Basics of contrast media

BASICS OF CONTRAST MEDIA
Dr. MOHAMMAD NAUFAL B.Y.(M.D. RADIODIAGNOSIS)
AL AMEEN MEDICAL COLLEGE
VIJAYAPURA, KARNATAKA.

OVERVIEW OF CONTENT
1) History
2) Introduction
3) Physiology
4) Mode Of Administration
5) Classification
6) Contrast media for XRAY and CT
7) Ultrasound contrast media
8) MR contrast agents

BRIEF HISTORY
• 1896 -WALTER BRADFORD discovered contrast
media.
• 1897 - First reported GI contrast study performed
using Bismuth - TOXIC!
• 1910 - Barium Sulphate used (safer)
• 1920’s - Sodium Iodide used to treat syphilis.
Iodine was found to be radio opaque to x-rays.
Basis of all modern contrast agents.
• 1927 - First reported IVU with iodised organic salts
(Uroselectan)

INTRODUCTION
1)CONTRAST:
It is the difference in optical density between different parts of image on
radiograph.
It depends on absoprption coefficients of different tissues.

2)CONTRAST MEDIUM:
It is a chemical substance of very high or very low atomic number or
weight, therefor it increase or decrease the density of the organ
under examination.
A substance which when introduced into the body will increase the
radiographic contrast in an area where it was absent or low before.
OR

3)USE:
Arteriography
Angiography (DSA) – Cardiology
Venography (replaced by ultrasound Doppler)
IVU
Fluoroscopy – Alimentary tract, hyserosalpingography, sialography,
CT
MRI
Ultrasound – Liver, kidney
Myelography (replaced by MRI)
Arthrography – Knee joints.

4)M/C Side effect:
metal taste
feeling of warmth
5)Products like air, carbon dioxide, tap water, and juices containing
manganese,(e.g. blueberryjuice, pineapple juice)can be used as contrast
media.

PHYSIOLOGY
Concentration and excretion
1) >90%: passive glomerular filtration.
2) 1%: liver and intestine.
Half life: 30-60 minutes.
Do not enter the interior of cells.
Rapidly excreted, over 90% being
eliminated by glomerular filteration by
kidneys within 12 hrs.
Leaves the body within 24 hours(if
normal kidney) and weeks( if diseased
kidney).
IV CONTRAST
EXTRAVASCULAR SPACE
EXCRETED
EQULIBIRIUM BETWEEN INTRA AND EXTRAVASCULAR
SPACE IN 10 MINUTES

MODE OF ADMINISTRATION
1) Orally.
2) Rectally.
3) Intravenously – (injection/ infusion).
4) Mechanically – Filling of a body
cavity or potential space.
5) Intra-muscularly

CLASSIFICATION OF CONTRAST MEDIA
X-RAY & CT ULTRASOUND MRI
Oily/non water soluble IODINATED CM Water soluble IODINATED CM
Hepatic excretion Renal excretion
Iopanoic acid
High osmolar low osmolar
Ionic monomers Ionic dimers Non-ionic monomers Non ionic dimers
IOTHALAMATE
DIATRIZOATE
IOXAGLIC ACID
IOCAMIC ACID
METRIZAMIDE
IOHEXOL
IOTROL
IOTROLAN
Non water soluble BaSO4 IODINATED CM
Positive CM Negective CM
water,air,CO2

POSITIVE CONTRAST
 Contrast material is radiopaque.
 high atomic number material
 white on film
Example:
1) Barium sulfate
USE:
 GI Studies.
2) Iodine compounds.
USE:
 angiography,
 intravenous and retrograde urography
 hysterosalphingography
 sialography
 myelography
 cholangiography
NEGATIVE CONTRAST
 Contrast material that is not
radiopaque
 Low atomic number material
 Black on film
Example:
1) Water, Air and carbon dioxide
CONTRAST MEDIA FOR X-RAY AND CT

BARIUM SULPHATE
1) Atomic number:56
2) Highly radiopaque.
3) Non absorbable.
4) Non toxic.
5) Insoluble in water/lipid.
6) Inert to tissues.
7) Can be used for double contrast studies.
8) Route: Orally Or Rectally (aqueous suspension
with 0.3 to 1 g dry weight per milliliter)
9) Uses:
 barium swallow
 barium meal
 barium meal follow through
 Enteroclysis
 barium enema

BARIUM SWALLOW BARIUM MEAL BARIUM MEAL FOLLOW THROUGH

10) CONTRAINDICATION:
Integrity of gut wall compromised or GI Perforation.
Previous allergic reactions to barium.
Suspected fistula between oesophagus and lung.
11) Side effects:
Aspiration.
Granuloma(Leakage:Mediastinum, tissue around Rectum or Intraperitoneal cavity).
Leakage into the vasculature(life threatening).
Constipation.
worsening ulcerative colitis inflammation.
peritonitis through perforation.
Fatal Reaction(rare).

IODINATED CONTRAST MEDIA
Oily/non water soluble IODINATED CM Water soluble IODINATED CM
Iopanoic acid
IOTHALAMATE
DIATRIZOATE
IOXAGLIC ACID
IOCAMIC ACID
METRIZAMIDE
IOHEXOL
IOTROL
IOTROLAN

IODINE:
1) Atomic number 53
2) Atomic weight 127
1) Radioopacity depends on:
 iodine concentration of the solution, so dependent on number of iodine atoms in
each molecule of the contrast medium.
4) Iodine particle ratio:
 the ratio of number of iodine atoms per molecule to the number of osmotically
active particles per molecule of solute in solution
5) Iodine is preferred because:
 High contrast density due to high atomic number
 Allows firm binding to highly variable benzene ring
 Low toxicity

OILY/NON WATER SOLUBLE IODINATED CM
Fatty Acids
Insoluble in water
White on the radiograph
Examples:
1) Iophendylate (Myodil, Pantopaque)-
myelographic agent
2) Lipiodrol Ultrafluide (Ethiodol)-
lymphangiographic agent.
 COMPLICATION:
1) Fat Embolism LYMPHANGIOGRAPHY

USE:
1) Sialography
2) Hysterosalpingography
3) Myelography
4) Lymphangiography
5) Dacryocystography
1) Galactography
2) Broncography

SIALOGRAPHY HYSTROSALPHINGOGRAPHY MYELOGRAPHY

DACROCYSTOGRAPHY GALACTOGRAPHY BRANCHOGRAPHY

Iopanoic acid
IOTHALAMATE
DIATRIZOATE
IOXAGLIC ACID
IOCAMIC ACID
METRIZAMIDE
IOHEXOL
IOTROL
IOTROLAN
WATER SOLUBLE IODINATED CM

IOPANOIC ACID
 is an iodine-containing radiocontrast
medium.
 potent inhibitors of thyroid hormone release
from thyroid gland, as well as of peripheral
conversion of thyroxine (T4)
to triiodothyronine (T3)
Hepatic excretion
• Use:
1) Cholecystography
2) Hyperthyroidism:adjunctive therapy
with thioamides
(propylthiouracil, carbimazole).

HIGH OSMOLAR IODINE CONTRAST MEDIA
IONIC MONOMER

HIGH-OSMOLAR IODINE CONTRAST MEDIA
a.k.a Conventional contrast media.
All are Ionic monomers
Salts with sodium or meglumine(N-methylglucamine) as the non-radiopaque cation
and a radiopaque tri-iodinated fully substituted benzoic acid ring as the anion.
triiodinated at (C2, C4 & C6) of benzene ring.
C3 & C5 are connected to amines which reduce the toxicity & increase the solubility.
Iodine particle ratio= 3:2
Molecular weight= 600-800
Iodine content at 0.3 osmol/kg H2O= 70mg I/ml
Osmolality at 280mgI2/ml= 1500 osmol/kg H2O
LD50(lethal dose) = 7(g of I/kg wt of mouse)
Rarely used.

DIFFERENCES B/W MEGLUMINE & SODIUM SALTS
MEGLUMINE SALTS SODIUM SALTS
• Solubility Better Same, less in some acids
• Viscosity High Low
• Tolerance Better Less,nausea & vomiting
• Blood Brain Barrier No effect Crosses BBB
• Vascular effects Less Marked
• Diuretic effect Strong Less
• Opacification Poor Better
• Bronchospasm causes(C/I:Asthma) No

Example:
1) Diatrizoate(urograffin, angiograffin , urovideo, urovision,
trazograff)
2) Iothalamate(conray, Triovideo)
3) Ioxithalamate
4) Metrizoate
Disadvantage:
High osmolality (8 X plasma) because of the non radiopaque cations
(Na & meglumine) is responsible for the adverse effects.

LOW OSMOLAR IODINE CONTRAST MEDIA
1) IONIC DIMERS.
2) NON IONIC MONOMERS.
3) NON IONIC DIMERS.

IONIC DIMERS
 Ioxaglate (Hexabrix)
Only compound, mixture of sodium and
meglumine salts
Two benzene rings (each with 3 iodine atoms)
are linked by a bridge to form a large compound,
carries only one carboxyl group, so known as
monoacid dimers
Iodine particle ratio is= 6:2 or 3:1
Molecular weight is= 1269
Iodine content at 0.3 osmol/kg H2O= 150mg I/ml
Osmolality at 280mgI2/ml= 560 osmol/kg H2O
LD50 = 12(g of I/kg wt of mouse)

NON IONIC MONOMERS
• Carboxyl group (-COOH) at C-1 is replaced by non ionising radical & CONH2
• Iodine particle ratio= 3:1
• Molecular weight= 600-800
• Iodine content at 0.3 osmol/kg H2O= 150mg I/ml
• Osmolality at 280mgI2/ml= 600 osmol/kg H2O
• LD50 = 22(g of I/kg wt of mouse)

• First generation-
*Metrizamide(ampipaque-expensive & unstable)
• Second generation-
*Iopromide (Ultravist)
*Iohexol (Omnipaque)- USED IN OUR DEPARTMENT.
*Iopamidol (Iopamiro)
*Ioversol (Optiray)
*Ioxilan
*Iomeron
*Xenetix

NONIONIC DIMERS
 Example:
*Iotrolan(Isovist)
*Iodixanol (Visipaque)
A.k.a Isoosmolar C.M.
Each molecule contains 2 non ionosing tri-
iodinated benzene rings linked together.
Iodine particle ratio= 6:1
Molecular weight= 1550-1626
Iodine content at 0.3 osmol/kg H2O= 300mg
I/ml
Osmolality at 280mgI2/ml= 300 osmol/kg
H2O
LD50 = >>26(g of I/kg wt of mouse)

IONIC MONOMER IONIC DIMER NONIONIC MONOMER NONIONIC DIMER
Iodine particle ratio 3:2 6:2 OR 3:1 3:1 6:1
Molecular weight 600-800 1269 600-800 1500-1626
Iodine content at 0.3 osmol/kg H2O
(300mg I/ml)
70 150 150 300
Osmolality at 280mgI2/ml
(osmol/kg H2O)
1500 560 600 300
LD50
(g of I/kg wt of mouse)
7 12 22 >>26

ADDITIVES USED IN CONTRAST MEDIA
1) Stabilizer:
Ca or Na EDTA
2) Buffers:
Stabilizes pH during storage, Na acid phosphates
3) Preservatives:
Generally not disclosed by the manufacturers.

IDEAL CONTRAST MEDIA
1) High water solubility.
2) Heat & chemical stability(shelf life) ideally- 3 to 5yrs.
3) Biological inertness( non antigenic).
4) Low viscosity.
5) Low or isoosmolar to plasma.
6) Selective excretion, like excretion by kidney is favorable.
7) Safety: LD50 (lethal dose) should be high.
8) Reasonable cost.

POINTS TO REMEMBER
Contrast media used for myelography- non-ionic CM.
CM used for cerebral angiography- only meglumine salt.
Least osmolar- Ioxaglate (Hexabrix).
Most hyperosmolar- Iohexol.
Max nausea & vomiting- Ioxaglate (Hexabrix).
Bronchospasm- Meglumine salts.
Viscosity:
• Increase with concentration
• Higher for dimers(big size)
• High viscosity interferes with mixing of contrast media with plasma & body fluids.
• Least viscosity- Omnipaque240
Meticulous heparinization is required during angiography as incidence of thromboembolic
phenomenon is high when CM is mixed with blood.

ULTRASOUND CONTRAST AGENTS
• A.k.a Echo Enhancing Agents.
• These agents Increase The Echogenicity Of Blood,
which heightens the tissue contrast & allows better
delineation of body cavities.
• Consist of Microscopic Gas Filled Bubbles.
• Their Extremely High Reflectivity(backscatter)
arises from the fact that microbubbles easily
change their size, contracting in compression part
of the ultrasonic cycle & expanding in the
rarefaction part.
• Thus They Resonate in the ultrasound beam when
there is a mismatch b/w their diameter and
ultrasonic wavelength, which occurs for
microbubbles in 2 to 7um at usg freq of 2-10 MHz

GENERATIONS OF ECHO ENHANCERS
FIRST GENERATION SECOND GENERATION THIRD GENERATION
1) unstabilised bubbles
in indocyanine green.
2) cant survive
pulmonary passage,
therefore used only
for cardiac & large
vein study.
Longer lasting bubbles
coated with shells of
protein, lipids or
synthetic polymers.
Encapsulated
emulsions or bubbles,
offer high reflectivity.

NON ENCAPSULATED MICROBUBBLES ENCAPSULATED MICROBUBBLES
Encapsulated Air Microbubbles Encapsulated Perflurocarbon MB
1)Albunex
2)Echovist
galactose
3)Levovist
galactose & palmitic acid
4)Cavisomes –
gas filled cyanoacrylate
microspheres for Liver, spleen &
LN
Optison:
Albumin coated microspheres
that contain Octafluropropane
gas
Uses:Cardiac app
1)Formed by hand agitation
2)Unstable & breech quickly
3)Large size, small fraction pass
through pulmonary circulation
4)Adequate for right heart
visualization
TYPES OF ULTRASOUND AGENTS

IDEAL ULTRASOUND CONTRAST AGENT
1) Be injectable by a peripheral vein
2) Be non toxic
3) Small enough to pass through pulmonary, cardiac & capillary systems
4) Stable enough to undergo the shear forces, hydrostatic pressure changes
& diameter changes
5) Half life should be sufficient to allow complete examination
6) Should require little preparation

MECHANISM OF ACTION
Primary mechanism of signal enhancement is Microbubble Backscatter, which
relates to differences in microbubble versus blood compressibility.
Increased echogenicity may be seen as an increased signal in color or spectral
doppler signal strength or gray scale image intensity.
The halflife or rsistence of microbubble depends on:
1) size(<7um passes through pulmonary circulation)
2) surface tension & gas diffusion across the bubble shell.
3) transducer frequency & power
Mechanical index (MI): Peak pressure of USG beam calculated from frequency &
power of USG beam. Higher the MI, more likely the bubble will break

DOPPLER RESCUE
Application of ultrasound contrast agents results in enhancement of colour,
power & spectral doppler waveform & this improves doppler imaging & is
termed as “doppler rescue “

APPLICATIONS
1) Evaluating normal, increased or decreased vascularity.
2) Detecting vascular stenosis & occlusions.
3) Improving neoplasm detection.
4) Analysing & characterizing tumour neovascularity.
5) Differentiating normal variants such as renal column of bertin from
neoplasm.
6) Echocardiography – cardiac cavities, valves, coronary artery & myocardial
viability

APPLICATIONS
HEPATIC
1)Neoplasm evaluation.
2)Vessel evaluation:
-portal hypertension.
-TIPSS.
-Buddchiari syndrome.
-Liver transplant
evaluation.
RENAL
1)Solid masses.
2)Pseudomases.
3)Cysts.
4)Renal artery stenosis.
5)Renal transplants.
VASCULAR
1)Lower extremity Doppler:
native & bypass grafts
2)Abdominal arterial
examination:
-stenosis.
-Coeliac.
-SMA.
-Renal.
3)Carotid & transcranial
Doppler.

ARTIFACTS
1)COLOUR BLOOMING:
Grey scale pixels are displayed as colour
pixel in areas that lack flow, occurs when
high concentration of ultrasound contrast
agents is delivered by bolus inj.
2)Bubble Noise:
Audible sound accompanied on visible
spectral doppler tracing blips.
3)An increase (17 to 45 %) in maximum
Doppler Shift Frequency.
COLOUR BLOOMING

CONTRAST MEDIA USED IN MRI
1) Gadolinium chelates
2) Blood pool agents
3) Liver contrast agents
4) Endoluminal contrast agents
5) Targeted contrast agents

GADOLINIUM
Is the standard exogenous contrast agent used in clinical
MR imaging.
It is T1 relaxing agent
Paramagnetic.
It belongs to lanthanide metal group with atomic no. 64.
It has a high spin contrast number which produces
desirable relaxivity contrast agents.
Three agents have been approved by FDA, they are-
1) Gd-HP-DO3A: Gadoteridol/ProHance (non ionic)
2) Gd-DTPA : Gadopentetate diglumine/Magnevist (ionic)
3) Gd-DTPA-BMA: Gadodiamide/Omniscan (nonionic)

These function as extracellular contrast agents.
They are rapidly excreted by glomerular filteration
half lives: 1 – 2hrs.
As these compounds are excreted by renal excretion, caution shoud be taken
in renal impaired patients.
S/E: Nausea(3 –5%)
Dose: 0.1 to 0.3mmol/kg body weight
Disadvantages:
1) Enhancement is non specific neither organ specific or pathology specific.
2) Short window for imaging of blood vessels as it is diluted in blood stream
and excreted rapidly.

WITHOUT CONTRAST WITH CONTRAST

BLOOD POOL AGENTS
These agents reversibly bind to plasma albumin achieving a substantial improvement in
magnitude and duration of blood pool enhancement.
EXAMPLE:
1)SPIO-super paramagnetic iron oxide crystals
2)USPIO
3)Magnetite
These cause predominant T2 shortening.
USES:
• 1)To image small vessels (eg:coronary artery).
2)Vessels with slow flow (eg pulmonary embolism, DVT),
3)Arteriovenous malformation
4)Perfusion studies
DISADVANTAGE:
• Overlap b/w arterial and venous structures and separation is difficult

LIVER CONTRAST AGENTS
Gadobenate dimeglumine:
-MultiHance,Bracco.
Small iron particles:
-Endorem & Resovist.
Manganese containing contrast
agents:
-Teslascan: Absorbed by liver,
pancreas and cortex of kidneys, T1
relaxation. MANGANESE CONTAINING CONTRAST

ENDOLUMINAL CONTRAST AGENTS
1)Negative contrast agents:
• Based on iron particles(Abdoscan, Nycomed-Amersham) for
• Use:
1)MR Enteroclysis.
2)MR imaging of rectal cancer.
2)Combination of Methyl Cellulose Solution for bowel distention &
I.V Gadopentate Dimeglumine for bowel wall enhancement.
3)Natural contrast:
• Blueberry juice acts as a negative contrast in upper abdominal MR imaging.
• eg MRCP

TARGETED CONTRAST AGENTS
1) Blood pool agents
2) Liver specific agents
3) Necrosis specific agents (bis-gadolinium-mesoporphyrin)
4) Lymphographic contrast agents
5) Agents targeted at inflammation detection.

REFERENCES
1) Grainger & Allison –Diagnostic radiology.
2) Radiological procedures- Dr.Bhushan N Lakhkar.

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