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Technology 1 Contrast Media and Contrast studies Jeremy Oates Michal Smolski Thiru Gunendran.

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Presentation on theme: "Technology 1 Contrast Media and Contrast studies Jeremy Oates Michal Smolski Thiru Gunendran."— Presentation transcript:

1 Technology 1 Contrast Media and Contrast studies Jeremy Oates Michal Smolski Thiru Gunendran

2 References Campbell Walsh FRCS Lectures Scientific basis of Urology Standards for intravascular contrast agent administration to adult patients. RCR 2010 Manual on Contrast Media. ACR 2012 Literature

3 Technology 1 Types media and basic structures Toxicity of media, Contrast mediated nephrotoxicity Principles of contrast studies (KUB, IVU, retrograde, angiography) How do X-Rays work?

4 Types media and basic structures Radiological (Iodine based, Barium sulfate, Thorium dioxide – past) MR ( Gadolinium ) Ultrasound (CEUS – Contrast –enhanced ultrasound – microbubbles )

5 Why use contrast media Where 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 CBD 55 years of age male presented to a Urologist with recurrent UTI’s CT shows 22 mm mid polar L kidney stone Treatment: PCNL What type of contrast will you use for CTU What 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-radioopaque All IV RCM Benzene ring 3 atoms of iodine at C 2,4,6 positions Classification Ionic or non-ionic High or Low osmolar Monomeric or Dimeric

8 Osmolality Dependent 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 in a contrast medium Inversely related to temperature Not related to pressure

10 Radiological Contrast Media 4 types RCM Ionic monomer= high osmolar Ionic dimer= low osmolar Non-ionic monomer= low osmolar Non-ionic dimer= iso-osmolar Distribution Hydrophilic Capillary 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 water e.g. Diatrizoate = Hypaque 50 ( 300 mg Iodine/ mL ) Urografin, Gastrografin Metrizoate = Isopaque 370 ( 370 mg Iodine/ mL ) Ionic high osmolar RCMs not used IV Retrogrades Cheap Side effects 10x non-ionic Also used to treat tape worms

12 Ionic Dimer Iodine atoms per molecule = 6 Osmotic particles per molecule = 2 Ratio = 6:2 Low osmolar = ~600 mOsm/kg water e.g. Ioxaglate = Hexabrix ( 320 mg Iodine/ mL) Toxicity - High protein binding Electrical charge

13 Non-Ionic RCM Cation replaced by non-dissociating organic chain Tri-iodinated non-ionising compounds Fewer particles per iodine atom Lower osmolality Fewer side effects More expensive

14 Non-Ionic Monomer RCM Iodine atoms = 3 Osmotic particles = 1 Ratio 3:1 Low osmolar e.g. Iohexol = Omnipaque

15 Non-Ionic Dimer RCM Iodine atoms = 6 Osmotic particles = 1 Ratio 6:1 Iso-osmolar ~ 300 mOsm eg Iodixanol = Visipaque


17 Points to Remember for RCM Radio-opacity Iodine conc. of solution No. of iodine atoms per molecule Conc. of molecules in solution Osmolality No. of particles – Ionic vs. Non-ionic Low osmolality – Fewer side effects / reactions –  pain of injection High osmolality – Greater risk reactions – Causes osmotic diuresis

18 Points to Remember for RCM Dimers Large size  higher viscosity Less lipophilic  more inert Strength = conc. of iodine mg/mL Viscosity & osmolality related to conc. of media Omnipaque Type Strength mg/mL Osmolality mOsm/kg H 2 O Viscosity Use Video UDS, Retrograde Retrograde IVU, CTU

19 MCQ Types media and basic structures



22 Toxicity of media, Contrast mediated nephrotoxicity CBD 55 years of age male presented to a Urologist with recurrent UTI’s, CT shows 22 mm mid polar L kidney stone Treatment: PCNL What do you need to ask/ check with a patient before performing CTU What are the contraindications for contrast use? What is an alternative test which can be used and why?

23 Toxicity of media Osmolality Ionic vs. Non-ionic Dimer vs. Monomer Electrical charge Lipophilicity Correlates 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 binding Protein receptors Membranes Mediator release

24 Toxicity of media Major life threatening contrast reaction is rare – Non-ionic agents – Severe 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 reactions Not dose related – Non-idiosyncratic chemotoxic reactions Dose dependent Molecular toxicity Physiological characteristics Mechanisms – Chemotoxic – Hyperosmolar

26 Idiosyncratic Not dose related MildIntermediateSevere Mild urticariaExtensive urticaria Cardiopulmonary collapse Angio-oedemaPulmonary oedema Bronchospasm LayngospasmLaryngospasm Hypotension

27 Non-idiosyncratic Dose dependent MinorIntermediateSevere Tachy/bradyOliguria/anuriaVT/VF AzotaemiaMI Myocardial ischaemia Arrhythmia Bronchospasm

28 Adverse Drug Reactions - RCM Ionic HOCMPatientsNonionic LOCM 169,284Total No.163, %Total ADR3.13% 0.22%Severe ADR0.04% (1)Deaths(1) Katayama et al, Radiology 1990

29 ADR - Symptoms Experienced Ionic HOCM % SymptomNonionic LOCM % 4.58Nausea Heat Vomiting Urticaria Flushing Venous pain Coughing Dyspnoea0.04

30 Severe ADR to RCM Ionic HOCM ADR%Clinical historyNon-ionic LOCM ADR% 0.18No Hx of allergy Hx of allergy No previous ADR to RCM Previous ADR to RCM Asthma Atopy Heart disease Renal disease Diabetes0.05

31 Iodinated Contrast Media: Adverse Reaction Summary, 1985–1999 Cochran et al Year Ionic Nonionic Agent Unknown Overall Injection Adverse Reactions Injections Adverse Reactions Injections Adverse Reactions Injections Adverse Reactions Rate (%) NA 11, , NA 10, , NA 9, , NA 8, , NA 5, , NA 6, , NA 4, , NA 6, , NA 4, , , , , , , , , , , , NA 0 NA Total 12, , , ,

32 Iodinated Contrast Media: Adverse Reaction Summary, 1985–1999 Cochran et al Mild and moderate adverse events more common with ionic contrast material than with non-ionic Severe reactions are seen equally with ionic and non-ionic contrast material but differ in type: – Ionic – allergic-like – Non - ionic cario-pulmonary decompensation

33 Risk factors for adverse intravenous contrast media reactions Previous reaction to CM – 5 x increased risk True allergies – 2 x Asthma – 6 x iso-, non-ionic, 10 x – HOCM Renal problems – risk proportional to the pre-existing impairment Metformin therapy Miscellaneous Risk Factors: Multiple myeloma and HOCM, B-blocker, sickle cell trait, pheochromocytoma and HOCM, thyroid cancer, cardiac status, anxiety, pregnancy

34 Previous reaction to CM Exact nature of ADR Agent used Re-examine need for RCM study Risk/benefit ratio Alternative - non-contrast, USS, MRI If RCM necessary Use different RCM LOCM / iso-osmolar CM Prophlactic steroids - no conclusive evidence

35 Other known allergies - Atopy and CM Increased risk – 2 x Confirm previous type of allergic reaction Re-examine need for RCM study Risk/benefit ratio Alternative - non-contrast, USS, MRI If RCM necessary Use different RCM LOCM / iso-osmolar CM

36 Asthma and CM  Risk severe ADR LOCM x6, HOCM x10 Confirm diagnosis Determine if well controlled Defer if exacerbation or poor control Rx as per previous reaction

37 Metformin therapy Excreted exclusively via kidneys Can cause/exacerbate lactic acidosis Normal Cr range of eGFR – don’t stop If out of range consult stopping for 48 hrs with referring clinic Standards 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 agent Maintain close medical supervision Leave the cannula in place and observe the patient for 30 minutes Be ready to treat promptly any adverse reaction and ensure that emergency drugs and equipment are available Standards for intravascular contrast agent administration to adult patients. RCR 2010


40 MCQ





45 Incidence 3-5% inpatients develop ARF No strict definition of CMN – % increase in 24-72hr (50% seems best) Occurs in % with normal renal function Risk factors – Renal impairment (creat>140, GFR<70ml/min) – DM – Volume depletion – Heart failure – High doses, repeated doses – AGE – NSAIDS, 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 kidneys – Half life (with normal function) : approx 2 hours – Freely filtered, osmotic force results in diuresis – Concentration in urine x that of plasma – Elimination by intestine and biliary tree may increase But accumulation also occurs with normal function – Plasma concentration: bi-exponential decay curve 1.Mixing of contrast into interstitial space 2.(after 2 hours); as excreted in normal function – Inhibition of Na and water reabsorption in proximal tubule Increased flow rates Increased perfusion of distal portion of loop Decrease in GFR (tubuloglomerular feedback- TGF)

47 Pathophysiology – Incompletely understood – Animal studies Transient increase in renal perfusion Abrupt prolonged decrease – Seems 2 main mechanisms 1.Hypoperfusion – Contrast and osmotic stress – Endothelin, prostoglandins, NO reduced: vasoconstriction – High osmolar : TGF response; » vasoconstriction afferent arterioles » Decrease in GFR, increase in renal vascular resistance – Cannot be only mechanism as failure of vasodilators 2.Direct toxicity to tubular cells – Cytotoxic reactive oxygen species – Rationale for anti-oxidant (N-acetyl cysteine) – Structural effects: vacuolization proximal tubules, DNA fragmentation, necrosis of thick ascending limb of L of H – Long term affects unknown (glomerulosclerosis?)

48 Diagnosis CMN Form of ATN Differential; – Ischaemic ATN – Atheroembolic disease GFR ideal, but difficult Mild proteinuria and oliguria may occur Contrast media can affect protein assays Granular casts (muddy brown) Persistent nephrogram Most resolve in 1-2 weeks, peak creat at 3-5 days Recent study 1826 patients coronary angiography – 14% CMN, mortality 7% – Odds ratio for mortality of approx. 5

49 Prevention of CMN Volume expansion – Solomon et al % saline 12 hrs before and after 2.(1. + frusemide) 3.(1. + manitol) Advantage in group 1 and 3 same. Frusemide group worse Isotonic saline best Sodium bicarbonate may be better than NaCl N-acetylcysteine Conflicting reports Meta analysis shows mixed benefits 600mg BD day before and day of contrast Others suggested; ANP, dopamine NSAIDS; discontinue 24hr before and after

50 Ultrasound CM & CEUS Alters echo amplitude in ultrasonography Changes in absorption, reflection & refraction Encapsulated microbubbles <10µm diameter Confined to vascular space Increase echo strength up to 300 fold Can 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 kinetics Increased sensitivity of TRUSS guided prostate biopsy (38-54% vs %) Eg: Levovist, Sonovist Complications 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 fibrosis – Severe 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 >60 RCR 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 CaP Sens 91% vs 35%, Spec 98% vs 90% - compared to standard MRI Mukesh 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 PET Detects 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 1896 Electromagnetic radiation Photon energies between  -rays and UV radiation Basis for medical use Differential attenuation of x-rays interacting with tissues Transmitted x-ray ‘flux’ depends on attenuation of beam along path Superimposed shadow of internal anatomy X-ray sensitive detector captures transmitted fraction X-rays converted to visible projection image


58 X-Ray Production Conversion of kinetic energy attained by electrons accelerated under a potential difference X-ray generator Provides voltage to energise tube X-ray tube Environment = vacuum Cathode - filament Separate filament circuit Anode - tungsten target Collimators - 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 = Rotor S = Stator windings T = Target W = X-ray window

60 X-Ray Production Cathode filament Filament circuit activated Intense heating Thermionic emission  electrons released X-ray generator Applies high voltage to cathode & anode Electrons accelerated to +ve anode Anode Highly energised electrons interact with target Target = tungsten - high atomic no. & high Tm (3653 K) Interactions  x-ray photon generation Bremsstrahlung effect = braking radiation Deceleration of electrons due to +ve nucleus Kinetic energy lost  converted to UV x-ray photons Characteristic radiation - displaced orbital electron

61 Bremsstrahlung This is radiation given off by the electrons as they are scattered by the strong electric field near the nuclei Electron ‘braked’ by positive charge of nucleus. As brakes looses energy emitted as X-ray photon.

62 Characteristic radiation

63 Output of typical X-ray tube

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 & scattering Attenuation by patient volume  pattern detected Mechanisms Photoelectric absorption Compton scatter Rayleigh scatter Pair production Combine to attenuate incident photon beam Removal of photons as beam passes through matter

66 X-Ray Detection Film - analogue Silver bromide Pattern of X-ray beam incident on film Lots of photons  opaque silver specks = black Fixation - unaffected silver bromide crystals removed Photostimulable luminescence Photostimulable storage phosphor Analogue to digital conversion Digital signal converted to output e.g. video Rapid sampling of digital image matrix  real time imaging

67 Digital Radiography Flat 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.

68 EMQ

69 Principle of IVU To obtain clinically useful information about the upper tract & related structures Adequate dose of contrast Radiograph – Control – Nephrogram – Pyelocalyceal phase – Sequence to assess dynamics of urine formation & propulsion Adequate distention of opacified collecting system Tomography Use of oblique, prone, upright positions Minimise risk to patient How to - viva question Metformin and - viva question

70 How to perform IVU?

71 Bolus dose eg. 50ml Omnipaque (350mg/ml) Additional films:inspiratory/expiratory, tomography, prone, delayed Tomography at 9cm means F2 located 9cm from loin skin - therefore 9cm = upper pole, 11cm lower pole Prone 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 & pathology Not functional - independent of renal function 5 to 7ch ureteric catheter 5-10 ml warm omnipaque - use minimum Strength mg/ml Avoid obscuring subtle details Slow injection - avoid high pressure Overdistention Rupture Backflow - pain, obscures findings

73 Indications for Retrograde Non-visualisation of upper tract on IVU Inconclusive or suspicious IVU / CT Incomplete IVU Previous RCM adverse reaction Part of other procedure PCNL Pyeloplasty URS

74 Principle of DSA Indications for angiography Investigation renovascular hypertension Trauma - view to embolise Transplant – Pre-op donors – Post – occlusion / stenosis anastamosis, acute thrombosis Suspected renal artery disease Vascular anatomy - complex surgery MR angiography and CT angiography superseding in certain situations

75 Principle of DSA Technique Seldinger - needle, wire, catheter Aortogram  locate renal artery L1/L2 screen Mask image Contrast - fast infusion - 10mls in1.5 secs Images – 4 per sec for 2 sec, then 2 per sec for 6 sec Digital subtraction Optimises images Enhances electronically the contrast Minimum contrast,  dose 30-50% Removes background

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