4.CONTRAST MEDIA APPLICATION ADVERSE REACTIONS AND THEIR MANAGEMENT.pptx By Ravindra Kumar.pptx

Small differences in tissue densities of the body do not allow optimal radiographic evaluation without contrast enhancement.
Soon after the discovery of X-ray ,enhancement of radiopacity was felt necessary to obtain better contrast of images.
It became obvious that element with high atomic no. would enhance x-ray images.
Bismuth, Lead and Barium salts were used to develop the first angiogram of an Amputed hand in 1896.
However these heavy metal salts were not safe enough to be used in living humans.
For last few decades, modifications in the structure of these contrast agents were continually sought in an effort to limit their toxicity.
Contrast Media are agents, which are used to opacify organs or body structures after introducing directly into the body cavities or through blood vessels for better visualization of the anatomical structures.
Contrast media are commonly used for imaging to enhance the differences of structures or fluids within the body tissue.
They may be used in radiological procedures such as Radiography, Fluoroscopy, Angiography, Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Ultrasound.
Various types of contrast media exist for each technique, and their applications depend on the chemical and physical properties of the agents.
A positive contrast medium attenuates the X-rays significantly stronger than the body’s soft tissues and in the appropriate concentration.
They can be divided into
Water-soluble (iodine-containing).
Water-insoluble (barium-containing).
Oily contrast media
Negative Contrast
Neutral Contrast.
Ultrasound contrast media for intravenous injections are usually gas-filled microbubbles with a mean diameter less than a red blood cell (i.e. 2–6 μm).
They are composed of a shell of biocompatible materials, including proteins, lipids, or biopolymers containing a filling gas.MR contrast agents are diagnostic pharmaceutical compounds, which mainly contain paramagnetic metal ions that affect MR signal properties of surrounding tissues.
Paramagnetic agents are positive enhancers that reduce the T1 and T2 relaxation times and increase tissue signal intensity on T1-weighted images and have nearly no effect on T2-weighted images.
Every drug given to a patient by whatever route may cause adverse reactions, which are sometime fatal.
Diagnostic procedures and contrast media for radiography and CT, MRI and ultrasound are no exceptions.
Even when administered appropriately, contrast agents will occasionally result in a severe or even fatal adverse reaction.
They are generally classified into those that occur only in susceptible subjects (Anaphylactic Reaction) and those that may occur in anyone (Anaphylactoid Reaction).
Whenever contrast medium is being injected, make sure that appropriate equipment for initial treatment of contrast reactions, is kept ready.
Contrast agents are one of the safest pharmaceutical agents that promote efficient diagnosis and treatment of diseases.

1. CONTRAST MEDIA APPLICATION, ADVERSE REACTIONS AND THEIR MANAGEMENT 1 Department of Radio-diagnosis and imaging, pgimer , Chandigarh Ravindra kumar M.SC. Medical Technology (Radiodiagnosis and imaging) PGIMER Chandigarh, India PRESENTER RAVINDRA KUMAR TECHNOLOGIST

2. Contents Introduction Types of contrast media Properties of contrast media Routes of administration Contrast used for CT & Special investigations Contrast used for GIT studies. Contrast used for USG Contrast used for MRI. Adverse effects of contrast. Precautions and treatment. Responsibilities of Technologist Conclusion. 2

3. Introduction Contrast Media are agents, which are used to opacify organs or body structures after introducing directly into the body cavities or through blood vessels for better visualization of the anatomical structures. Contrast media are commonly used for imaging to enhance the differences of structures or fluids within the body tissue. They may be used in radiological procedures such as Radiography, Fluoroscopy, Angiography, Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Ultrasound. Various types of contrast media exist for each technique, and their applications depend on the chemical and physical properties of the agents. 3

4. History Small differences in tissue densities of the body do not allow optimal radiographic evaluation without contrast enhancement . Soon after the discovery of X-ray ,enhancement of radiopacity was felt necessary to obtain better contrast of images. It became obvious that element with high atomic no. would enhance x-ray images. Bismuth, Lead and Barium salts were used to develop the first angiogram of an A mputed hand in 1896 . However these heavy metal salts were not safe enough to be used in living humans. For last few decades, modifications in the structure of these contrast agents were continually sought in an effort to limit their toxicity. 4

5. 5

6. Contrast Media For Radiography And CT A positive contrast medium attenuates the X-rays significantly stronger than the body’s soft tissues and in the appropriate concentration. They can be divided into Water-soluble (iodine-containing). Water-insoluble (barium-containing). Oily contrast media Negative Contrast Neutral Contrast 6

7. Ideal Contrast media Water soluble Chemical and heat stability Biological inertness Low viscosity Low or same osmolality as human plasma Selective excretion (i.e. kidneys) Safety Low cost Not interfere with physiological homeostasis High LD 50 7 The ideal contrast medium does not exist. Almost all agents cause discomfort and adverse reactions to some degree d iscomfort, e.g. metal taste and/or feeling of warmth, is frequent. Serious reactions requiring treatment.

8. Why Iodine? Most of the i.v contrast media contain iodine which has an atomic number 53 and atomic weight 127. Total iodine content in the adult human body is 40-50 mg. It's preferred because High contrast density due to high atomic number Allows firm binding to highly variable benzene ring Low toxicity MORE THE IODINE CONCENTRATION, MORE THE RADIOOPACITY, MORE ADVERSE REACTIONS 8

9. 9

10. Route of Administration Contrast given via Intravenous injection: Intravenous contrast help to highlight blood vessels & to enhance the tissue structure of various organs of the body. “Intravenous” means that the contrast is injected into a vein. 10 Contrast given via Oral route: Oral contrast is used to enhance CT images of the abdomen & pelvis or to see any leak in the GI track. The contrast agent are used Barium Sulphate & Gastrograffin .

11. Conti. Contrast media given via rectal route: The contrast agent is usually used for rectal study. The rectal contrast helps outlining the large intestine. 11

12. Conti. Contrast directly injected into the cavities: The iodine contrast media is also used to opacify the cavities by injecting directly into the cavities of the body. 12

13. Conti. Contrast directly injected into the ducts : 13

14. Properties of CM All contrast media are not the same: There are major differences between the general contrast media, not only whether they are ionic or non-ionic relative to blood, but also between non-ionic molecules, which differ in many other parameters e.g. Viscosity Osmolality Chemo toxicity 14

15. Viscosity The viscosity describes the thickness or resistance to flow of contrast media. The viscosity can be reduced by lowering the concentration of the contrast medium , but reducing the iodine concentration in this way may also result in unsatisfactory opacification. Note: Viscosity is inversely related to temperature . Viscosity is directly related to concentration . 15

16. Osmolality The Concentration of a solution expressed as the total no. of solute particles per kg. of solution. The closer the osmolality of radiological contrast media is to that of body fluids the better the tolerance. The osmolality of blood, and of the cerebrospinal fluid, is about 290mOsml/kg-303mOsml/kg. 16

17. Chemotoxicity The term ‘Chemotoxicity' refers to the mechanism responsible for causing the toxic effects of contrast media that cannot be explained by other means (e.g. osmolality, ionicity). There are a number of properties of contrast media that relate to this term (e.g. hydrophilicity/lipophilicity , protein-binding , histamine release). 17

18. Types of Contrast media Based on their 1. Osmolality 2. Ionicity Based on Water soluble based- Iodine-Based Contrast Insoluble in water based- Barium-Based Contrast Oil based –lipiodol Negative contrast media Neutral contrast media 18

19. 1. OSMOLALITY OSMOLALITY is no. of particles in the solution, per unit liquid, as compared to blood. High osmolar contrast media->1400mOsml/kg (5-8 times the osmolarity of plasma). Low osmolar contrast media-600-800mOsml/kg (2-3 times the osmolarity of plasma). Iso osmolar contrast media-290mOsml/kg-303mOsml/kg (same osmolarity as blood , plasma or cerebrospinal fluid). 19

20. 2. IONICITY IONICITY is characteristic of the molecule to break into positively charged cation and negatively charged anion- >more molecules per kg of water, Increasing osmolality. IODINE PARTICLE RATIO: For ionic contrast media-3:2 For non ionic contrast media-3:1   20

21. A. Iodine-Based Contrast Media Iodine (atomic number 53 and atomic weight of 127) is the only element that is proved satisfactory for general use as an intravascular contrast medium for radiography including angiography and CT. The iodine provides the radiopacity and the other elements of the contrast medium molecule provide no radiopacity but act as carriers of the iodine, greatly increasing the solubility and reducing the toxicity of the molecule. The problem has always been how to pack the iodine so it may be delivered safely into very sensitive arterial systems. 21

22. Conti.. Since the 1950s, four chemical varieties of iodine-based contrast media in clinical use have been introduced. High-Osmolar Ionic Contrast Media Low-Osmolar Ionic Contrast Media Low- Osmolar Non-ionic Contrast Media Iso-Osmolar Non-ionic Contrast Media All four are tri- iodo benzene ring derivatives with three atoms of iodine at 2,4,6 positions in monomers and six atoms of iodine per molecule of the ring atom in dimers, they are: highly hydrophilic, have low lipid solubility, low toxicity, low binding affinities for protein, receptors or membranes. 22

23. 1. High-Osmolar Ionic Contrast Media/Ionic Monomer All ionic monomers are 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. These anions include Diatrizoate Ioxithalamate Iothalamate. 23

24. Conti.. Each molecule completely dissociates in water into two ions one non-radiopaque as cation one radiopaque tri-iodinated benzoic acid ring as anion It gives iodine a particle ratio of 3 : 2. They are very hypertonic ~1600mOsml/kg of water. High-osmolar monomeric contrast media are rarely used intravascularly nowadays and have almost been replaced by non-ionic low-osmolar contrast media. 24

25. 2. Low-Osmolar Ionic Contrast Media/IONIC DIMERS Ioxaglate , is the only compound in this group. It is a mixture of Sodium and Meglumine salts of a mono acidic double benzene ring with each benzene ring having three atoms of iodine at C2, C4, C6 positions. The total molecule, therefore, contains six atoms of iodine and in solution each molecule dissociates into one radiopaque hexa-iodinated anion and one non-radiopaque cation (sodium and/or meglumine). Ioxaglate, therefore, has an iodine-to-particle ratio of 6 : 2 or 3 : 1. The osmolality is similar to that of the non-ionic monomers. 25

26. 26

27. 3. Low-Osmolar Non-ionic Contrast Media/NON IONIC MONOMERS The first agent was Metrizamide introduced by Torsten Almén in 1969. Today, second-generation non-ionic monomers ( Iohexol , Iopamidol , Iopromide , Ioversol , Ioxilan, Iomeron , Iobitridol, Iopentol , Iobiditrol ) have taken over and are much more stable, much more soluble and much less toxic. 27

28. CONTI. None of these molecules dissociate in solution . They are iodinated non-ionic compounds and therefore in solution they provide three atoms of iodine to one osmotically active particle (the entire molecule), producing an iodine-to-particle ratio of 3 : 1. They have less than half of the osmolality of HOCM of about 600 mosmol /kg water at a concentration of 300 mgI /ml. 28 IOHEXOL IOPROMIDE IOPAMADOL IOMERON

29. 4. Iso-Osmolar Non-ionic Contrast Media/NON IONIC DIMERS Isomenol , Iotrolan , Iodixanol and GE-145 are examples of non-ionic chemicals. They do not dissociate in solution . Each molecule, therefore, provides in solution six atoms of iodine for one molecule, i.e. a n iodine-to particle ratio of 6 :1. Having an osmolality lower than that for the non-ionic monomers has a price: the viscosity is high even at body temperature. The high viscosity makes it more difficult to inject the agent through thin IV lines or angiography catheters with small lumen. Therefore, the contrast agents are typically preheated before injection. NOW ISO-OSMOLAR contrast media are available i.e.VISIPAQUE which is non ionic dimer. ~300mOsml/kg of water. 29 IODIXANOL

30. Conti. After intravascular injection, all of the four types are distributed rapidly because of high capillary permeability into the extravascular, extracellular space (except in the central nervous system as they do not pass an intact blood–brain barrier). They do not enter the interior of blood cells or tissue cells. Protein binding is minimal . Contrast substances are excreted unchanged by glomerular filtration. In people with normal glomerular filtration rate (GFR; >60 mL/min/1.73 m 2 ) more than 80% is excreted after 4 hours, and 98% after 24 hours. In renal disease, it can take days/weeks depending on their impairment. In most patients, small amounts (<1%) are excreted via the bile i.e. liver. The hydrophilic contrast agents are not absorbed from the intact gastrointestinal tract and the high-osmolar contrast agents will draw water into the gastrointestinal lumen, with the risk of dehydrating the patient. 30

31. Contrast Media Classification Summarized in table as availability in India 31

32. Ionic vs Non Ionic Contrast Media Ionic Non ionic Dissociates into ions when injected Does not dissociate when injected Creates hypertonic solution Remains nearly isotonic solution Increase in blood osmolality No significant increase in osmolality More adverse reactions Fewer adverse reactions Less cost More cost 32

33. 33 IONIC CONTRAST w/v (g/100 ml) Na + meg Iodine mg/ml Viscosity at 37 C AVAILABLE IN INDIA as Urograffin 60% Urograffin76% 52 + 8 66 + 10 292 370 4 8.9 GERMAN REMEDIES Angiograffin 65 306 5 GERMAN REMEDIES Urovision Na : Meg 40 : 18 325 3.3 GERMAN REMEDIES Triovideo 280 Triovideo 400 60 66.8 280 400 4 4.5 BRACCO Urovideo 75 % Urovideo 60 % 68 + 8.3 54.4 + 6.7 370 296 8.4 4.1 BRACCO Trazograff 76 % Trazograff 60 % Trazograff plus 10 + 66 66 41.5 + 18.5 370 282 334 8.9 5 3.4 JB CHEMICALS

34. NON IONIC CONTRAST NON IONIC CONTRAST mgI /ml Viscosity at 37 C AVAILABLE IN INDIA AS Iopamidol 150 Iopamidol 200 Iopamidol 300 Iopamidol 370 150mgI/m 200mgI/m 300mgI/m 370mgI/m 1.5 2 4.7 9.4 BRACCO Omnipaque 140 Omnipaque 180 Omnipaque 240 Omnipaque 300 Omnipaque 350 Omnipaque 400 140mgI/ml 180mgI/ml 240mgI/ml 300mgI/ml 350mgI/ml 400mgI/m 1.5 2 3.3 6.1 10.6 12.6 NYCOMED – NOW GE HEALTHCARE Ultravist 150 Ultravist 240 Ultravist 300 Ultravist 370 150mgI/m 240mgI/m 300mgI/m 370mgI/m 31.2 49.9 62.3 76.9 GERMAN REMEDIES 34

35. General Guidelines For ICM Administration All ICM stock should be monitored by designated Nursing and CT Staff. All nurses/technologists/radiologists should personally inspect contrast containers/vials for integrity, signs of contamination and also check expiry date . The ICM should be stored at less than 37 degree C . All multidose contrast containers/vials should be properly labelled along with the time when they were opened. All expired contrast containers/vials should be properly disposed. The dosage and technique of ICM should be decided under the guidance of a radiologist. Only authorised persons ,i.e. technologists and nurses should inject ICM under supervision of a radiologist. 35

36. B. Barium-Based Contrast Agents The gastrointestinal tract is most frequently studied with very poorly soluble barium Sulphate (BaSO 4 ) which is administered orally or rectally and not Intravenously. At present, the contrast medium of choice is Barium Sulphate for GI studies because of: High atomic number of 56 so highly radiopaque Non absorbable Non toxic Insoluble in water and lipid Can be used for double contrast studies Can be used for reduction of intussusception of intestine. 36

37. Properties of an ideal barium preparation High density Stable suspension which does not settle Should not flocculate with secretions Low melting characteristics to give a good and stable mucosal coating. Advantages: Non absorbable so it does not get degrade throughout the bowel. As it coats the mucosa, it is suitable for double contrast studies. 37

38. Conti.. Commercially prepared Barium formulations in India are manufactured by M/s. Eskayef Fine Chemicals Ltd. Under the brand name of “MICROBAR” in following specifications: Microbar paste: 100% high viscosity paste in collapsible tubes which is high density, high viscosity preparation used for conventional studies of the pharynx and esophagus . 2. Microbar suspension: 95% moderate density and viscosity suspension for esophagus, stomach and small intestinal studies. Marketed in one liter bottles. 38

39. Conti. 3. Microbar HD: 200% high density, low viscosity preparation, supplied in a powdered form in a tumbler pack. By adding 70ml of water to this and shaking the tumbler for desired amount i.e. 150ml of barium Sulphate HD is formed which is ideal for double contrast studies for esophagus, stomach and duodenum. Sachets of gas producing powder are supplied with this pack. 4. Microbar for Enema: 1Kg and 5Kg pack of powder are available. Desired suspension can be prepared. 39

40. Characteristics influencing coating Additive: Additives are added to influence the rate of settling, viscosity, mucosal coating, thickness and flocculation. If too much additive is used, the viscosity will be so high that the suspension flows only with difficulty. Stability: It indicates that the suspension will not settle down . Suspending agents i.e. Gum acacia or Carboxymethyl cellulose (CMC) are hygroscopic , therefore retains water and prevents settling of particles. 40

41. Conti. Flocculation: Flocculation is reduction in the number of particles by the formation of large masses. When the suspension comes in contact with intestinal or gastric secretion, the suspension will form clumps. To prevent this, antacids i.e. Sodium citrate, Al. hydroxide and Magnesium sulphate , are added which will neutralize the gastric acid. Preservatives: Methyl paraben and Sodium metabisulphate is used to avoid any fungal growth because of added additive. Antifoaming Agents: Simethicone or Melthypolysiloxone are added to prevent formation of air bubbles. 41

42. Conti. Coloring Agents: Erythrocin is used as coloring agent Sweetening Agent: Saccharine of fruit essences are used to mask the unpleasant chalky taste of Barium. Chocolate is not added because of possible allergic reaction. 42

43. C. Negative Contrast Media CO 2 and room air used with Barium to achieve double contrast effect. For upper GI tract CO 2 is administered orally in the form of gas producing granules/ powder. The requirements of these agents are: Production of adequate volume of gas i.e., 200-400ml. Non interference with the Barium coating No bubble production Rapid dissolution ,leaving no residue Easily swallowed Low cost 43

44. Gas producing agents 44 SODIUM BICARBONATE ENO COKE CITRIC ACID & TARTARIC ACID CO 2 Advanced Insufflator 9. Air Insufflator

45. Air Versus Carbon Dioxide 45 AIR CARBON DIOXIDE Air is absorbed slowly than CO 2 . CO 2 is absorbed across the intestines 160 times more rapidly than Nitrogen and 13 times more rapidly than Oxygen , which are the main components of air . Air insufflation leads to abdominal pain in most cases. Studies have shown that CO 2 insufflation leads to reduced post procedure pain. The mean amount of air insufflated at routine colonoscopy has ranged from 8.2 to 17.8 . The mean volume of CO 2 used at colonoscopy has ranged from 8.3 to 14 .

46. D. Oily Contrast Media Sicard and Forrestier in 1923 first reported the use of iodized poppy seed oil as contrast medium. They injected Lipiodol into an antecubital vein to observe blood flow through the heart and pulmonary arteries. Oily contrast media include Lipiodol, a stable compound of 40% iodine in poppy seed oil. Note:- 480mgI/ml 46

47. Conti. The oily contrast media is phagocytized by polymorphic nuclear cells and metabolized to sodium iodide by Esterase. After elimination of oily substance, the foreign body reaction subsides. Excretion of sodium iodide occurs mainly via the kidneys, but the pancreas, liver and salivary glands also take part in its elimination. It was used for Bronchography, HSG, Sialography and Myelography . 47

48. Conti. Oil-based iodine contrast media are made from fatty acids . Poppy seed oil containing 48% and 37% iodine. Fatty Acids Insoluble in water. White on the radiograph = Radiopaque Uses Bronchography (lungs) Tear ducts (DCG) Salivary glands (SIALOGRAPHY) Lymphatic system HSG Galactography (Breast ducts) Ductography FAT EMBOLUS IF IT GETS INTO BLOOD VESSEL . Instilled in ORGAN – Not vessels. 48

49. E. Neutral Contrast Media 49 WATER PEGLEC

50. CONTI. 50 CT ENTEROGRAPHY SHOWN THE NEUTRAL CONTRAST MEDIA TERMINAL ILEUM PATHOLOGY TERMINAL ILEUM PATHOLOGY

51. USG Contrast Media Ultrasound contrast media for intravenous injections are usually gas-filled microbubbles with a mean diameter less than a red blood cell (i.e. 2–6 μm ). They are composed of a shell of biocompatible materials, including proteins, lipids, or biopolymers containing a filling gas. 51

52. Conti. The microbubble shell may be stiff (e.g. Albumin) or Lipid flexible (phospholipids) It has a thickness ranging from 10 to 200 nm . High-molecular-weight and low solubility filling gases (perfluorocarbon or Sulphur hexafluoride) produce a raised vapor concentration inside the microbubble relative to surrounding blood and increase the microbubble stability in the peripheral circulation. 52

53. There are currently three principally different agents available: A ir with a galactose and palmitic acid as a surfactant ; O ctafluoropropane ( perflutren ) with an albumin shell or a lipid shell ; and Sulphur hexafluoride with a phospholipid shell . From 10 to 15 min after injection, the microbubble gas content is exhaled via the lungs, while the components of the shell are metabolized or filtered by the kidney and eliminated by the liver. 53

54. Indications: Cardiac US Characterization of focal liver lesion Monitoring of percutaneous tumor ablation Vascular US Assessing vascularity of focal lesion especially when CT and MRI contrast agents are contraindicated 54

55. Preparation of SonoVue contrast for US 55

56. 56 STEPS OF FILLING SONOVUE

57. MRI Contrast Media MR contrast agents are diagnostic pharmaceutical compounds, which mainly contain paramagnetic metal ions that affect MR signal properties of surrounding tissues. Paramagnetic agents are positive enhancers that reduce the T1 and T2 relaxation times and increase tissue signal intensity on T1-weighted images and have nearly no effect on T2-weighted images Copper (Cu2+), manganese (Mn2+) and gadolinium (Gd3+) were considered as potential paramagnetic ions to be used for MRI since1980s. 57

58. Conti. However, Gd (atomic number 64 and atomic weight of 157) turned out to be the most powerful, with seven unpaired electrons, but, unfortunately, it is toxic. Therefore, it is necessary to encapsulate it by a chelate . The first MR contrast agent to be introduced into clinical practice was the gadolinium diethylenetriamine pentaacetic acid salt ( Gd -DTPA). Several gadolinium-based MR contrast agents are currently available for clinical use in addition to Gd-DTPA. 58

59. COMMERCIAL BRANDS OF MRI CONTRAST AVAILABLE IN INDIA NAME OF BRAND IONICITY OSMOLALITY ( mOsml / kg H 2 O) VISCOSITY ( mPa.s at 37 C) OMNISCAN Prohance Gadovist Non ionic Non ionic Non ionic 780 630 1603 1.9 1.3 4.96 Magnevist Dotarem MultiHance Ionic Ionic Ionic 1960 135 1970 2.9 2 5.3 59

60. C helates Two principally different chelates were introduced to detoxify gadolinium: Linear or acyclic (the gadolinium is held less strongly) Macrocyclic or cyclic (the gadolinium is caged in the molecular ring) Just like the iodine-based contrast media, both are available as ionic and non-ionic. These agents have more or less affinity to albumin. 60

61. 61

62. Conti.. Unlike iodinated contrast agent, the differences in osmolality do not have any effect on the incidence of adverse reactions. The viscosity of the agents is low and NOT important. Gadolinium in itself does not change the signal, it is the surroundings that change signal intensity when the agent is there . The effect increases when gadolinium is bound to a chelate and the addition of albumin increases the effect further. 62

63. Stability of chelates The molecular structure of the chelate affects the stability of the molecules, i.e. how tightly the gadolinium is held within them. The Macrocyclic or cyclic chelates are the most stable and that the non-ionic linear or acyclic chelates are the least stable. In the cyclic molecules, the gadolinium is caged in the molecular ring, while in the acyclic molecules the gadolinium is held less strongly. The agents have low molecular mass and they rapidly diffuse into the interstitial extravascular space after intravenous injection. Gadolinium chelates are constantly eliminated from the intravascular compartment by passive glomerular filtration. Subsequently, more than 95% of the injected dose is excreted in urine within 24 hours in the presence of normal renal function and it may take several days/weeks in patients with severely reduced renal function. MR contrast agents do not cross vascular blood–brain barrier nor bind to proteins or receptors and there is no intracellular penetration . These agents accumulate in tissues with abnormal vascularity (malignant and inflammatory lesions) and in regions where the blood–brain barrier is disrupted. 63

64. Iron-Based Contrast Media These comprise Superparamagnetic iron oxide (SPIO ) that is administered intravenously or orally. The iron is covered by dextran or carbodextran and is produced in three sizes: large, medium and ultra small. The medium sized particles accumulate within the Kupffer cells in the normal liver within less than 60 minutes , resulting in reduction in signal intensity of the liver at T2*-weighted gradient-echo imaging. Lesions containing Kupffer cells demonstrate signal reduction, whereas lesions that are Kupffer cell-depleted retain high signal. Some ultra small particles (USPIO) also accumulate in normal lymph nodes or in their portion with normal tissue and in other reticuloendothelial system (RES)-containing organs such as liver, spleen or bone marrow during the 24 hours after administration. The large particles are used for enhancement of the gastrointestinal tract. 64

65. Conti.. Iron oxide nanoparticles shorten T2- and T2*-relaxation times of the neighboring regions, and produce a decreased signal intensity in T2- and T2*-weighted MR images. Iron oxide agents do not leak into the interstitial and therefore, act as intravascular contrast agents or blood pool agents. They are eliminated from blood by uptake into the reticuloendothelial system (RES) cells in liver, spleen, bone marrow and lymph nodes. They have been subdivided into two groups according to their mean total diameter ( i ) Superparamagnetic iron oxide particles (SPIOs) and (ii)Ultrasmall superparamagnetic iron oxide particles (USPIOs). 65

66. Superparamagnetic iron oxide particles ( SPIOs ) Particle diameter greater than 50 nm. 1.Fexumoxide (also known as Feridex or AMI-25) with a particle size of 50–180 nm. It has a thin, incomplete coating that causes individual particles to form polycrystalline aggregates. It is administered as a slow I/V infusion over 30–60 minutes. Imaging is typically performed 1–4 hours after infusion . The liver appears darkest on T2* weighted and T2-weighted images in the first 24 hours after the infusion 2.Ferucarbotran (also known as Resovist ) has a particle size of about 60 nm. Resovist is provided as a ready to use formulation and is administered as a rapid bolus and so is used with both dynamic and delayed imaging. 66

67. Ultrasmall superparamagnetic iron oxide (USPIOs) These are particles with non-aggregated ( monodisperse ) iron oxide cores with mean diameter less than 50 nm. As USPIOs are very small, they are extravasated from the blood vessels into interstitial spaces and transported to lymph nodes via the lymphatic channels. MR imaging is done 24–36 hours after contrast administration . The accumulation of the contrast within the normal nodes causes them to appear dark in T2 or T2* weighted while diseased nodes (e.g. metastatic nodes) do not show any change in signal intensity and appear uniformly or focally bright Sinerem and Combidex are two commercially available USPIO agents 67

68. Manganese-Based Contrast Media Manganese-based agents can be infused intravenously or be administered orally. Compared with other ions, manganese is selectively taken up by the hepatocytes and excreted via the bile. The uptake is correlated with the mitochondrial function and is thus a sign of the oxygenation of the hepatocyte. Manganese is a relatively non-toxic ion, but in high doses it may be toxic; it may accumulate, in the brain, where it may cause degenerative lesions with Parkinsonism as a result. A normal liver removes 80 to 90% of the manganese during a single passage. 68

69. Conti. Manganese-based agents can be infused intravenously or be administered orally. Compared with other ions, manganese is selectively taken up by the hepatocytes and excreted via the bile. Its compound, Mangafodipir trisodium (Mn-DPDP, Teslascan ) has a chemical similarity to vitamin B6, and because of this, it is specifically taken up by hepatocytes. The uptake is correlated with the mitochondrial function and is thus a sign of the oxygenation of the hepatocyte. After infusion, manganese can be seen in the pancreas, adrenal glands and the pituitary, which also opacifies the bowel content. 69

70. ORAL MRI CONTRAST AGENTS Positive contrast agents- enhances on T1wt. Sequences e.g. Gd DTPA ,mineral oil. Mannitol, PEGLEG, sorbitol –enhance over T2W Sequence. Negative contrast agents- shortens the T2 time and appear dark. superparamagnetic agents Perfluorocarbons Blueberry and pineapple juice. Barium sulphate 70

71. Acyclic/Non-ionic Acyclic/ionic Acyclic/ionic Acyclic/ionic Cyclic/Non-ionic 71 Cyclic/ionic

72. Use of MR Contrast Agents for Radiographic Examinations Gadolinium attenuates X-rays. Hence, their use for radiographic examinations instead of iodinated contrast media has been advocated in patients with a history of serious adverse reactions to iodinated contrast media. In patients with renal impairment, gadolinium-based contrast media should not be used for radiographic examinations as they can induce nephrotoxicity at the doses required to produce adequate radiographic enhancement. 72

73. Adverse Reactions of Contrast Medium 73

74. Adverse reactions of contrast medium Every drug given to a patient by whatever route may cause adverse reactions, which are sometime fatal. Diagnostic procedures and contrast media for radiography and CT, MRI and ultrasound are no exceptions. Even when administered appropriately, contrast agents will occasionally result in a severe or even fatal adverse reaction. They are generally classified into those that occur only in susceptible subjects ( Anaphylactic Reaction ) and those that may occur in anyone ( Anaphylactoid Reaction ). 74

75. Adverse reactions to Iodinated Contrast Media 75 LOCM HOCM Lesser adverse reactions More adverse reactions Incident of mild and moderate adverse reaction(0.2%) Incident of mild and moderate adverse reaction(6-8%) Anaphylactoid reactions Cardiac decompensation

76. 76

77. A. Idiosyncratic Reactions Idiosyncratic reaction typically begin within 20 min of the contrast injection, independent of the dose that is administered. A severe idiosyncratic reaction can occur after an injection of less than 1 ml of contrast agents. Previous sensitization is not required. Idiosyncratic reaction may occur in people with a previous reaction to ionic or non ionic Contrast Media, asthma, food or medication allergies. Previous reactions to ionic or non ionic contrast media increase the relative risk of a repeat reaction 3-7 fold compared with the risk in general public. 77

78. Conti. Mild (Self Limiting) Moderate (Required Medication) Severe (Requires Immediate Treatment) Nausea Excessive Urticarial Circulatory collapse Vomiting Facial edema Pulmonary edema Mild rash bronchospasm Severe angina Light Head ache Laryngeal edema Myocardial infarction Mild dyspnoea Mild chest pain or hypotension Coma Cardiac/Respiratory arrest 78

79. B. Non idiosyncratic reaction Non idiosyncratic reaction includes Bradycardia Hypotension Vasovagal reaction Neuropathy Cardiovascular reaction Extravasation 79

80. Contrast Induced Nephropathy (CIN) It is defined as the impairment of renal function measured as either a 25% increase in serum creatinine from base line or a 0.5mg/dL increase in absolute serum creatinine value within 48 to 72 hours after intravenous contrast administration. For renal insufficiency attributable to contrast administration, it should be acute, usually occurring within 2-3 days. 80

81. Adverse effects of Barium Sulphate Extravasation into bronchial tree or other body cavities will produce inflammation. Peritonitis due to extravasation. Barium Inspissation in case of colonic obstruction forms hard stones. Intravascular entry of Barium can cause embolism. Appendicitis Barium Encephalopathy Longstanding Barium deposits are carcinogenic. Sepsis 81

82. Adverse reaction of USG Contrast Media Ultrasound contrast agents are generally safe with a low incidence of side effects. They are not nephrotoxic . The incidence of severe hypersensitivity or anaphylactoid reactions is lower than with current iodine-based contrast agents and with MR contrast agents. 82

83. Adverse reaction of MRI Contrast Media Reactions along the venous injection site, such as Mild and transient burning Pain Feeling of warmth Coldness Side effects of headache, nausea, abnormal taste and feeling hot . 83

84. Nephrogenic Systemic Fibrosis Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. 84 Nephrogenic Systemic Fibrosis

85. CONTI. The GBCAs-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The GBCAs-associated NSF risk appears moderate for patients with chronic, moderate kidney disease (GFR 30-60 mL/min/1.73m 2 ). The risk appears lower for patients with chronic, mild kidney disease (GFR 60-90 mL/min/1.73m2). 85

86. CONTI. Clinical features of NSF from the day of exposure for up to 2–3 months, sometimes up to years after exposure. Initially: Pain Pruritus(itchiness) scratches skin to get relief. Swelling Erythema (skin redness ) Usually starts in the legs Later: Thickened skin and subcutaneous tissues—‘woody’ texture and brawny plaques. Fibrosis of internal organs, e.g. muscle, diaphragm, heart, liver, lungs. 86

87. Hypersensitivity Reactions Anaphylactic and A naphylactoid reactions have been reported with GBCAs , involving cardiovascular, respiratory, and/or cutaneous manifestations. In most cases, initial symptoms occurred within minutes of GBCAs administration and resolved with prompt emergency treatment. 87

88. Acute Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis mostly within 48 hours of Contrast injection. The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insufficiency. 88

89. Management of Adverse Reaction 89

90. Treatment of Adverse Reaction Whenever contrast medium is being injected, make sure that appropriate equipment for initial treatment of contrast reactions, is kept ready. Two basic rules to be remembered are Make sure that the drugs for allergic reactions are available before injecting the contrast. Never leave the patient unattended after contrast has been injected until examination is complete. 90 No patient will have a serious reaction after 60 min. of contrast administration .

91. 91 EPINEPHRINE 1:1000 I.M AVIL DIAZEPAM 5mg/ml HYDROCORTICOSONE SODIUM SUCCINATE DEXAMETASONE SODIUM PHOSPHATE 4mg/ml ATROPINE BUSCOPAN

92. 92

93. Mild Reaction Reassure the patient and tell him the reaction will go away. Loosen tight clothing if any. Tell the patient to take a few deep breaths in and out to relax. Stay with the patient and watch until symptoms subside. 93

94. Moderate and Severe Reaction 1. Skin Reactions They can occur any part of the body commonly face, neck and chest. They are usually pruritic. Usually no treatment is needed. If pruritus is severe use Diphenhydramine (50 mg) If patient develops severe diffuse erythema or angioedema use Cirnetidine-300 mg in 20 ml. If no response use Epinephrine 0.1-0.3 ml (1 in 1000). 94

95. Conti. 2. Respiratory Reactions Causes of respiratory decompensation Airway and laryngeal oedema Bronchospasm Pulmonary oedema 95 3. Laryngeal edema management Oxygen Epinephrine Intubation may be necessary

96. Conti. 4. Bronchospasm Mild Oxygen 6-10 L/min face mask metered dose inhaler Albuterol 2-3 inhalation. Moderate Epinephrine (1 in 10,000) 0.1-0.3 ml IV and repeat 10-15 min. Aminophylline - 5 mg/kg IV. slowly over 10-20 min. Severe Epinephrine - (1 in 10,000) 0.1-0.3 ml IV. and repeat 3-5 min. 96

97. Conti. 5. Pulmonary edema Elevate head end of bed Oxygen 6-10 L/min face mask Furosemide 40 mg IV. slowly Morphine 1-3 mg IV. Hydrocortisone 100 mg I.V. slowly Shift to ICU. 97

98. Conti. 6. Hypotension Mild Release any abdominal compression Elevate legs Oxygen 10 L/min Isotonic I.V. fluids - administer rapidly 98

99. Severe Reaction Tachycardia Epinephrine I.V. Dopamine 99 Bradycardia Atropine 0.6-1 mg I.V., slowly Repeat 3-5 min

100. Seizures or Convulsions Mild Turn the patient to one side to avoid aspiration. Be sure airway is clear and open. Oxygen 10 L/min. Moderate and Severe Diazepam , 5 mg I.V. slowly 100

101. Hypertensive Crises Oxygen 10 L/min Nitroglycerine , 0.4 mg tablet sublingually. If no response, Nifedipine - 10 mg capsule, puncture end of capsule and drop sublingually. Monitor B.P. closely. Frusemide 40 mg I.V. slowly. 101

102. Extravasation of Contrast Media Extravasation is spill of contrast material from the vessel into which it is introduced, into the surrounding tissue or body cavity . Can occur during hand or power injection. Frequency is not related to injection flow rate. May involve large volumes of contrast media. More common with injections on dorsum of hand ,foot or ankle. LOCM rarely cause severe adverse effect. Most extravasations are limited to immediately soft tissues. No permanent injury. 102

103. Conti. 103

104. Conti.. Initial symptoms may be relatively mild. Severity and prognosis difficult to determine on initial evaluation of affected site-close follow up for several hours is essential. No effective treatment Elevation of affected extremity above the level of heart to decrease capillary hydrostatic pressure and promote absorption of fluid. No clear evidence regarding use of warm or cold compresses, aspiration of Extravasated fluid and injection of Corticosteroids. 104

105. Extravasation of contrast-Treatment OPD patient should be released from radiology department only after the radiologist is satisfied that the signs and symptoms have improved or new symptoms have not developed. Clear instructions for additional medical care in case of worsening of symptoms, skin ulceration, development of any neurologic deficit or circulatory symptoms. Surgical consultation for severe extravasation injury. Proper Documentation must be mention on file. Ice packs three times per day for 1–3 days Document extravasation Have patient call referring physician if problem arises. 105

106. PREGNANCY AND LACTATION No contrast agent has been tested in pregnant and lactating women. Generally, contrast media should not be administered to pregnant women. However, there are instances where enhanced imaging is vital for the mother. With regard to iodine-based agents, they are considered safe, whereas X-rays are more harmful. <1% OF CONTRAST MEDIUM IS SECRETED IN BREAST MILK AND <1% OF INGESTED CONTRAST IS ABSORBED BY THE GUT SAFE TO CONTINUE BREAST FEEDING but avoiding lactation after contrast agent 36 to 48 hours. 106

107. Radiopharmaceuticals Radiopharmaceuticals or medicinal radio compounds are a group of pharmaceutical drugs which have radioactivity. Radiopharmaceutical can be used as diagnostic and therapeutic agents that emit radiation themselves which is different from contrast media. Main group of these compound are the radiotracers used to diagnose dysfunctions in body tissue. 107

108. Conti. 108 Ethylene Dicysteine ( EC) SCAN Renal Cortex - Tc99m DMSA Diethylene Triamine Penta Acetate (DTPA)

109. Conti.. Name Pharmaceutical Emitter Investigation Route of administration Tc-99m Di- mercapto -succinic acid (DMSA III) Gamma Renal imaging IV Di- mercapto -succinic acid (DMSA V) Gamma Tumor imaging IV Hepatic amino- diacitic acid Gamma Functional biliary system imaging IV 109

110. RADIOGRAPHER RESPONSBILITIES Check Test reports within limits. Informed consent should be taken after full explanation about the procedure. Patient history. Written consent should be taken. Drug allergy or any previous reactions. Check contrast media expiry dates. Take care of patient. Ask to patients came with one attendant. Check i.v line and instruct the patient about procedure. 110

111. Conclusion Contrast agents are one of the safest pharmaceutical agents which promote efficient diagnosis and treatment of disease, However adverse effects may occur and severity depends upon chemical construction of contrast and anaphylactoid reaction. Contrast should be used for appropriate patient and indication by knowing risk vs benefit of contrast. To deal with these adverse reaction proper preparation should be done. 111

112. References AIIMS-MAMC-PGI’s Comprehensive textbook of diagnostic radiology, vol.1section- 2 Grainger & Allisons Diagnostic Radiology, 6th Ed. Radiological Procedure (Dr. Bhushan N Lakhar ) A Guide to Radiological Procedures (Stephen Chapman ) Wikipedia.com Google.com 112

113. Thank you 113