CONTRAST MEDIA

1. CONTRAST MEDIA Presented by Moderator Dr.Ranjitha. G Dr. Raghuram. P DNB resident HOD, dept of radiodiagnosis KMIO, Bengaluru KMIO, Bengaluru

2. OVERVIEW • Introduction & Definition • Classification • Water soluble iodinated contrast media • Physiology of contrast media • Adverse reactions to contrast media • Contrast induced nephrotoxicity • Ultrasound contrast media • MR contrast agents

3. Definition • Contrast medium-a substance used in radiography which permits visualization of internal body structures, also called contrast agent, contrast material. • Positive contrast.-the use of a contrast material that is radiopaque such as insoluble salt barium sulfate and a variety of organic iodine compounds. Barium is used for gastrointestinal studies. Water-soluble, iodinated contrast media are used for many procedures, including all types of angiography, intravenous and retrograde urography, hysterosalphingography, sialography , myelography ,cholangiography etc • Negative contrast material that is not radiopaque such as air or carbon dioxide

4. Classification CONTRAST MEDIA X-RAY & CT ULTRASOUND MRI BaSO4 Oily 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 Diatrizoate Ioxaglic acid Iopromide Iotrol Iothalamate Iohexol Iotrolon Iopamidol Ioversol

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 & atomic weight 127 • Radio-opacity is dependent on iodine conc of the solution, so dependent on number of iodine atoms in each molecule of the contrast medium. • 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 • High radio-opacity & low osmolality are required. • Iodine is preferred because *High contrast density due to high atomic number *Allows firm binding to highly variable benzene ring *Low toxicity

7. Conventional contrast media / High osmolar / Ionic monomers These are salts of sodium or meglumine cation & triiodinated benzoate anion(C2, C4 & C6). C3 & C5 are connected to amines which reduce the toxicity & increase the solubility. *Diatrizoate (urograffin , angiograffin , urovedeo, trazograff) *Iothalamate(conray , triovideo) *Ioxithalamate *Metrizoate

8. Conventional contrast media / High osmolar / Ionic monomers • Iodine particle ratio is 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 • LD-50 = 7(g of I/kg wt of mouse) Disadvantage : high osmolality (8 times that of plasma), responsible for the adverse effects, because of the non radiopaque cations( Na & meg)

9. 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 No so CI in asthma

10. 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

11. 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 • Osmolality at 280mgI2/ml 560 osmol/kg H2O • LD-50 = 12(g of I/kg wt of mouse)

12. 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

13. NON IONIC MONOMERS • Iodine particle ratio is 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 • LD-50 = 22(g of I/kg wt of mouse)

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

15. NONIONIC DIMERS • Iodine particle ratio is 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 • LD-50 = >>26(g of I/kg wt of mouse)

16. 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.)

17. Ideal contrast media should have: • High water solubility • Heat & chemical stability(shelf life) ideally- 3 to 5yrs • Biological inertness( non antigenic) • Low viscosity • Low or iso osmolar to plasma • Selective excretion, like excretion by kidney is favorable. • Safety: LD50 (lethal dose) should be high • Reasonable cost

18. 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

19. Imp points to remember • Contrast media used for myelography are non-ionic CM. • CM used for cerebral angiography, are CM containing only meglumine cation. • CM containing only meglumine cation- conray 280, triovideo 280, trazograff60% and angiograffin. • CM which cause max nausea & vomiting are – Ioxaglate (Hexabrix). • Meglumine salts cause bronchospasm, so CI in bronchial asthma. • Among newer CM, Iohexol is most hyperosmolar • Viscosity increases as conc increases & tends to be higher for big sized molecules (dimers). High viscosity interferes with mixing of contrast media with plasma & body fluids. Omnipaque240 has least viscosity. • Meticulous heparinization is required during angiography as incidence of thrombo embolic phenomenon is high when CM is mixed with blood

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

21. Idiosyncratic anaphylactic reactions • Most dreaded and most frequent serious and fatal complications as they occur without warning, cannot reliably predicted, and are not preventable. • Not dose dependent • They begin during or after injection and 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

22. Idiosyncratic anaphylactic reactions Possible mechanisms: • Inhibition of enzymes, viz cholinesterase - ^ach- vagal over stimulation- cardiovascular collapse, bradycardia, bronchospasm • Release of vasoactive substancessuch 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

23. 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

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

25. Hyperosmolar reactions Due to high osmolarity of the contrast media than plasma, more common with conventional CM. • Erythrocyte damage:loss of H2O from RBC –dehydrated shrunken RBC- increased internal viscosity- loss of ability of RBC to deform to traverse capillaries- obstruction of imp capillary beds (cerebral, coronary, renal, pulmonary) • Endothelial damage & BBB damage: shrinkage of endothelial cells- widening of intercellular gaps- capillary permeability. • Vasodilatation :of the arteriolar or capillary bed of the injected artery, due to direct effect of hyperosmolar CM, manifested as warmth, heat discomfort or severe pain during peripheral arteriography. • Hypervolumia : due osmotic extraction of extravascular fluid- ^ blood volume by about10 to 20%. • Cardiac depression with hypotension, diminished venous return, myocardial ischaemia and direct depression of myocardial contractility

26. Vasomotor & vasovagal reactions • Occur either following idiosyncratic or nonidiosyncratic reactions or may occur independently. • 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

27. 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

28. Severe life threatening reactions Occur 1 in 2000 (0.2 to 0.04%) Convulsions, unconsciousness, laryngeal edema, severe bronchospasm, pulmonary edema, severe cardiac dysrhythmias, cardiac arrest, cardiovascular & pulmonary collapse. Treatment : • Airway must be secured & o2 , artificial respiration, external cardiac massage & electrical DC defibrillation administered as and when required. • IV line is secured to restore blood volume and administer drugs • A powerful diuretic such as 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 , - bronchospasm, angioneurotic edema and other anaphylactoid reactions

29. Deaths/ Mortality :1 in 14000 to 1 in 170000 following iv inj of HOCM or LOCM • Usually results from intractable cardiopulmonary collapse, pul edema or intense bronchospasm. • It is not proven that LOCM reduces fatality rate but there is no doubt that it produces less discomfort on iv inj , less pain on intraarterial inj, fewer physiological & haemodynamic disturbances and fewer adverse reactions to contrast agents than does HOCM.

30. 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

31. 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.

32. Ultrasound contrast agents • Also called 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 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. • 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

33. 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.

34. 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

35. 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

36. Mechanism of action • Pri 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 persistence of microbubble depends on – *size(<7um passes through pul cirltn) *surface tension & gas diffusion across the bubble shell. *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

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

38. Applications • Evaluating normal, increased or decreased vascularity. • Detecting vascular stenosis & occlusions • Improving neoplasm detection • Analysing & characterizing tumour neovascularity • Differentiating normal variants such as renal column of bertin from neoplasm. • Echocardiography – cardiac cavities, valves, coronary artery & myocardial viability

39. Applications RENAL *Solid masses *Pseudomases *Cysts *Renal artery stenosis *Renal transplants VASCULAR *lower extremity Doppler- native & bypass grafts *abdominal arterial examntn- stenosis Coeliac, SMA, Renal) *Carotid & Transcranial doppler HEPATIC *Neoplasm evaluation *Vessel evaluation -portal hypertension -TIPSS -Buddchiari syndrome -Liver transplant evaluation

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

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

42. 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

43. Contrast media used in MRI • Gadolinium chelates • Blood pool agents • Liver contrast agents • Endoluminal contrast agents • Targeted contrast agents

44. Gadolinium • Is the standard exogenous contrast agent used in clinical MR imaging. • It is T1 relaxing agent and is 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- *Gd-HP-DO3A:Gadoteridol/ProHance (non ionic) *Gd-DTPA :Gadopentetate diglumine/Magnevist(ionic) *Gd-DTPA-BMA: Gadodiamide/Omniscan (nonionic)

45. Gadolinium • These function as extracellular contrast agents. • They are rapidly excreted by glomerular filteration with half lives b/w 1 – 2hrs. • As these compounds are excreted by renal excretion, caution shd be taken in renal impaired patients. • 3 –5% of adverse reactions, occur in the form of nausea • Dose- 0.1 to 0.3mmol/kg body weight • Disadvantages *enhancement is non specific neither organ specific or pathology specific. *short window for imaging of blood vessels as it is diluted in blood stream and excreted rapidly.

46. Blood pool agents • These agents reversibly bind to plasma albumin achieving a substantial improvement in magnitude and duration of blood pool enhancement. • Eg- SPIO-super paramagnetic iron oxide crystals -USPIO -Magnetite • These cause predominant T2 shortening. • Uses – to image small vessels(eg acc renal,cor ). –vessels with slow flow (eg pul emb, DVT), -arteriovenous malformation - perfusion studies • Disadv: overlap b/w arterial and venous structures and separation is difficult

47. 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

48. Endoluminal contrast agents • Negative contrast agents, based on iron particles(Abdoscan, Nycomed-Amersham) for use in MR enteroclysis & MR imaging of rectal cancer. • Combination of methyl cellulose solution for bowel distention & iv gadopentate dimeglumine for bowel wall enhancement. • Natural contrast- blueberry juice acts as a negative contrast in upper abdominal MR imaging, eg MRCP

49. Targeted contrast agents • Blood pool agents • Liver specific agents • Necrosis specific agents (bis-gadolinium-mesoporphyrin) • Lymphographic contrast agents • Agents targeted at inflammation detection.

50. References • Grainger & Allison –Diagnostic radiology. • Radiological procedures- Dr.Bhushan N Lakhkar.