5 Why use contrast mediaWhere considerable difference between the densities of two organs exists then the outlines of the structures can be visualised on a radiograph due to natural contrast.Similarly, if there is a difference between the average atomic numbers of two tissues, then the outlines of the different structures can be seen by natural contrast.However, if the two organs have similar densities and similar average atomic numbers, then it is not possible to distinguish them on a radiograph, because no natural contrast exists.This situation commonly occurs - it is not possible to identify blood vessels within an organ, or to demonstrate the internal structure of the kidney, without artificially altering one of the factors mentioned earlier.
6 Radiological Contrast media CBD55 years of age male presented toa Urologist with recurrent UTI’sCT shows 22 mm mid polar L kidney stoneTreatment: PCNLWhat type of contrast will you use for CTUWhat contrast will you use for retrograde pyelogram?Explain the choice of CM
7 Radiological Contrast media Iodine - provides radio-opacity(discovered treating syphilis in the 1920’s with sodium iodide)Other elements of RCM molecule = carrier toxicity, solubility of iodine, non-radioopaqueAll IV RCMBenzene ring3 atoms of iodine at C 2,4,6 positionsClassificationIonic or non-ionicHigh or Low osmolarMonomeric or Dimeric
8 OsmolalityDependent solely on number of dissociated particles (not number of molecules).The closer the osmolality of RCM to that of plasma the better the tolerance.Osmolality is directly responsible for a number of clinically important effects. The sensations of heat and discomfort or even pain from contrast media are directly related to the osmolality.
9 Viscosity Resistance of a liquid to various forces (and hence to flow) Related to concentration of the Iodine ina contrast mediumInversely related to temperatureNot related to pressure
10 Radiological Contrast Media 4 types RCMIonic monomer = high osmolarIonic dimer = low osmolarNon-ionic monomer = low osmolarNon-ionic dimer = iso-osmolarDistributionHydrophilicCapillary permeability throughout extracellular compartment.Filtered unchanged in glomerulus.Excreted - 90% by glomerular filtration in 12 hrs
11 Ionic Monomer RCM Iodine atoms = 3 Osmotic particles = 2 Ratio 3:2 High osmolar 1550 mOsm /kg watere.g. Diatrizoate = Hypaque 50 ( 300 mg Iodine/ mL ) Urografin, GastrografinMetrizoate = Isopaque 370 ( 370 mg Iodine/ mL )Ionic high osmolar RCMs not used IVRetrogradesCheapSide effects 10x non-ionicAlso used to treat tape worms
12 Ionic Dimer Iodine atoms per molecule = 6 Osmotic particles per molecule = 2Ratio = 6:2Low osmolar = ~600 mOsm/kg watere.g. Ioxaglate = Hexabrix ( 320 mg Iodine/ mL)Toxicity - High protein bindingElectrical charge
13 Non-Ionic RCM Cation replaced by non-dissociating organic chain Tri-iodinated non-ionising compoundsFewer particles per iodine atomLower osmolalityFewer side effectsMore expensive
17 Points to Remember for RCM Radio-opacityIodine conc. of solutionNo. of iodine atoms per moleculeConc. of molecules in solutionOsmolalityNo. of particlesIonic vs. Non-ionicLow osmolalityFewer side effects / reactions pain of injectionHigh osmolalityGreater risk reactionsCauses osmotic diuresisThe osmalility of blood, and of the cerebrospinal fluid, which surrounds the brain and spinal cord, isabout 290mOsm/kg. Almost all of the currently available ionic, non-ionic monomeric and ionic dimericcontrast media have osmolalities in excess of this figure, though some are very much higher than others(see Fig. 2).Osmolality is directly responsible for a number of clinically important effects. The sensations of heat anddiscomfort or even pain that many patients experience when undergoing arteriography with somecontrast media are directly related to the osmolality.Other clinically significant effects that can be attributed to the osmolality problem include damage to theblood-brain barrier, renal damage and disturbance or electrolyte balance in small children.Both the viscosity of a contrast medium and its osmolality are related to the concentration of the contrastmedium, usually referred to as its strength. The strength of a contrast medium is usually given as itsconcentration in iodine, a figure after the brand name, indicating the concentration in milligrams of iodineper millilitre.With increasing strength of contrast medium, the opacifying power of the solution increases, but so, ofcourse, do the osmolality and viscosity, while tolerance tends to decline. These considerations
18 Points to Remember for RCM DimersLarge size higher viscosityLess lipophilic more inertStrength = conc. of iodine mg/mLViscosity & osmolality related to conc. of mediaOmnipaque TypeStrength mg/mLOsmolality mOsm/kg H2OViscosityUse1402901.5Video UDS , Retrograde2405103.3Retrograde3006406.1IVU, CTU
22 Toxicity of media, Contrast mediated nephrotoxicity CBD55 years of age male presented toa Urologist with recurrent UTI’s,CT shows 22 mm mid polar L kidney stoneTreatment: PCNLWhat do you need to ask/ check with a patient before performing CTUWhat are the contraindications for contrast use?What is an alternative test which can be used and why?
23 Toxicity of media Osmolality Electrical charge Lipophilicity Ionic vs. Non-ionicDimer vs. MonomerElectrical chargeLipophilicityCorrelates with the toxicity of ionic contrast media. Non-ionic contrast media very hydrophilic, properties other than lipophilicity (e.g. hydrogen bonding) are responsible for interactions with biological molecules and membranes.Protein bindingProtein receptorsMembranesMediator releaseChemotoxicityThe term 'chemotoxicity' refers to the mechanism responsible for causing the toxic effects of contrastmedia that cannot be explained by other means (e.g. osmolality, electrical charge). There are a numberof properties of contrast media that relate to this tem (e.g. hydrophilicity/lipophilicity, protein-binding,histamine release).The hydrophilicity of a contrast medium is its preference for aqueous solvents, whereas its lipophilicityrefers to its preference for fat-like (lipid) organic solvents such as the chemical solvent n-butanol. Sincen-butanol does not mix with water, it is possible to assess the relative degree of lipophilicity by addingequal parts of water and n-butanol to a small quantity of contrast medium and shaking the mixture well,after which the solvents are allowed to separate into two layers and the amount of contrast mediumdissolved in each layer is measured. The ratio of the amount in the lipid layer to the amount in theaqueous layer is termed the partition coefficient, which is therefore high for compounds of highlipophilicity and low for compounds of lower lipophilicity.Lipophilicity has been found to correlate roughly with the toxicity of ionic contrast media. Non-ioniccontrast media seem to be too hydrophilic to make differences in the partition coefficient a critical issue.In this case properties other than lipophilicity (e.g. hydrogen bonding) are responsible for interactionswith biological molecules and membranes.Protein-binding refers to the percentage of contrast medium which becomes bound to the plasmaproteins in the blood stream. The cholegraphic media discussed in the previous chapter derive theirability to be excreted and concentrated in the bile, rather than to be rapidly eliminated by the kidneys,from their very high degree of protein-binding. In line with the above hypothesis, the cholegraphic agents(which are also ionic) have a rather higher chemotoxicity than the urographic contrast media.
24 Toxicity of media Major life threatening contrast reaction is rare Non-ionic agentsSevere 0.04%Very serious reactions 0.004%Deaths 0.001%Katayama et al, Radiology 1990
25 Toxicity of media Classification of adverse reactions Idiosyncratic anaphylactoid reactionsNot dose relatedNon-idiosyncratic chemotoxic reactionsDose dependentMolecular toxicityPhysiological characteristicsMechanismsChemotoxicHyperosmolar
26 Idiosyncratic Not dose related MildIntermediateSevereMild urticariaExtensive urticariaCardiopulmonary collapseAngio-oedemaPulmonary oedemaBronchospasmLayngospasmLaryngospasmHypotension
30 Severe ADR to RCM Ionic HOCM ADR% Clinical history Non-ionic LOCM ADR% 0.18No Hx of allergy0.030.53Hx of allergy0.100.13No previous ADR to RCM0.73Previous ADR to RCM1.88Asthma0.230.49Atopy0.11Heart disease0.20Renal disease0.040.22Diabetes0.05
32 Iodinated Contrast Media: Adverse Reaction Summary, 1985–1999 Cochran et al. 2001 Mild and moderate adverse events more common with ionic contrast material than with non-ionicSevere reactions are seen equally with ionic and non-ionic contrast material but differ in type:Ionic – allergic-likeNon - ionic cario-pulmonary decompensationCONCLUSION:Mild and moderate adverse events are more common with ionic contrast material than with nonionic. Most reactions are allergic-like. Severe reactions are seen equally with ionic and nonionic contrast material but differ in type. The reactions were allergic-like in the ionic group but were predominantly attributable to cardiopulmonary decompensation in the nonionic group. Helical CT angiography may play a role in reactions.
33 Risk factors for adverse intravenous contrast media reactions Previous reaction to CM – 5 x increased riskTrue allergies – 2 xAsthma – 6 x iso-, non-ionic, 10 x – HOCMRenal problems – risk proportional to the pre-existing impairmentMetformin therapyMiscellaneous Risk Factors:Multiple myeloma and HOCM, B-blocker, sickle cell trait, pheochromocytoma and HOCM, thyroid cancer, cardiac status, anxiety, pregnancyParaproteinemias, particularly multiple myeloma, are known to predispose patients to irreversible renal failure after high-osmolality contrast media (HOCM) administration due to tubular protein precipitation and aggregation; however, there is no data predicting risk with the use of low-osmolality or iso-osmolality agents.Age, apart from the general health of the patient, is not a major consideration in patient preparation . In infants and neonates, contrast volume is an important consideration because of the low blood volume of the patient and the hypertonicity (and potentially detrimental cardiac effects) of even nonionic monomeric contrast media. Gender is not considered a major risk factor for IV contrast injection.Some retrospective case control studies suggest a statistically significant risk that the use of beta-adrenergic blocking agents lowers the threshold for and increases the severity of contrast reactions, and reduces the responsiveness of treatment of anaphylactoid reactions with epinephrine .Others have suggested that sickle cell trait or disease increases the risk to patients; however, in neither case is there evidence of any clinically significant risk, particularly after the injection of low-osmolality contrast media (LOCM) .Concomitant use of certain intra-arterial injections, such as papaverine, is believed to lead to precipitation of contrast media during arteriography. There have been reports of thrombus formation during angiography using nonionic as opposed to ionic agents. In both cases, there are in-vitro studies that suggest possible explanations.Some patients with pheochromocytoma develop an increase in serum catecholamine levels after the IV injection of HOCM. A subsequent study showed no elevation of catecholamine levels after the IV injection of nonionic contrast media . Direct injection of either type of contrast medium into the adrenal or renal artery is to be avoided, however, as this may cause a hypertensive crisis.Some patients with hyperthyroidism or other thyroid disease (especially when present in those who live in iodine-deficient areas) may develop iodine-provoked delayed hyperthyroidism. This effect may appear 4 to 6 weeks after the IV contrast administration in some of these patients. This can occur after the administration of any iodinated contrast media. It is usually self-limited.Patients with carcinoma of the thyroid deserve special consideration before the IV or oral administration of iodinated contrast media (ionic or nonionic). Uptake of I-131 in the thyroid becomes moderately decreased to about 50% at one week after iodinated contrast injection but seems to become normal within a few weeks. Therefore, if systemic radioactive iodine therapy is part of planned treatment, a pretherapy diagnostic study of the patient using an iodinated radiographic contrast medium (intravascular or oral) may be contraindicated; consultation with the ordering clinician prior to contrast administration is recommended in these patients.
34 Previous reaction to CM Exact nature of ADRAgent usedRe-examine need for RCM studyRisk/benefit ratioAlternative - non-contrast, USS, MRIIf RCM necessaryUse different RCMLOCM / iso-osmolar CMProphlactic steroids - no conclusive evidence
35 Other known allergies - Atopy and CM Increased risk – 2 xConfirm previous type of allergic reactionRe-examine need for RCM studyRisk/benefit ratioAlternative - non-contrast, USS, MRIIf RCM necessaryUse different RCMLOCM / iso-osmolar CM
36 Asthma and CM Risk severe ADR Confirm diagnosis LOCM x6, HOCM x10Confirm diagnosisDetermine if well controlledDefer if exacerbation or poor controlRx as per previous reaction
37 Metformin therapy Excreted exclusively via kidneys Can cause/exacerbate lactic acidosisNormal Cr range of eGFR – don’t stopIf out of range consult stopping for 48 hrs with referring clinicStandards for intravascular contrast agent administration to adult patients.RCR 2010
38 Risk factors for adverse intravenous contrast media reactions Use a non-ionic low or iso-osmolar agentMaintain close medical supervisionLeave the cannula in place and observe the patient for 30 minutesBe ready to treat promptly any adverse reaction and ensure that emergency drugs and equipment are availableStandards for intravascular contrast agent administration to adult patients. RCR 2010
45 Incidence 3-5% inpatients develop ARF No strict definition of CMN 25-100% increase in 24-72hr (50% seems best)Occurs in % with normal renal functionRisk factorsRenal impairment (creat>140, GFR<70ml/min)DMVolume depletionHeart failureHigh doses, repeated dosesAGENSAIDS, gentamicin, chemotherapeutic agents (eg cisplatin)Mild/mod renal impairment: 5-10% CMN+DM : 10-40%Severe renal impairment: 50%
46 Renal processing of contrast >99% excreted by kidneysHalf life (with normal function) : approx 2 hoursFreely filtered, osmotic force results in diuresisConcentration in urine x that of plasmaElimination by intestine and biliary tree may increaseBut accumulation also occurs with normal functionPlasma concentration: bi-exponential decay curveMixing of contrast into interstitial space(after 2 hours); as excreted in normal functionInhibition of Na and water reabsorption in proximal tubuleIncreased flow ratesIncreased perfusion of distal portion of loopDecrease in GFR (tubuloglomerular feedback- TGF)
47 Pathophysiology Incompletely understood Animal studies Transient increase in renal perfusionAbrupt prolonged decreaseSeems 2 main mechanismsHypoperfusionContrast and osmotic stressEndothelin, prostoglandins, NO reduced: vasoconstrictionHigh osmolar : TGF response;vasoconstriction afferent arteriolesDecrease in GFR, increase in renal vascular resistanceCannot be only mechanism as failure of vasodilatorsDirect toxicity to tubular cellsCytotoxic reactive oxygen speciesRationale for anti-oxidant (N-acetyl cysteine)Structural effects: vacuolization proximal tubules, DNA fragmentation, necrosis of thick ascending limb of L of HLong term affects unknown (glomerulosclerosis?)
48 Diagnosis CMN Ischaemic ATN Atheroembolic disease Form of ATNDifferential;Ischaemic ATNAtheroembolic diseaseGFR ideal, but difficultMild proteinuria and oliguria may occurContrast media can affect protein assaysGranular casts (muddy brown)Persistent nephrogramMost resolve in 1-2 weeks, peak creat at 3-5 daysRecent study 1826 patients coronary angiography14% CMN, mortality 7%Odds ratio for mortality of approx. 5
49 Prevention of CMN Volume expansion Isotonic saline best Solomon et al.0.45% saline 12 hrs before and after(1. + frusemide)(1. + manitol)Advantage in group 1 and 3 same.Frusemide group worseIsotonic saline bestSodium bicarbonate may be better than NaClN-acetylcysteineConflicting reportsMeta analysis shows mixed benefits600mg BD day before and day of contrastOthers suggested; ANP, dopamineNSAIDS; discontinue 24hr before and after
50 Ultrasound CM & CEUS Alters echo amplitude in ultrasonography Changes in absorption, reflection & refractionEncapsulated microbubbles <10µm diameterConfined to vascular spaceIncrease echo strength up to 300 foldCan use targeting ligands to bind to endothelial receptors (integrins & growth facor receptors) enableing microbubble complex to accumultae in area of interest.Can derive measures of tumor blood flow and blood volume by employing high mechanical index ultrasonography to destroy micro bubbles in a given region and then determining the rate at which they reappear; a process termed replenishment kineticsIncreased sensitivity of TRUSS guided prostate biopsy (38-54% vs %)Eg: Levovist, SonovistComplications very rare
51 MRI Contrast Media Gadolinium (paramagnetic agent) T1 - This tissue-specific time constant for protons, is a measure of the time taken to realign with the external magnetic field.Gadolinium decreases T1 relaxation time.Enhanced tissues and fluids appear extremely bright on T1-weighted images.Provides high sensitivity for detection of vascular tissues (e.g. tumors).Dynamic Contrast Enhanced MRI more sensitive than T2W images for prostate cancer localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593).Jackson et. al B J Radiol. 2009
52 Complications Minimal nephrotoxicity Allergy rare Nephrogenic systemic fibrosisSevere delayed fibrotic reaction of tissues (from day of exposure up to 2-3 months)Can be progressive & fatal in around 5%Starts with red, itchy painful swelling on limbs progressing to muscle weakness and contractures.Risk with GFR <60 (Highest if <30)Not reported GRF >60RCR 2007
53 Lymphotropic Superparamagnetic Nanoparticles Particles are taken up by macrophages of the reticuloendothelial system and accumulate in lymph nodes.Passive, cell-specific targeting of the iron oxide nanoparticles to lymph nodes.Differential cellular content of benign versus malignantly infiltrated nodes make this method suitable for cancer staging.Lymphotropic nanoparticle enhanced MRI, differences in benign versus malignant infiltration of lymph nodes can be visualised, which adds accuracy to standard MRI beyond criteria based solely upon the size and shape of lymph nodes.LN staging CaPSens 91% vs 35%, Spec 98% vs 90% - compared to standard MRIMukesh et al NEJM, June 2003
54 Mechanism of action of lymphotropic superparamagnetic nanoparticles Mouli, S. K. et al. (2010) Lymphotropic nanoparticle enhanced MRI for the staging of genitourinary tumors Nat. Rev. Urol. doi: /nrurol
55 PETDetects pairs of gamma rays emitted indirectly by positron (anti-particle of electron) emitting radionucleotide.Combined with CT or MRI.Carbon-11, Nitrogen-13, Fluorine-18 attached to glucose, water or a specific ligand.Commonest agent:Fluorine 18 fluorodeoxyglucose (FDG)
56 X-Rays - the unknown quantity Wilhelm Conrad Roentgen 1896Electromagnetic radiationPhoton energies between -rays and UV radiationBasis for medical useDifferential attenuation of x-rays interacting with tissuesTransmitted x-ray ‘flux’ depends on attenuation of beam along pathSuperimposed shadow of internal anatomyX-ray sensitive detector captures transmitted fractionX-rays converted to visible projection image
58 X-Ray ProductionConversion of kinetic energy attained by electrons accelerated under a potential differenceX-ray generatorProvides voltage to energise tubeX-ray tubeEnvironment = vacuumCathode - filamentSeparate filament circuitAnode - tungsten targetCollimators - define x-ray beam shape incident on patient
59 X-Ray Production Rotating Anode X-ray generator: A = Anode C = Cathode E = Envelope (Vacuum)R = RotorS = Stator windingsT = TargetW = X-ray window
60 X-Ray Production Cathode filament X-ray generator Anode Filament circuit activatedIntense heatingThermionic emission electrons releasedX-ray generatorApplies high voltage to cathode & anodeElectrons accelerated to +ve anodeAnodeHighly energised electrons interact with targetTarget = tungsten - high atomic no. & high Tm (3653 K)Interactions x-ray photon generationBremsstrahlung effect = braking radiationDeceleration of electrons due to +ve nucleusKinetic energy lost converted to UV x-ray photonsCharacteristic radiation - displaced orbital electron
61 BremsstrahlungThis is radiation given off by the electrons as they are scattered by the strong electric field near the nucleiElectron ‘braked’ by positive charge of nucleus.As brakes looses energy emitted as X-ray photon.
63 Output of typical X-ray tube f the electron has enough energy it can knock an orbital electron out of the inner electron shell of a metal atom, and as a result electrons from higher energy levels then fill up the vacancy and X-ray photons are emitted. This process produces an emission spectrum of X-rays at a few discrete frequencies, sometimes referred to as the spectral lines. The spectral lines generated depend on the target (anode) element used and thus are called characteristic lines. Usually these are transitions from upper shells into K shell (called K lines), into L shell (called L lines) and so on
64 Characteristic radiation varies with type of anode
65 X-Ray Interactions Relative transparency of body to x-rays Attenuation Removal of x-rays by absorption & scatteringAttenuation by patient volume pattern detectedMechanismsPhotoelectric absorptionCompton scatterRayleigh scatterPair productionCombine to attenuate incident photon beamRemoval of photons as beam passes through matter
66 X-Ray Detection Film - analogue Photostimulable luminescence Silver bromidePattern of X-ray beam incident on filmLots of photons opaque silver specks = blackFixation - unaffected silver bromide crystals removedPhotostimulable luminescencePhotostimulable storage phosphorAnalogue to digital conversionDigital signal converted to output e.g. videoRapid sampling of digital image matrix real time imagingPhotostimulated luminescence (PSL) is the release of stored energy within a phosphor by stimulation with visible light, to produce a luminescent signal.
67 Digital RadiographyFlat Panel Detectors (FPD) in place of X-ray film (Two types)Indirect FPD's – Amorphous silicone (a-Si) is the most frequent type of FPD sold in the medical imaging industry today. Combining a-Si detectors with a scintillator in the detector’s outer layer, which is made from Cesium Iodide, or Gadolinium Oxysulfide, converts X-ray to light. Because the X-ray energy is converted to light, the a-Si detector is considered an indirect image capture technology.Direct FPD's – Amorphous selenium (a-Se) are known as “direct” detectors because X-ray photons are converted directly to charge.
69 Principle of IVUTo obtain clinically useful information about the upper tract & related structuresAdequate dose of contrastRadiographControlNephrogramPyelocalyceal phaseSequence to assess dynamics of urine formation & propulsionAdequate distention of opacified collecting systemTomographyUse of oblique, prone, upright positionsMinimise risk to patientHow to - viva questionMetformin and - viva question
71 How to perform IVU? Bolus dose eg. 50ml Omnipaque (350mg/ml) Additional films: inspiratory/expiratory, tomography, prone, delayedTomography at 9cm means F2 located 9cm from loin skin - therefore 9cm = upper pole, 11cm lower poleProne films – contrast heavy, therefore tends to pool in kidney when supine; prone more readily identifies level of obstruction
72 Principle of Retrograde Detailed image of upper tract anatomy & pathologyNot functional - independent of renal function5 to 7ch ureteric catheter5-10 ml warm omnipaque - use minimumStrength mg/mlAvoid obscuring subtle detailsSlow injection - avoid high pressureOverdistentionRuptureBackflow - pain, obscures findings
73 Indications for Retrograde Non-visualisation of upper tract on IVUInconclusive or suspicious IVU / CTIncomplete IVUPrevious RCM adverse reactionPart of other procedurePCNLPyeloplastyURS
74 Principle of DSA Indications for angiography Investigation renovascular hypertensionTrauma - view to emboliseTransplantPre-op donorsPost – occlusion / stenosis anastamosis, acute thrombosisSuspected renal artery diseaseVascular anatomy - complex surgeryMR angiography and CT angiography superseding in certain situationsThe DSA image is produced by electronically subtracting images without contrast media from imagesafter contrast media injection.The result of this subtraction process is the visualisation of contrast filled vessels which are free from thedistraction of overlying structures.
75 Principle of DSA Digital subtraction Technique Seldinger - needle, wire, catheterAortogram locate renal artery L1/L2 screenMask imageContrast - fast infusion - 10mls in1.5 secsImages – 4 per sec for 2 sec, then 2 per sec for 6 secDigital subtractionOptimises imagesEnhances electronically the contrastMinimum contrast, dose 30-50%Removes backgroundFluoroscopy and ct and mri