Contrast Agents

positive contrast increases (due to high Z) absorption, negative decreases (due to low density) and double contrast uses both

need to consider solubility, viscosity (water at 20°C is 1cP [centipoises]), toxicity and osmolality (concentration hence density; normal serum 300 mosm/kg)

Iodine Compounds

At energies > KE (33.2) iodine has high attenuation properties, hence kVp should be 60-80

Ionic Water-Soluble Agents

ratio 1.5 agents – dissociate in solution to produce 2 ionic particles for each of 3 iodine atoms (in a benzene ring), hence high osmolality (~6x blood) increasing pain on injection, endothelial damage, vasodilatation, large fluid shifts, red cell deformation, osmotic diuresis)

  • sodium or methylglucamine salts; sodium generally less viscous, but both ~ twice as water but methylglucamine les irritating to vascular endothelium and end-organs
  • diatrizoate = Urografin 76% (1690 mosm/kg), Angiografin 65% (1530mosm/kg)
  • iothalamate = Conray 280 (1220 mosm/kg)
  • metrizoate = Isopaque
  • iodamide
  • amidotrizoate = Gastrografin (2150 mosm/kg). Stimulate intestinal peristalsis. Aspiration causes chemical pneumonitis (high osmolality). Larger volumes in the GIT draw water into the gut, may cause hypovolaemia, shock.

ratio 3 agents – dissociate to produce 2 ionic particles for each 6 iodine atoms

  • mixture of sodium and methylglucamine salts
  • ioxalgic acid = Hexabrix (580mosm/kg)

no significant absorption from normal GI mucosa (administered IV or arterial), not suitable for intrathecal

should terminate when 300mL of 76% diatrizoate equivalent has been injected

<5% protein bound and crosses placenta

@5min, concentration in intravascular and extravascular compartments virtually identical (except brain, neural tissues and testes with tight junctions; hence delayed neural scans helpful to show areas of blood-brain barrier breakdown in tumours/demyelinating plaques)

excretion almost entirely renal (<1% by liver, SB) with glomerular filtration and concentration but only ~½ of normal tubular resorption of water (due to osmolality)

backflow = steep rise in concentration in collecting tubules in papillary region

in normal patient 50% excreted in 1h, 83% at 3h, ~100% at 24h

in advanced renal failure 20-50% eliminated at 3d, causes opacification of GB due to liver being major alternate excretory pathway

no significant metabolism of contrast agent

Non-Ionic Agents

do not dissociate in solution, hence suitable for intrathecal use, less toxic than ratio 1.5 agents but 4-5 times the cost and less anticoagulant effect (thus meticulous flushing required). Osmolality 1-3x blood. Reduced osmolality reduces haemodynamic alteration on injection.

some hospitals use non-ionic agents exclusively (instead of ionic), others use for intrathecal, risk of pain or organ damage (peripheral arteriography, cerebral and coronary angiography), risk of ADRs (previous reactions to contrast, previous asthma/allergy/anaphylaxis, elderly, cardiac disease, renal insufficiency, IDDM, sickle cell disease, polycythaemia, phaeochromocytoma, myeloma, anxious)

ratio 3 agents are nonionic monomers

  • iopamidol (Isovue)
  • iohexol (Omnipaque, 700-800 mosm/kg)
  • ioversol (Optiray)
  • iopromide (Ultravist)

ratio 6 agents are nonionic dimers or monoacidic dimers (ioxaglate)

  • iodixanol (Visipaque, ~300mosm/kg, iso-osmolar with plasma)
  • iotrolan
  • ioxilan (Oxilan)
  • ioxaglate (Hexabrix)

excretion almost entirely renal with less osmotic dieresis

higher urinary iodine concentration for denser pyelogram, but reduced distension of collecting systems; better in renal impairment

intrathecal use

low concentration 15mL of 180mg/mL or 12mL 240mg/mL of iodine

there is penetration of neural tissue by agent (CSF and ECF in neural tissue thought to comprise one compartment)

@ 15min of lumbar injection contrast detectable in blood, absorption via arachnoid villi related to nerve roots (rather than sup sagittal sinus), hence more rapid absorption in sitting position

@24h 60-85% has been excreted

arachnoiditis – meningeal irritation from contrast and other trauma, lower with non-ionic agents (cf older oily Myodil), risk close to zero in those with no previous surgery

seizures – 9/30,000, risk increases with more contrast and those taking phenothiazides

headache, hallucinations, psychosis, aphasia, hearing loss, motor paralysis almost always temporary, lower with non-ionic agents; improved with erect/semi-erect position for 8hrs (minimise exposure of neural tissue) and hydration (reducing headache)

Intravenous Cholangiographic Agents

meglumine iotroxate (Biliscopin) has reversible binding to plasma proteins (preferentially albumin, hence limited renal excretion) to ensure biliary excretion without conjugation

slow infusion (~100mL over 30-60min) optimises biliary excretion and reduces side-effects (similar but greater frequency than other iodinated contrast media due to protein-binding characteristics)

optimal biliary opacification at 20-90min following completion of infusion

poor opacification when bilirubin levels >1.2mg/dL

Barium Sulphate

EK 37.keV so low kVp desirable but not required as usually used in high concentrations (except air-contrast techniques). ‘Thin’ suspensiosn used for single-contrast stidues, ‘thick’ viscous suspensiosn coat the mucosa for double-contrast examinations.

Aspiration rarely causes a problem. Small amounts are cleared from the lungs within hours, huge amounts may cause pneumonia.

Barium peritonitis (spill into peritoneal cavity from perforation) – deposits act as foreign bodies, inducing fibrin deposition and massive ascities. Bacterial contamination causes sepsis, shock and death in up to 50%.

Rare reports of suspected allergic reactions.

Magnetic Resonance Imaging Contrast Agents

Paramagnetic Agents

one or more particles (p,n,e) with unequal spin, larger for unpaired electrons such as transitional elements (gadolinium contains 7 unpaired electrons)

induce strong local magnetic fields that shorten T1 and T2 of adjacent protons; clinically T1w images are used post-contrast

Gadolinium-based contrast agents (GBCAs):

Trade name generic Structure T1 relaxivity at 1.5T (L/mmol-s) Notes
Dotarem gadoterate (Gd-DOTA) macrocyclic ionic 3.6-3.9
Gadovist gadobutrol (Gd-BT-DO3A) macrocyclic nonionic 4.6-5.2
ProHance gadoteridol (Gd-HP-DO3A) macrocyclic nonionic 4.1-4.4
Primovist/Eovist gadoxetate (Gd-EOB-DTPA) linear ionic 6.9-7.2 50% hepatocyte uptake
Multihance gadobenate (Gd-BOPTA) linear ionic 6.2-6.3 3-5% hepatocyte uptake
Magnevist gadopentetate (Gd-DTPA) linear ionic 4.1-4.3 oldest agent
Omniscan gadodiamide (Gd-DTPA-BMA) linear nonionic 4.3-4.5
OptiMark gadoversetamide (Gd-DTPA-BMEA) linear nonionic 4.4 discontinued by manufacturer

Macrocyclic agents have kinetic stability with gadolinium confined within the molecule (linear instability). Ionic agents have thermodynamic stability, with the negative change attracting Gd3+ to the molecule (nonionic relative instability).

Usual dose 0.1mmol/kg of 0.5mmol/mL solution (10mL adults, 0.2mL/kg children) which primarily effects T1 relaxation and excessive dose counterproductively affects T2 relaxation. T1 relaxivity reduces with higher MR field strength.

can be used as XR contrast in patients with history of ADR to iodinated agents with dose 1.5mmol/kg

little protein binding, rapidly becoming dispersed into extracellular and intravascular spaces

does not penetrate intact blood-brain barrier, some passage across placenta

most eliminated by glomerular filtration with 83% eliminated by 6h

no metabolism

1% faecally excreted

adverse reactions (1.47%) – mucosal reactions, urticaria, nausea, vomiting, local warmth and pain, headache, parasthaesia, dizziness, itching. Life-threatening reactions rare (<0.01%).

Nephrogenic systemic fibrosis (NSF) – deposition of collagen with fibrosis of skin, lungs, skeletal muscle, heart, vessels, diaphragm, oesophagus. Limited treatment. Higher incidence with repeat exposure, higher dose, severe renal failure with GFR <30mL/min, liver and renal transplant patients. No reported cases in the literature since 2009. Macrocyclic agents have the lowest risk of NSF. Linear agents have highest risk of NSF (in some regions use is only allowed as hepatobiliary agent).

Gadolinium deopsition has shown to occur (particularly with repeated doses) in the brain (dentate nuclear, globus pallidi), liver, bones. In the brain, pathway thought to be via CSF (glymphatic system) through perivascular spaces, infiltrating into brain interstitial space (?via aquaporin 4 or between glia footplates). Gad may leak into the CSF via cortical veins. A small proportion of linear agents may then dechelate and bind to proteins/macromolecules, ‘stuck’ in the interstitium. Macrocyclic agents are stable (do not dechelate), and over weeks-months will be excreted (via glymphatics). There have been no attributable symptoms/signs to gadolinium deopsition.

Caution should be used with using gadolinium agents with eGFR <30, further dose within 7days. Should only be used in pregnancy if essential. Discard of milk in lactating patients not required. “Hosever, do not avoid or defer necessary GBCA MRI scans” (FDA).

Superparamagnetic Agents

induce strong magnetisation several orders higher than paramagnetic, but no magnetisation in absence of external field

particulate ion <300 Angstrom units; larger ions are ferromagnetic (retain magnetisation due to ordering of unpaired electron spins into domains)

superparamagnetic and ferromagnetic agents destroy signal, hence produce negative contrast

accumulate in Kupffer cells in liver, destroying signal from normal liver tissue <br>

Ultrasound Contrast Agents

stabilised gas microbubbles (1-20μm radius, similar size to RBC) with a shell or gas which does not dissolve readily in blood; some small and stable enough to traverse pulmonary circulation intact

resonate when insonated with 1-10MHz pulse, causing 10-25dB enhancement 20-30s following IV administration and lasting for a few min

  • galactose-palmitic acid microparticles (Echovist, Levovist)
  • albumin microspheres (Infoson, Albunex)
  • perflutren lipid microspheres (Definity)

for heart, major vessels, perfusion in capillary bed (kidneys, liver, brain) with increased sensitivity of Doppler detection

contrast harmonic imaging – non-linear scatterers with 2f0 much higher than from tissue

agents are being developed to concentrated selectively in particular types of tissue

minimal side effects and toxicity; contraindication to Levovist is galactossaemia

Adverse Side Effects

Uncommon, from 5-12% ionic or 1-3% nonionic iodinated agents on intravascular injections. Pathophysiology of reaction is unknown ?true allergic reaction mediated by IgE, ± trigering mast cells to release histamine if severe.

  • Mild effects – common, incl nausea, vomiting, urticaria, warmth w injection, pain at site. Most do not requrie treatment. Observation fot 20-30min to ensure Sx do not progress.
  • Moderate effects – not life threatening, but usuall yrequire treatment. Severe hives, vasovagal reaction, bronchospasm, mild laryngeal oedema. Tx antihistamines for hives, salbutamol for bronchosapsm, adrenaline for laryngeal spasm, leg elevation for vasovagal reaction and hypotension.
  • Severe, potentially life-threatening – rare, almost all within 1st 20min, death in 1:130,000. Severe bronchospasm, severe laryngeal oedema, LOC, seizure, cardiotoxic effects (hypotension, dysrhythmias, acute CHF).

Increased risk of reactions in:

  • Previous reaction (excluding sensation of heat, flushing or single episode of nausea/vomiting)
  • Clear history of asthma or allergies/atopy (excluding shellfish, topical iodine)
  • Known cardiac dysfuntion incl severe CFH, severe arrhtymias, unstable angina, recent MI, pulmonary HTN
  • renal insufficiency esp diabetes
  • Sickle cell disease
  • Multiple myeloma
  • Age >55yo.

Premedication reduces, but doesn’t elimate reactions. Nonionic agent should be used. Regimes include:

  • Prednisone 50mg at 13, 7 and 1 hr prior, diphenhydramine 50mg po/IV/IM 1hr prior.
  • methylprednisolone 32mg at 12 and 2hrs prior ± diphenhydramine.

Local adverse effects include:

  • Venous thrombosis from endothelial damage.
  • Extravasation causign pain, oedema, skin slough or deeper tissue necrosis. Warm compress may increased contrast absorption, cold compress (recommended at CDHB) reduces pain. XR to look for extent. If large or distal (eg dorsum of hand) then plastics review.

Nephrotoxicity increaseed risk in multiple myeloma (or other paraproteinemias), severe diabetes, dehydration, recent aminoglycosides, anuria, hepatorenal syndrome, serum creatinine >3mg/dL, metormin use.

Contrast-induced nephropathy – acute renal failure within 48hrs of contrast administration. Cr may rise in 1st 24hrs, peak at 3-5/ then return to baseline by 10-14/7, some let w permanent renal damage. Increased riwk w diabetes and chronic renal failure. Reduced with iodixanol (Visipaque). N-acetylcysteine 600mg BD po the day before and day of contrast or 150mg/kg in 500mL NS over 30min IV prior and 50mg/kg in 500mL NS over 4hrs after may help. Patients on dialysis should have the contrast dialysed on the same day.

Metformin with contrast may precipidate fatal lactic acidosis, and should be disontinued for 48hrs after administration, restarted after renal function is normal. Should also be witheld if large doses of gadolinium use.