumours is at the sensitivity limit of today's
Doppler ultrasound. With the increased Doppler signal intensity after the use of
echogenic contrast media, the vascularity of tumours is well-seen by Dopplersonography. The signal increase results in a higher sensitivity for low and slow
flow; this enables the imaging of the neovascularity of tumours which, in its
spatial arrangements and in its flow properties, is fundamentally different from
the vascularity of normal tissue. With the use of ultrasound contrast media,
complete imaging of the region of interest is possible, enabling a clearer assessment of tumour vascularity. An example of the prostate imaged with contrastenhanced Doppler sonography, Figure 10.2.3, shows the higWy vascularized part
of the tumour visualized quite clearly after the use of Levovist®. The new application of tumour vascularity assessment by colour Doppler is also valuable
295
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CHAPTER 10 Contrast Media for Clinical Magnetic Resonance Imaging and Ultrasound
Fig. 10.2.3. Thmour vascularity imaging is made possible by the use of echo-enhancers. The
highly vascularized part of this prostate cancer is only apparent after the IV administation of
Levovist~. Before echo-enhancement, the prostate appears normally vascularized (image
kindly provided by Dr D. O. Cosgrove)
for gliomas and breast tumours. Additionally, dynamic aspects similar to dynamic contrast-enhanced CT can be studied by ultrasound with the use of echo
enhancers as a bolus tracking agent Potentially, this may playa role in the differential diagnosis of liver lesions.
Outlook: Microbubble-Specific Scanning
In addition to the potential of being used as a signal-enhancing agent, microbubbles offer an additional perspective. While interacting with the ultrasonic
sound field, the microbubbles start to oscillate, and the reflected echo from
these oscillating microbubbles also contains echoes at double the frequency
insonated. The new type of digital ultrasound systems enables a very flexible
handling of processing and can concentrate on this so-called "harmonic echo"
of the microbubbles. This enables contrast-specific scanning, similar to DSA in
X-ray, and allows an increase in spatial resolution and contrast sensitivity of
current ultrasound equipment. In the future, this will enable an optimization
of machine technology towards the use of contrast agents and imaging organ
perfusion.
With the use of new ultrasound technologies and the potential of new ultrasound contrast media, the spectrum of ultrasound diagnosis is significantly
enhanced. Ultrasound contrast media are expected to play a similar role in
diagnostic imaging to that played today by iodine contrast agents in X-ray
imaging and Gadolinium contrast agents in MR imaging.
References
1. Gramiak R, Shaw PM (1968) Echocardiography of the aortic root. Invest Radiol3: 356 - 366
2. Ophir J, Parker KJ (1989) Contrast agents in diagnostic ultrasound. Ultrasound Med BioI
15: 319-333
3. Fritzsch T, Miitzel W, Schartl M (1986) First experience with a standardized contrast
medium for sonography. In: Otto RC, Higgins CB (eds) New Developments in Thieme,
Stuttgart, pp 141-149
4. Degenhardt F, Jibril S, Eisenhauer B (1996) Hysterosalpingo contrast sonography
(HyCoSy) for determining tubal patency. Clin Radiol51: 15 -18
10.2 Ultrasonographic Contrast Media
J, Levene H, Villapando E et al. (1990) Characteristics of Albunex, air-filled
albumin microspheres for echocardiography. Invest Radiol 25: 162 -164
Dittrich HC, Bales GL, Kuvelas T (1995) Myocardial contrast echocardiography in experimental coronary artery occlusion with a new intravenously administered contrast
agent. JAm Soc Echocardiogr 8: 465 - 474
Schwarz KQ, Becher H, Schimpfky C, Vorwerk D, Bogdahn U, Schlief R (1994) A study of
the magnitude of Doppler enhancement with SH U 508 A in multiple vascular regions.
Radiology 193(1) : 195 - 201
Nanda N, Schlief R (1993) Advances in echo imaging using contrast enhancement. Kluwer,
Dordrecht
Schlief R (1991) Ultrasound contrast agents. Curr Op Rad 3: 198 - 207
Bauer A, Becker G, Krone A, Frohlich T, Bogdahn U (1996) Transcranial duplex sonography using ultrasound contrast enhancers. Clin Rad 51 : 19 - 23
Sitzer M, FUrst G, Siebler M (1994) Usefulness of an intravenous contrast medium in the
characterization of high grade internal carotid stenosis with color Doppler assisted
duplex imaging. Stroke 25 : 385 - 389
Allen CM, Balen FG, Musouris C, McGregor G, Buckenham T, Lees WR, (1993) Renal artery
stenosis: diagnosis using contrast enhanced doppler ultrasound. Clin Rad 48 : 5
Langholz J, Wanke M, Petry J, Schuermann R, Schlief R, Heidrich H (1993) Indikationen
zur Unterschenkelarteriendarstellung mit Kontrastmittel bei der farbkodierten Duplexsonographie. Ultraschall Klin Prax 8(3) : 196
Becker G, Bogdahn U, Gehlberg C, Frohlich T, Hofmann E, Schlief MD (1995) Transcranial
color-coded real-time sonography of intracranial veins. Normal values of blood flow
velocities and findings in superior sagittal sinus thrombosis. JNeuroimaging, 5 (2): 87 - 94
5. Barnhart
6.
7.
8.
9.
10.
11.
12.
13.
14.
297
Subject Index
abdominal compression 196
absorption (see pharmacokinetics)
acetylcholine 80
additives 60 - 61
adenosine antagonists 86
adverse reactions 141-154
- acute 144
- age dependent 112-113
- dose dependent 146
- dose independent 146
- fatalities 143, 150
- intermediate (moderate) 142
- late (delayed) 144 -146,149 -151
- minor 142
- predisposing factors (see risk factors)
- severe 142
- time of onset 144
age 97, 103, 112
aggregation (see blood)
agitation 91, 122
allergy 97-99,146,152-153,177
amnesia 91
anaesthesia 121-123
anaphylactoid (pseudoallergic) reactions
98,148
- dose relation 134
- mode of CM administration 99
- pathomechanisms 148 -149
- preclinical test model 21
anaphylactoid shock 167, 220
angiocardiography 180 -188
- catheters 185 -186
- complications 187-188
- contrast media 185 -186
- interventional procedures 186 -187
- technique 184-186
angiography of breast 239
angiography of extremities 163 -169
- complications 166 -168
- technique 164-166
angiography of internal genitalia 238
- technique 239
angiography of kidneys and adrenal glands
232-235
- complications 234 - 235
- technique 233 - 234
angiography of liver, spleen and pancreas
189-197
- catheter selection 194
- complications 195 -196
- technique 193-194
angioplasty (see interventional radiology)
- blood flow 78
antibodies 151-152
anticoagulation 62,136,156, 254
- ionic CM 79,156
- nonionic CM 79, 156
anuria 84,105
anxiety 121
aortography 180
arachnoiditis 91,154
arthrography 239 - 249
- complications 246
- technique 243 - 246
aspirin 157
atheroma 187
autoclaving 59, 62
autoimmune disorders 97,110
barium sulphate 1,203 - 215
- area gastricae 212
- coating ability 208
- complications 215
- double contrast 211
- electrostatic charge 207
- particle size 207
- viscosity 205
biostatistics (see clin. testing)
biotransformation 32
bismuth 203
300
Subject Index
blood 76-80
- coagulation 79
- echinocytes 77
- flow 77-78
- microcirculation 76 -78, 89
- platelet aggregation 89,157
- rheological effects 78,80
- rouleaux formation 77
- thrombus 78
- viscosity 76 -79, 89
blood-brain barrier 87-91,279-280
blood pressure 103, 108
bradykinin 148
breast feeding 116
bronchography 82
bronchospasm 82, 104, 148
brown glass 69
buffers 60, 76
calcium antagonists 86
calcium binding 61- 62, 81
carbon dioxide angiography 273
- complications 275
- properties of carbon dioxide 273
- technique 274
cardangiography (see angiocardiography)
cardiovascular function 80
cardiovascular insufficiency 97, 103
catheters 73, 79
(see also resterilisation)
- flushing solutions 136,157
cavernosography 227, 228
- complications 228
- technique 227
central nervous system 89 - 91
cerebral angiography 65, 89, 155 -157
- complications 65,89,156 -157
- technique 155-156
chemistry 6 -15,281
chemotoxicity 75 -76, 89, 93
cholangio-cholecystography 218 - 220
- complications 219
- technique 219
chromatography 63
cirrhosis 83
clinical testing 40 - 57
- efficacy 40
- safety and tolerance 40
- statistical design and analysis 43 - 57
clots (see coagulation)
clotting system 98
coagulation 79,136,148
- catheters and syringes 79
- formation of clots 79, 98, 136
- ionic CM 79
- nonionic CM 79
colour changes of CM solutions 65
complement activation 98
complexing agents 59 - 61
confusion 91
contamination 58, 65 - 66, 70 -71, 167
- microbial 58, 71
- particles 58, 66, 70
- pyrogens 58, 65, 71, 167
contractility 80
contrast media for MRI 276 - 297
- extracellular substances 279 - 280
- intracellular substances 285 - 287
- intravascular (blood pool) substances
287-288
- paramagnetic substances 277-278 (see
also extracellular paramag. CM for MRI)
- superparamagnetic substances 278 - 279
contrast media for ultrasound 290 - 297
- basic physics and pharmacology 291
- contrast echocardiography 293
- contrast enhanced doppler sonography
293
- contrast enhanced hysterosalpingography
-
293
extracranial carotid artery 294
peripheral vascular system 295
peripheral venous system 295
renal artery doppler sonography 294
transcranial doppler sonography 294
tumor vascularity imaging 295 - 296
contrast media for X-ray diagnostics
- chemistry 6-15
- gaseous 1,196,211-214,244-245,273
- hepatobiliary 2, 35, 218 - 220
- historical overview 1- 6
- mixing/dilution 72-73
- negative 1, 4, 211, 244
- oily 1,81, 176, 178, 198, 224
- pharmacokinetics 31- 39
- physicochemical properties 24 - 30
- positive 1, 6 -15
- production steps 58
- RES-specific 37, 286
coronary angiography 180 -188
coronary blood flow 80
cortical blindness 90,156
creatinine clearance 84, 137 -138
crystallization 71
CT angiography 255 - 265
- advantages and limitations 264
- indications 258-264
- technique 255-258
CT in liver, pancreas and spleen 197 - 203
- complications 202
Subject Index
- technique 199-202
CT in kidneys and adrenal glands 229 - 235
- complications 232
- technique 230 - 232
cystography 196,223
degradation products 59 - 60, 68
- aromatic amines 60
- iodide 59,68
dehydration 97,109,118 (see also risk
factors)
diabetes mellitus 97,106
dialysis (haemodialysis) 33,105,106,
137 -138, 284
dissection 172, 273, 187
drawing up devices 70 -71
driving fitness 126
dyspnoea 84
electrical charge 30
electrolytes 61
- imbalance 84, 249
electrophysiology 80
embolisation 156,187
endoscopic retrograde cholangiography
(ERe) 218
endothelin 86
endothelium 92-93,161,168,173,174
enzymuria 105
epileptogenicity 154
excretion (see pharmacokinetics)
extracellular paramagnetic chelates
279-284
(see also contrast media for MRI)
- blood-brain-barrier 280 .
- haemodialysis 284
- pharmacodynamics 281
- pharmacokinetics 282
- special formulations 284 - 285
- tolerance and safety 282 - 284
extravasation 138-140,177,178,194,228
fasting 118
fever 167
flushing solutions 136,157
gastrointestinal tract 203 - 217
- complications 215 - 216
- technique 212-215
goitre 101-103
hallucination 91
headache 91
haematocrit 77
haemodialysis (see dialysis)
heating cabinet 131
hemiparesis 156
heparine 136,157,254
hepatocytes 35 - 36, 133, 285 - 286
histamine release 80, 98, 125, 148
hydration 85,105, 205
hydrophilicity 7,15,29,31,75
hyperhydration 85
hyperosmolality 93
hypersensitivity to CM 97 - 98
hypertension 105
hypertensive crisis 108, 235
hyperthyroidism 86, 100 -103, 249
- diagnosis
- prophylaxis
hypohydration 84
hypoproteinaemia 105
hypothyroidism 87,249
- neonates, babies 249
hysterosalpingography 235 - 237
- complications 236 - 237
- technique 236
incompatibilities 114·
injection (flow) rate 104,135
inotropic effect 81
interactions 74,115
- ACE inhibitors 115
- beta-blockers 115
- calcium antagonists 115
- cardiac glycosides 115
- chlorpromazine 115
- disposable catheters 74
interventional radiology 78,186, 253, 254
intrathecal CM (myelography) 90-91
- complications 91
intravasation 226
iodine allergy 99
iodine release 59,86
kidney function 84 - 86
(see also renal failure)
- alpha microglobulin 85
- creatinine clearance 84
- glomerular fIltration 31
- serum creatinine 85
- tubular marker enzymes 85
laboratory test falsifications 94 - 95
lactating (see nursing)
late reactions (see adverse reactions)
leucotrienes 148
lipiodol 81,176,198,199,202
(see also eM for X-ray diagnostics)
lipophilicity 29
301
302
Subject Index
liver (hepatic) function 83
- enzymes 83
lung disease 104
lung function 81- 82
lymphography (direct and indirect)
174-179
- complications 177 -178
- technique 176 -177
lymphography of groin. pelvic and paravertebral area 237
lymphography of the breast 237
magnetic resonance imaging 276 - 297
mast cells (see histamine release)
maximum doses 132-134
- angiography 132
- cholangiography 133
- myelography 133
microbubbles (see CM for ultrasound)
microcirculation 76 -78.84
micturating cystography
(see cystography)
MR angiography 265 - 273.280
- clinical applications 271- 273
- technique 266 - 270
myelography 90 - 91
- complications 91
myeloma 193
necrosis 139. 173. 177
nephrotoxicity 84 - 86
nephrotoxic drugs 84. 107
neuroangiography (see cerebr. angiography)
- complications 65. 89
neurotoxicity 89 - 91. 161
- nodular goitre (non-toxic) 97
- sodium salts of CM 90
Nokor cannula 70
nursing 101,116
oedema 81- 84.148
- pulmonary 81- 82
- renal failure 84
osmolality (osmot. pressure) 4,26
osmotic diuresis 193
- meglumine salts 193
- sodium salts 193
overdose 134
paediatric radiology 249 - 253
- angiocardiography 251
- angiography 251
- bronchography 251
- choice of CM 249 - 250
- computerised tomography 250 - 251
- excretory urography 250
- gastrointestinal tract 252
- voiding cysto-urethrography 251
paraproteinaemia 97. 107
particles (see contamination)
patient consent (see pat. information)
patient information 127. 129
patient supervision 144
percutaneous transhepatic cholangiography (PTC) (see cholangio-cholecystography)
perforation 205
phaeochromocytoma 97,108.235
- hypertensive crisis 108
- prophylaxis 108
pharmacokinetics 31- 39
- binding to plasma proteins (see protein
binding)
- biodistribution 31
- blood-brain barrier 32
- distribution coefficient 31
- elimination half-life 31
- gastrointestinal mucosa. absorption
32
- placenta passage 32
- renal clearance 31
- renal impairment 32
- transfer to human milk 32
phlebography 92 - 93, 238
- complications 172 -173
- technique 171-172
pH value 60, 64. 72
plasma proteins 77
plasma volume 76
polyuria 105,109
precautions concerning defined risks
84
pregnancy 116
premedication (see prophylaxis)
- antihistamines 93
- corticosteroids 94
- general anaesthesia 92
- sedation 91
pretesting 120
prophylaxis 93, 114 -125
- anaesthesia 122-123
- antihistamines 114,123 -124,194
- corticosteroids 114.124-125.194
- fasting 118
- sedation 121-122
prostaglandins 148
protein binding 1. 31
proteinuria 105
pulmonary angiography 180
Subject Index
pulmonary function 81- 82
pyrogens 65,167
- limulus test 65
- rabbit test 65
red cell morphology 77
renal failure 97,104-107
(see also kidney function)
- Bence Jones proteins 85,107
- diabetic nephropathy 85
- endothelin release 85
- obstructive nephropathy 85
- oliguria 84,105
- polyuria 105
- prophylaxis 85-86
- pseudoagglutination 84
- renal impairment 84
- renin-angiotensin 85
- structure-toxicity relationship 15
- serum creatinine 85,198
- Tamm-Horsfall mucoproteins 85,107
- vacuolation (tubular epithelium cells)
18
resterilisation 72 -74
(see also catheters)
- disposable articles 73
- quality criteria 73
risk factors 96 -117,143
- age 112,193
- allergy 97-99
- autoimmune disorders 110
- cardiovascular disease 103
- dehydration 109,193-195
- diabetes mellitus 106
- hypersensitivity 98
- hyperthyroidism 100,102-103
- hypohydration 84
- lung disease 104
- non-toxic nodular goitre 101-103
- paraproteinaemia 107
- phaeochromocytoma 108
- renal impairment 104-105,193
- sickle-cell anaemia 111
sedation 121
seizures 90
seminal vesiculography 228 - 229
- complications 229
- technique 228
sensitization 153 -154
serotonin release 98
serum creatinine (see renal failure)
shear rate 77,205
sickle-cell anaemia 111
side effects (see adverse reactions)
skin desinfectants 177
spinal angiography 90,158-162
- complications 161
- technique 159-160
spinal phlebography 162 -163
- complications 163
- technique 162 -163
splenic arteriography 162
stability 59 - 60,63,64 - 65, 67 -70
(see also storage recommendations)
- light 59 - 60, 64 - 65, 67 -70
- pH value 60
- temperature 59 - 60, 64 - 65, 67 -70
sterility test 62 - 63
storage recommendations 67 -70
structure-toxicity relationship 15
tachycardia 103
thorium-dioxide 3
thrombin 157
thromboembolism 157
thrombophlebitis 75, 173
thrombosis 75,92,157,172-173
thromboxane 148
thyroid function 86-87
- nodular goitre 102
- thyroid depressants 100
- thyroid hormones 101
- Plummer's treatment 86
- Wolff-Chaikoff effect 86
thyrotoxic crisis 87,100 -101,249
tissue-specific CM for MRI 285 - 287
tolerance 131-135
- heated CM 131
- injection rate 135
toxicity (preclinical tests) 16 - 20,75
- acute 16
- local 20
- mechanisms 75
- mutagenic potential 18
- renal 17
- reproduction toxicology 19
- subacute 17
ultrafIltration 58
urethrography 224 - 225
- complications 226
- teclmique 224
urography (intravenous) 220-223
- technique 221- 222
vacuolation 17 -18
- hepatocytes 18
- tubulus cells 17
vasodilatation 80 - 81
303
304
Subject Index
vasography 228 - 229
- complications 229
- technique 228
vasovagal dysregulation 172
ventricular fibrillation 61, 81, 103
vessel wall injury 92-93
viscosity 7,21,47,54 - 56,
- blood 76
- contrast medium 12,15, 25 - 26
visual disturbances (see cortical blindness)
water solubility (see hydrophilicity)
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