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Dr Justin jose
Contrast media are agents which permit visualization of details of internal structure or organs that would not otherwise be demonstrable. Classification
Classification
MANUFACTURE
Manufactured from mines STEPS Mined basulfate is reduced to basulfide Basulfide+sod carbnte-barium carbonate Ba carbonate+sulfuric acid-insoluble basulfate Basulfate being insoluble in water is used in the form of suspension .Conc is indicated by wt/volume
flocculation
Flocculation is reduction in no of particle by formation of large masses To prevent this antacidsare used which neutralises gastric acids &prevent flocculation Antacids used are sod citrate,alum hydroxide,mag sulfate
Preservatives are added to prevent bacterial&fungal growth. Methyl paraben&sod metabisulfite are used Antifoaming agents are added to prevent air bubbles .simethicone&polysiloxane are added Colouring&sweetening agents are also added
ADVERSE EFFECTS
Constipation Barium inspissation incolonic obstn lead to hard stone Hypersensitivity rean to additives like cmc has been described .methyl paraben&similar comp used as preservatives can induce hypersenstivity rean
Ba crystals in peritonial cavity cause extensive fibrosis&granulomatous reaction Intravasclar ba cause embolism Barium encephalopathy due to abspn from peritonium in cases of perforation Prev contrast medium extravasation may mimic cancer
A positive contrast medium must increase ct attenuation value of bowel lumen by 40 hu Conventional ba sulfte suspnsn are too dense resulting in streak artefact Full strength ba preprn shouldn t be diluted to low conc needed for ct as barium particle settle out after ingesion leading to in homogenous opacification of bowel lumen 1%to3%w/vba sulfte susp or2%to5%gastrograffn or iodinated agents are typically used
IODINE
Most of the I V contrast media contain iodine which has an atomic number. 53 and atomic wt. 127 gm. Iodine (atomic weight 127) is the only element that has proved satisfactory for general use as an intravascular radiological contrast medium (RCM). Total iodine content in the body is 0.01 gm.
Iodine is preferred becoz :1) high contrast density due to high atomic number. 2) allows firm binding to highly variable benzene ring. 3) low toxicity.
CLASSIFICATION OF IODINATED CONTRAST MEDIA There are four chemical varieties of iodinated RCM in clinical use. 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 anion (in dimers).
Class 11, 111, 1v are collectively known as Low osmolar contrast medias.
All ionic monomers are salts consisting of a sodium or meglumine (N-methyl glucamine) as the non-radio opaque cation and a tri-iodinated benzoate as the radio opaque anion.
Anions consisting of a benzoic acid molecule with three atoms of iodine firmly attached at C2, C4 & C6. The C3 & C4 are connected to radicals R3 & R5 which are amines E-NH2, and which greatly reduces toxicity & increase solubility of the molecules.
Eg:- iothalamate
These anions include Diatrizoate (Urograffin, angiograffin, Hypaque) Iothalamate (Conray) Ioxithalamate, metrizoate Iodamic acid Each molecule completely dissociates in water solution into two ions one non-radio opaque cation and one tri-iodinated radio opaque anion, giving an iodine: particle ratio of 3:2 . They are very hypertonic - 1600 mosmols kg-1 water at 300 mg iodine /ml compared to physiological osmolality of 300 mosmol kg-1 water.
NON-IONIC MONOMERS
Include iohexol (omnipaque), iopamidol, iopromide (ultravist), ioversol, ioxilan. None of these molecules dissociate in solution. They are tri-iodinated non-ionizing compounds and therefore in solution they provide three atoms of iodine to one osmotically active particle (the entire molecule), producing an iodine: particle ratio of 3:1. They have an osmolality of about 600 mosmol kg-1 water at a concentration of 300 mg I/ml
compared to physiological osmolality of 300 mosmol kg-1 water.
IONIC DIMERS
Ioxaglate , Iocarmate are the compounds in this group. It is a mixture of the sodium and meglumine salts of a monoacidic double benzene ring with each benzene ring having three atoms of iodine at C2, 4, 6 positions. The total molecule therefore contains six atoms of iodine.
Eg:-Ioxaglate
In solution each molecule dissociates into one radio-opaque hexa-iodinated anion and one non-radio opaque cation (sodium and/or meglumine). Ioxaglate therefore has an iodine: particle ratio of 6:2 or 3:1. They have an osmolality of about 560 mosmol kg-1 water at a concentration of 300 mg I/ml compared to physiological osmolality of 300 mosmol kg-1 water.
NON-IONIC DIMERS
Iotrol, iotrolan and iodixanol are examples of non ionic dimers. They do not ionize or dissociate in solution. Each molecule contains two non-ionizing tri-iodinated benzene rings linked by a bridge.
Eg:- iotrolan
Each molecule therefore provides in solution six atoms of iodine for one molecule, i.e. an iodine:particle ratio of 6:1. Non-ionic dimers are physiologically isotonic (300 mosmol kg-1 water) in solution at a concentration of 300 mg I/ml.
Pharmacokinetics
After intravascular injection, the contrast media are distributed rapidly because of high capillary permeability into the extravascular, extracellular space (whole body opacification) (except in the central nervous system) & is simultaneously excreted. Then equilibrium is reached b/w intra & extravascular space in about 10 min. Continued excretion & re entry of contrast media from ECF to ICF leads to decrease in plasma level. Plasma half life is 30 60 min.
They do not enter the interior of blood cells or tissue cells and they are rapidly excreted, with over 90 % being eliminated by passive glomerular filtration by the kidneys within 12h.
IDEAL CONTRAST MEDIA SHOULD HAVE: 1) High water solubility. 2) Heat & chemical stability (shelf life). Ideally 3-5 yrs. 3) Biological inertness (non antigenic). 4) Low viscosity. 5) Low or iso osmolar to plasma. 6) Selective excretion, like excretion by kidney is favourable. 7) Safety: LD50 (lethal dose) should be high. 8) Reasonable cost.
ADVERSE REACTIONS
2 Non-idiosyncratic reactions
these are dose dependent related to the chemical composition, osmolality and concentration of contrast medium and the volume, speed and multiplicity of the injection
Non-idiosyncratic reactions
Unlike the idiosyncratic reactions, these nonidiosyncratic reactions are dose dependent and therefore relate to the chemical composition, osmolality and concentration of contrast medium and the volume, speed and multiplicity of the injection. 1 ) Chemotoxic reactions:- Chemotoxic adverse reactions are probably due to toxicity to the contrast medium anion rather than to its iodine content, as the iodine is very firmly bound to the benzene ring. Chemotoxic side effects include cardiac, neurological and renal toxicity as well as vascular manifestations.
2) Hyperosmolar reactions:- The very high osmolality of high concentrations of HOCM (ratio 3:2) is 5 8 times the physiological osmolality (300 mosmol kg-1 water) of every cell in the body. The degree of hyperosmolality is much reduced if non-ionic ratio 3:1 (LOCM) and (even more) if ratio 6:1 products isotonic non-ionic dimeric LOCM are injected instead of injecting HOCM of ratio 3:2.
The adverse reactions due in part to hyperosmolality of the contrast medium include:
Erythrocyte damage Capillary endothelial damage Vasodilatation Hypervolemia Cardiovascular effects Vascular pain Disturbance of BBB Thrombosis & thrombophlebitis
For clinical purposes contrast media reactions are divided into 3 categories: Minor (1 in 20 cases-5%) : Flushing, nausea, arm pain, pruritus, mild urticaria, vomiting and headache. Intermediate reactions (1 in 100 cases-1%): Severe urtricaria, facial edema, hypotension, bronchospasm. Severe (1 in 2000 cases-0.05%): Convulsions,
unconsciousness, laryngeal oedema, severe bronchospasm, pulmonary oedema, severe cardiac dysrhythmias and cardiac arrest, cardiovascular and respiratory collapse.
Incidence of reactions with Ionic contrast media & Nonionic contrast media in general population
CONTRAST MEDIA REACTIONS Incidence Mortality In high risk groups serious side effects Fatality rates In pts known to have prior reaction, reaction rate With premedication steroids, reaction rate ICM 3.8 to 12.7% 1/30 0.25% 157/100,000 18-20% Higher NICM 0.6 to 3.1% 1/207 0.045% 60 to 126/100,000 5-6% Lower
Treatment
Treatment must be urgently and expertly administered according to a pre-arranged wellpractised schedule. The airway must be secured and oxygen, artificial respiration, external cardiac massage and electrical DC defibrillation must be administered as and when required. IV fluid infusion (normal saline, lactated Ringer's solution) through an indwelling IV catheter is essential to restore blood volume and to administer IV drugs:
A powerful diuretic such as frusemide (Lasix) 20 40 mg IV slowly or IM for pulmonary oedema . Diazepam and barbiturates for convulsions . Adrenaline (epinephrine) (0.3 0.5 ml, 1/1000 solution [children 0.01 ml kgbody weight] by deep SC or IM injection repeated at 10 20 min intervals) provides the most rapid and reliable relief for bronchospasm, angioneurotic oedema and other anaphylactoid symptoms .
Salbutamol (b2 agonist metered dose inhaler). Hydrocortisone or methyl prednisolone (100 1000 mg) . Aminophylline (very slowly, 250 500 mg) intravenously for intense bronchospasm. Chlorpheniramine for allergic or anaphylactic symptoms.
Vasopressors, e.g. noradrenaline (or metaraminol [Aramine] 0.5 5 mg slow IV infusion). Dihydroxyphenylaline (or dopamine) infusion (2.5 5 g kg-1 min-1) for hypotension with monitoring of the blood pressure . Sodium bicarbonate infusion should be administered to correct any acidosis, and atropine 0.6 1.0 mg IV or IM repeated if necessary (children 0.02 mg kg-1 repeated if necessary to 2 mg total) is used for vasovagal reactions, bradycardia and cardiac failure.
SafetyMeasures
Appropriate indication and selection. Informed consent. Hydration. Test dose. Smallest dose. Alternative imaging Premedication. Adequate resuscitation facilities
i.v agents undergo hepatocyte uptake&biliary excrn by active transport Iodipamide meglumine(cholograffin)is only agent in u.s
The principal requirements for an ultrasound contrast agent is that it should be easily introducible into the vascular system, be stable for the duration of the diagnostic examination, have low toxicity, & modify one or more acoustic properties of tissues which determine the ultrasound imaging process. Contrast agents might act by their presence in the vascular system, from where they r ultimately metabolized (blood pool agents) or by their selective uptake in tissue after a vascular phase.
For gas bubbles to be used as transpulmonic contrast media, the gas bubbles should be stable and smaller than 5 m. Bubbles larger than 10 m may transiently obstruct the capillaries and act as gas emboli. Several stabilizing coatings have been developed to produce Encapsulated gas microbubble contrast media. The coatings include albumin(Albunex), gelatin, galactose microspheres & palmitic acid (Levovist), polyglutaminic acid, lipophilic monolayer surfactants, and lipid bilayers (liposomes).
Perfluorochemicals are eliminated either by phagocytosis of the reticuloendothelial system or by evaporation in the lungs. Due to the selective phagocytosis, liver and spleen show late phase enhancement. Particle suspensions are generally less effective than gas bubbles, and much larger doses are needed for enhancement. Perfluorocarbons may furthermore be less safe than the gas bubbles; a relatively high percentage of mild allergic reactions have been shown in humans.
Microbubble
First generation, non-transpulmonary
vascular Free microbubbles Echovist (SHU 454)
Gas
Stabilizing shell
Air Air
None None
CLASSIFICATION
NON TISSUE SPECIFIC ( extra cellular)
initial short intra vascular distribution --> extra cellular space throughout body.
TISSUE SPECIFIC
RE cell specific Hepatocyte specific Blood pool agents Enteral bowel
Gd CHELATES
Gadopentate Dimeglumine -Magnevist Gadoterate Meglumine- Dotarem Gadoteridol- Prohance Gadodiamide- Omniscan Gadobutrol- Gadovist Gadoversatamide- Optimark
PHARMACOKINETICS
The pharmacokinetics of all extracellular MRI contrast agents with the exception of Gd-BOPTA are similar to iodinated water-soluble contrast media. After IV injection they are rapidly diffused into the interstitial extravascular space. Gd chelates are eliminated unchanged from the intravascular compartment by passive glomerular filtration. By 24 hours >95 per cent of the injected dose is excreted in urine with normal renal function. A very small amount (<0.1 per cent) is eliminated via faeces. The biological half-life is approximately 1.5h. Extracellular MRI contrast agents do not cross the intact specialized vascular blood brain barrier .
These agents accumulate in tissues with abnormal vascularity (malignant, infective and inflammatory lesions) and in regions where the blood brain barrier is disrupted. DOSAGE
0.1 millimol/kg or 0.2 ml/kg max dose 20 ml lethal dose 10 mmol/kg
Extracellular MRI contrast agents are well tolerated with a low incidence of adverse effects. In blood, the osmotic load of all Gd-based contrast media is very low, compared to iodinated contrast media, because only a small amount of the contrast agent is required to produce a diagnostic MRI examination.
SIDE EFFECTS Minimal with standard dose. Slight transitory increase in bilirubin & blood iron. Mild transitory head ache (9.8%). Nausea (4 %). Vomiting ( 2%). Hypotension, rash ( 1%). Life-threatening reactions are very rare.
CONTRAINDICATIONS
No known contraindication. Although , caution in
hematological disorders- hemolytic anemia. pregnancy, lactation. respiratory disorders- asthma. previous allergy.
HEPATOCYTE SPECIFIC CM
Gadolinium based compounds:
These agents have a capacity for weak and transient protein binding and is eliminated through both the renal and hepatobiliary pathways. The hepatic uptake represents 2 4 per cent of the injected dose. It behaves as a conventional extracellular contrast agent in the first minutes following IV administration and as a liver-specific agent in a later delayed phase (40 120 min after administration) when it is taken up specifically by normal functioning hepatocytes. Gadobenate dimeglumine (gd- bopta)- multihance Gadoxetic acid ( gd-eob-dtpa)- eovist
so far approved by fda only for diagnosing liver lesions. acts by shortening T1 relaxation time.
RETICULO ENDOTHELIAL CELL SPECIFIC FERUMOXIDES are SPIO ( polysaccharide coated super paramagnetic iron oxide) particles. contain a central core of iron oxide particle surrounded by a thin incomplete dextran coating, that causes individual particles to form polycrystalline aggregates. they have a size of approx 50- 200 nm.
RES in liver, spleen, bone marrow take up the agent & has a low signal in TI or T2*. Lesions not containing REcells do not take up the agent & remain unaffected, so have a high signal. Immediately following IV administration, the contrast agent also causes T1 relaxation and early T1-weighted imaging may be performed. USES differentiate b/w hepatic origin tumor that contain RES & tumors that do not.
DOSE
IV slow infusion over 30 min. 0.56 mg of iron ( 0.05 ml feridex) /kg. Should be diluted in 100 ml of 50% dextran. Further delay of 30 min prior to imaging allow for maximum uptake by RE cells. Contrast enhancement observed from 30 min to 4 hrs following infusion.
SIDE EFFECTS
Has a good safety profile. But in <3 % pts- Low back ache during infusion, usually self limiting, disappear after stopping/ slowing, also leg, groin pain, head, neck pain. Rarely -Gi- nausea, vomiting, diarrhea, anaphylaxis, hypotension. C/I - pts with allergy, hypersensitive to iron, parenteral dextran.
USPIO: Ultra Small Super Paramagnetic iron Oxide agents. Contains a thicker, more complete coating which causes these particles to remain as small monocrystals in solution. So remain in circulation longer & are phagocytosed at a slower rate. Increase signal intensity on T1w, decrease signal intensity on T2w.
Necrosis- gadophorins used to assess myocardial necrosis. Tumor specific MR CM eg: monoclonal antibody labeled paramagnetic & super paramagnetic nanoparticles.
There is no doubt that high doses of contrast media impair renal function, usually peaking at 3 5d, causing a decrease in urine output and an increase in serum creatinine and urea levels, decreased creatinine clearance and reduced glomerular filtration rate (GFR). In some patients this may proceed to renal failure with anuria, uraemia and death. Renal dialysis (either intravascular or peritoneal) is very effective and may be life-saving as an alternative method of excreting RCM and uraemic metabolic products.
These severe adverse reactions are very unlikely to occur if the patient is well hydrated and has normal renal function before the RCM injection. Particularly important adverse factors are pre-existing renal failure and oliguria, diabetic nephropathy, nephrotoxic drugs, patients who are not well hydrated and patients who are liable to be injected with very high doses of RCM for multiple sequential examinations repeated within a few days. Alternative imaging procedures must always be considered.
The usual recommended dose for IV urography in the normally well-hydrated adult with normal renal function is 15 25 g iodine; this dose may be increased provided the patients are well hydrated (by IV normal saline if necessary before, during and after RCM injection). A maximum of about 70 g of iodine (1 g iodine kg-1 body weight in adults) is generally advisable even in patients with good renal function, but considerably larger quantities (up to 200 g or even 300 g of iodine, i.e. up to 600 g of RCM) may be required, particularly in difficult angiographic and interventional procedures.
After early uncertainty, it is now established that HOCMs are more nephrotoxic, and LOCMs are preferred for all patients considered to be at increased risk, especially with diabetic nephropathy. There is increasing evidence that RCM (particularly HOCM and large doses) may induce damage to the tubules in the renal medulla and reduce intra-medullary blood flow in patients with acute calculus renal colic.
NERVOUS SYSTEM
LOCMs are much more comfortable for cerebral arteriography in the conscious patient and are always preferred. Cerebral RCM photographic arteriography is being strongly challenged and partially displaced by CT and MR angiography (MRA). Cerebral angiography Adverse reactions to RCM include dilatation of the external carotid arterial territory causing facial pain and heat. Damage to the blood brain barrier may cause dangerous cerebral oedema, bradycardia and hypotension.
CARDIOVASCULAR SYSTEM
Peripheral Arteriography
The usual iodine concentration required for conventional film-screen angiography is about 300 mg I ml-1 contrast medium. Conventional HOCM (1500 mosmol kg-1 water) has been completely displaced for peripheral arteriography by LOCM (600 700 mosmol kg-1 water), because the latter causes much less warmth, discomfort, pain and movement. LOCM permits almost painless angiography in all territories, usually eliminating discomfort, movement and the need for general anaesthesia.
Peripheral Venography
Venography of the leg for possible deep vein thrombosis (DVT) is the most frequent venographic study. The procedure is performed by injecting RCM into a small vein of the foot, with the leg dependent and tourniquets restricting peripheral venous return. If the deep veins are already compromised and partly thrombosed, peripheral venography of the leg is a potentially dangerous procedure, as both deep and superficial venous return from the leg are compromised, and some cases of venous gangrene due to venous endothelial damage and thrombosis have been induced by attempted venography.
LOCM is strongly advised because of its lower osmolality and its less irritant effect on the venous endothelium. Endothelial contact time should be reduced to the minimum by washing out with saline, massaging and exercising the leg immediately after satisfactory radiographs have been obtained. Termination of the injection of contrast medium must be seriously considered if the injection causes pain or if the deep veins are seen to be extensively thrombosed, for all RCM may induce thrombophlebitis.
Aortography Injections of LOCM at the 300 400 mg ml-1 iodine concentration are greatly preferred as they cause much less discomfort and vasodilatation. Coronary angiography HOCMs (e.g. Urografin 76 per cent) with physiological levels of sodium and which do not bind avidly to serum calcium (related to buffer agents) had a good reputation for selective coronary angiography, but LOCMs are even safer for they cause less marked haemodynamic, myocardial and physiological changes and depression
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