contrast agents in imaging

1. Contrast agents
Dr.Athul D
JR MDRD

2. • substance used in radiography which permits better visualization
of internal body structures
• Positive contrast.-the use of a contrast material that is radiopaque
such as barium sulfate and a variety of organic iodine compounds.
• Negative contrast material that is not radiopaque such as air
or carbon dioxide

3. classification

4. • . Conventional Contrast Media/High Osmolarnonic Monomers
• salts of
• • Diatrizoic acid (Urovedeo, Trazograff, Urograffin, Angiograffin
• and Contrastin)
• • Iodamic acid
• • Ioglicic acid
• • Iothalamic acid (Conray, Triovideo)
• • Ioxithalamic acid
• II. Ionic Dimer
• salts of
• • Ioxaglic acid (Hexabrix)
• • Iocarmic acid
IIII. Non-Ionic Monomer
• Iohexol-(omnipaque)
• Iopamidol -(Iopamiro)
• Ioversol -(optiray)
• Iopromide-(Ultravist)
• Iopentol
IV. Non Ionic Dimer
• Iotrol
• Iotrolan (Isovist)
• Iodixanol
Class II, III and IV are collectively known as low osmolar
contrast media .

5. Barium sulphate
• Has high atomic number 56, highly radiopaque.
• Non absorbable, non toxic.
• Insoluble in water/lipid.
• Inert to tissues.
• Can be used for double contrast studies.
• Uses: barium swallow, barium meal, barium meal follow through,
enteroclysis, barium enema

6. Water soluble iodinated contrast media
• Iodine (atomic number 53 and atomic weight of 127)
• Very tight binding to benzene ring
• Special property of attenuation of routinely used X ray beams called as
“K-edge effect”
• Can be used in variety of routes
• Oral or Rectal
• IV
• Intravertebral
• Intrathecal (iohexol) & Intravesical

7. • Basic building block is benzene ring with three iodine molecules
attached at positions 2, 4, and 6.
• Side chains (at positions 3 and 5) are modified with hydroxyl
groups or other molecules that further define an agent’s
properties.
• Exist as monomers (one benzene ring) or dimers (two benzene
rings).
• Three defining physical characteristics of iodinated contrast
agents— ionicity, osmolality, and viscosity—play a distinct role in
the tolerance and adverse reaction profiles

8. Ionicity: Ionic vs Non-ionic
Ionic
Dissolve into solution
into anion and cation
Usually have high
osmolality
Associated with more
AE
Non-ionic
Dissolve into water; but do
not dissociate
Lower osmolality (fewer
particles in a solution
compared to ionic)
Lower incidence of AEs –
hydrophilic, reduced protein
binding, low tendency to
cross cell membranes

9. Osmolality: High, Low & Iso-osmolar
Number of moles of osmotically active particles
present in solution per kg of solvent
High-osmolar (≥1400 mOsm/kg) agents include the
ionic monomers
Low-osmolar (780–800 mOsm/kg) agents include
nonionic monomers
Iso-osmolar agents (approximately 300 mOsm/kg)
include the nonionic dimers

10. Osmolality of Various Contrast Agents

11. Osmolality, Tolerability & Safety Profile
• Hyperosmolar compounds – cause osmotic effect in
surrounding tissues causing fluid redistribution (vascular
overload)
• Decompensation among cardiac patients
• Deformed and rigid RBCs
• Rarely can cause thrombosis or ischemic (brain and
myocardium)

12. Cellular Effects of Osmolality – Fluid Shift
and Vasodilation 12

13. Cellular Effects of Osmolality – Cell Shrinkage
• Water drawn out from the cells leads to decrease in intracellular
volume—cell shrinkage
• Cells become rigid with loss of function

14. Low Osmolar Contrast Media: Practical !
• Usually non-ionic contrast media
• Fewer adverse reactions and improved intravascular
tolerability
• Lower protein binding, reduced tissue binding and low
tendency to cross cell membranes
• Commonly used owing to their favourable safety and
tolerability profile and economic cost

15. Iso-osmolar Contrast Media: Ideal Choice !
• Isomolar compounds have high tolerability and safety
profile
• Preferred especially in imaging of areas where
endothelium is sensitive to osmolality – brain, heart and
kidneys
• Least effect on blood-brain barrier
• Least effect on cardiac rhythm and function
• Overall lower risk of nephrotoxicity

16. Viscosity: Affects Rate of IV Inj. !
• Affects rate of iv injection
• High viscosity reduces optimal flow rates
• Warming to room temperature (370C) reduces viscosity

17. Factors Affecting Viscosity
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17
Molecular
shape and size
• Round,
smooth,
smaller
molecules
roll more
smoothly
than
irregularly
shaped large
molecules
Iodine
concentration
• The higher
the iodine
content, the
greater is the
viscosity
Electrical
charges
• Even
distribution
or no net
charge
molecules
roll more
easily than
charged
molecules
Temperature
• Increase in
temperature,
increases
Brownian
movements
• Increase in
inter-
molecular
space causes
decrease in
viscosity

18. Classification of Contrast Media
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18
First-generation HOCM
Ionic monomers
Dissociation in
solution causes an
increase in
osmolality
6-8 times higher
osmolality than
human plasma
Rarely used nowadays
Replaced by non-ionic low osmolar
contrast media
Second-generation
LOCM
Available as non-
ionic monomers or
ionic dimers
Osmolality less
than half that of
HOCM
2-3 times greater
osmolality than
that of blood
Third-generation IOCM
Available as non-
ionic dimers
Iso-osmolar with
plasma at all
available iodine
concentrations

19. Classification of Contrast Media

20. Low osmolar contrast media
• 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

21. IONIC DIMERS- Ioxaglate(Hexabrix)
• Iodine particle ratio is 6:2 or 3:1
• Molecular weight is 1269
• Iodine content at
0.3 osmol/kg H2O-
150mg I/ml

22. NON IONIC MONOMERS
• First gen- Metrizamide
• Sec gen
*Iopromide (Ultravist)
*Iohexol (Omnipaque)
*Iopamidol (Iopamiro)
*Ioversol (Optiray)
*Ioxilan
*Iomeron
*Xenetix
• Carboxyl group (-COOH) is replaced by non
ionising radical & CONH2

23. NON IONIC MONOMERS
• Iodine particle ratio is 3:1
• Molecular weight 600-800
• Iodine content at
0.3 osmol/kg H2O-
150mg I/ml

24. NONIONIC DIMERS
*Iotrolan(Isovist)
*Iodixanol (Visipaque)
• Each molecule contains 2 non ionosing tri-
iodinated benzene rings linked together

25. NONIONIC DIMERS
• Iodine particle ratio is 6:1
• Molecular weight
1550-1626
• Iodine content at
0.3 osmol/kg H2O- 300mg I/ml

26. Additives used in contrast media
• Stabilizer – Ca or Na EDTA
• Buffers – stabilizes pH during storage
Na acid phosphates
• Preservatives ( generally not disclosed by the
manufacturers.)

27. Iodine-to-Particle Ratio
Ratio of the number of molecules of
iodine in a compound to the number of
osmotically active particles that it can
produce
Higher the iodine-to-particle ratio, more
iodine /molecule of contrast

28. Iodine-to-Particle Ratio
Ionic HOCM – each molecule dissociates to anion and
cation and have iodine-to-particle ratio of 3:2 or 1.5:1
Low-osmolar ionic contrast has iodine-to-particle ratio
of 6:2 or 3:1
LOCM (non-ionic) have 3 iodine atoms to one molecule
of osmotically active particle – 3:1
IOCM is dimer and has 6 iodine atoms to one molecule –
6:1

31. Clinical Indications
• Oral – esophagus, stomach or proximal small intestine
• Rectal – Colonic evaluation (mild laxative effect)
• IV – angiocardiography, head and body imaging, renal
arteriography, excretory urography, central or renal venography,
• Intravesical – Urinary bladder or HSG
• Intravertebral disc or spleen injection – only diatrizoate
meglumine
• Intrathecal – iohexol
• Arthrography and fistulography

32. Indications: First Generation

33. Indications: Second & Third Generation

34. Summary
Iodinated contrast media classified into various types
Factors affecting performance of contrast media are ionic
state, osmolality, viscosity, and iodine-to-particle ratio
Currently most commonly employed contrast agents are 2nd
generation LOCMs
Holistic approach should be employed for each study

35. Physiology
• On intravascular injection , the contrast media is
distributed rapidly by capillary permeability into
extravascular, extra cellular space (except in CNS).
• They do not enter the interior of blood cells or tissue cells
and they are rapidly excreted, over 90% being eliminated
by glomerular filteration by kidneys within 12 hrs

36. Adverse reactions to contrast media
Idiosyncratic
Anaphylactic reactions
Combined
Non idiosyncratic reactions
Chemotoxic Osmotoxic Vasomotor Vasovagal
Cardiac
Renal
Neural
vascular
Erythrocyte damage
Endothelial damage
BBB damage
Vasodilatation &
hypervolumia
Cardiac depression

37. Idiosyncratic anaphylactic reactions
• Most dreaded and most frequent serious and fatal
complications as they occur without warning
• Not dose dependent
• 85% occur within 5 minutes of inj. They are more frequent in
patients who have had-
* a previous adverse reaction to contrast medium (4 to 6
times) .
*in asthmatics (5 times).
* impaired cardiovascular and renal systems.
* on B-blockers / NSAIDS

38. Idiosyncratic anaphylactic reactions
Possible mechanisms:
• Inhibition of enzymes , viz cholinesterase - ^ach- vagal over stimulation-
cardiovascular collapse, bradycardia, bronchospasm
• Release of vasoactive substances such as histamine, serotonin or
bradykinin- vasomotor collapse.
• Activation of physiological cascade systems- compliment activation
system, kinin system with bradykinin release, coagulation system inducing
intravascular coagulation and fibrinolytic system causing lysis of fibrin and
blood clots.
• Immune system disturbances
• Anxiety, apprehension and fear

39. Nonidiosyncratic reactions
Chemotoxic, hyperosmolar, vasovagal and vasomotor
reactions
• Dose dependent
• Related to osmolality and concentration of the contrast
medium.
• Volume of the contrast medium injected

40. Chemotoxic reactions
• Caused by toxicity to contrast medium molecule as a whole, and is
more often due to cations , particularly -Na.
• They may be cardiac, neurological,renal or vascular

41. Nephrotoxicity
* decreased renal perfusion (low BP, peripheral vasodilatation).
* glomerular injury – manifests as proteinuria.
*Tubular injury- due to osmolality, chemotoxicity, ischemia
*CM precipitation of Tamm Horsefall proteins that blocks
tubules
*Swelling of renal tubular cells causing obstruction

43. Contrast medium nephrotoxicity
• Defined as rise in serum creatinine by >25% or 44umol/L occurring within 3
days of inj of iv CM for which there is no other explanation.
• Risk factors:
*Impaired renal function, (esp sec to dia nephropathy)
*Dehydration
*HOCM
*Large doses of CM
*Concurrent nephrotoxic drugs- gentamicin, NSAIDS

44. Guidelines for avoiding CM nephrotoxicity in
patients with impaired renal function
• Use of LOCM
• Use of minimum CM necessary to achieve diagnosis
• Patient should be well hydrated (100ml fluid per hr for 4 hr)
• No further CM for another 48hrs.
• Nephrotoxic drugs should be discontinued.

45. Hyperosmolar reactions
• Erythrocyte damage:
• Endothelial damage & BBB damage:
• Vasodilatation :.
• Hypervolemia :
• Cardiac depression

46. Vasomotor & vasovagal reactions
• Vasomotor reactions are characterized by severe
hypotension, tachycardia or bradycardia with
depression of myocardial contractility , reduced
cardiac output, cardio respiratory collapse and
possibly death.
• Vasovagal reactions are characterized by
bradycardia

47. Severity of reactions
• Minor reactions: 1 in 20cases (5 to 15%)- nausea vomiting , arm pain , pruritus,
light headache and mild dyspnoea.
no treatment, assurance.
• Intermediate reactions: 1 in 100 (0.5 to 2%), more serious degrees of above symptoms,
moderate hypotension & bronchospasm.
* Chlorpheniramine (4 to 10mg orally, im or iv).
* Diazepam (5mg) for anxiety.
* Salbutamol inhalation for bronchospasm.
* Hydrocortisone 100- 500mg im/iv.
* Adrenaline 0.3 –1ml of 1/1000 im/sc

48. Severe life threatening reactions
Treatment :
• Airway.
• IV line
• frusemide 20 –40mg im/iv for pul edema
• Diazepam and barbiturates for convulsions
• Hydrocortisone/ methyl prednisolone
• Aminophylline 250-500mg iv for intense bronchospasm
• Chlorpheniramine for allergic reactions
• Vasopressors- noradrenaline/ dopamine iv infusion for hypotension
• Sodium bicarbonate for acidosis
• Atropine 0.6 to 1.2mg iv/im for vasovagal reactions
• Adrenaline 0.3 to 1.0ml of 1 in 1000 solution sc/im, repeated at 10 to 20mins ,

49. Ultrasound contrast agents
• Also called ECHO ENHANCING AGENTS.
• increase the echogenicity of blood, which heightens the tissue contrast
& allows better delineation of body cavities.
• Consist of microscopic gas filled bubbles whose surface reflect sound
waves.
• 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.

50. Mechanism of action
• 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.
• Mechanical index (MI) –peak pressure of usg beam calculated from frequency &
power of usg beam. Higher the MI, more likely the bubble will break

51. Generations of Echo Enhancers
• First gen- unstabilised bubbles in indocyanine green , cant survive
pulmonary passage, therefore used only for cardiac & large vein
study.
• Second gen- longer lasting bubbles coated with shells of protein,
lipids or synthetic polymers.
• Third gen- encapsulated emulsions or bubbles, offer high
reflectivity.

52. Types of agents
Non encapsulated
microbubbles
• Formed by hand
agitation
• Unstable & breech
quickly
• Large size, small
fraction pass through
pul cirltn
• Adequate for right
heart visualization
Encapsulated microbubbles
Encapsulated air
Microbubbles
*Albunex
*Echovist (galactose)
*Levovist (galactose
& palmitic acid)
*Cavisomes –gas
filled cyanoacrylate
microspheres for
Liver, spleen & LN
Encapsulated
Perflurocarbon MB
*Optison: albumin
coated microspheres
that contain
Octafluropropane gas
Uses:Cardiac app

53. Different Types of Ultrasound Contrast Agents
• (A) Tissue specific ultrasound contrast agents
• Improves the assessment of certain organs, by improving the acoustic differences
between normal & abnormal portions of organs.
• • Levovist
• • Sonovist [Schering]
• • Sonozoid [Nycomed-Amersham]
• The bubbles rupture produces a transient pressure wave, resulting in
characteristic mosaic pattern from the tissues, which is termed as induced
acoustic emission

54. Levovist
• • First generation ultrasound contrast agent consisting of galactose (milk
sugar) ground into crystals.
• • Used in echocardiography in left ventricle functional assessment.
• The shell stabilizer is galactose/palmitic acid and the gas used is air.

55. Sonovist (From Schering Ag)
• • A biodegradable synthetic capsule filled with sulphurhexa
fluoride.
• • It is a stable contrast media.
• •The shell stabilizer is cyanoacrylate and the gas used is sulphur
hexaflouride

56. Vascular Ultrasound Contrast Agent:
• These are gas microbubbles with a diameter less than 5 to 10 micrometer to
pass through lung capillaries and into the systemic circulation.
• • These are most likely to be used in imaging of malignant tumours in liver,
kidney, ovary, pancreas & prostate.
• • It is also used in cardiac evaluation.
• Example:-Albunex & infosan.
• • Albunex - shell stabilizer is albumin and the gas used is air.

57. Contrast Agents For Targeted Imaging:
• Improve the image contrast resolution through differential uptake.
• High sensitivity & specificity
•
• Possible targets are molecular makers on thrombus, endothelial cells &
leucocytes.

58. Ideal ultrasound contrast agent
• Be injectable by a peripheral vein
• Be non toxic
• Small enough to pass through pulmonary, cardiac & capillary
systems
• Stable enough to undergo the shear forces, hydrostatic
pressure changes & diameter changes
• Half life should be sufficient to allow complete examination
• Should require little preparation

59. Doppler rescue:
• Application of UCA results in enhancement of colour, power &
spectral doppler waveform & this improves doppler imaging & is
termed as “doppler rescue “

60. Applications
• Evaluating normal, increased or decreased vascularity.
• Detecting vascular stenosis & occlusions
• Improving neoplasm detection
• Analysing & characterizing tumour neovascularity
• Can be used to study the fallopian tube patency
• Echocardiography – cardiac cavities, valves, coronary
artery & myocardial viability

61. Enhancement on B-mode & Doppler after iv ECHOGEN

63. Reperfusion study of post transplant kidney, following infusion of
Optison.

64. Artifacts
• Colour blooming – grey scale pixels are displayed as colour pixel in areas
that lack flow, occurs when high conc of UCA is delivered by bolus inj.
• Bubble noise – audible sound accompanied on visible spectral doppler
tracing blips
• An increase (17 to 45 %) in maximum doppler shift frequency

65. • Thank you