MRI Contrast Media - Introduction · MRI Contrast Media - Introduction Amanda Walsh National...

MRI Contrast Media -Introduction

Amanda WalshNational Clinical SpecialistMay 2008

Covidien | June 20, 2008 | Confidential Formerly Tyco Healthcare2 |

More to it than just Gadolinium!

•Standard Gadolinium chelates

•Contrast enhanced angiography

•Liver specific agents

•Lymph node agents

•Blood pool agents

•Alternative agents

•NSF


Category of Contrast Agents

Extracellular space (ECS)– Standard agents– Increased relaxivity agents

Hepatobiliary– Taken up by hepatocytes

Reticuloendothelial System (RES)– Targeted to RES or blood pool– SPIO (superparamagnetic iron oxides) >50nm– USPIO (ultrasmall superparamagnetic iron oxides) <50nm

Blood Pool agents


Lanthanide rare earth metal

Toxic – Chelated by surrounding ion with stable complex of large organic molecules

Gd 3+ has only one un-paired electron in outer shell when chelated

Paramagnetic ion; attracted in magnetic field


MR effects of Gd agents

Visualise effect not actual contrast agent

Strongly paramagnetic Gd reduces T2 and T1 relaxation times of protons in immediate vicinity of molecule


Effects on T1 and T2

Consider BBB disrupted

Gd accumulates in tissue at 0.1 mmol L-1

Before Gd T1 = 800ms T2 = 80ms

Can calculate after GdT1Observed = 606msT2Observed = 77ms

T1 change 25%T2 change 4%


ECS agents – General Safety

Contraindications– None stated

Special warnings and precautions– Hypersensitivity reactions– Severe impairment of hepatic or renal function– Elevated levels of iron and bilirubin (clinical significance not known)– Results of serum iron levels may be reduced

Excreted unmetabolised - No interaction with body

Excretion is determined by glomerular filtrationLess than 0.1% excreted in faeces

Half-life 90 minutes


Gadovist

Gadobutrol [Gd(DO3A-butrol)] (Schering)1.0mol/L concentration

ECS agent similar to Magnevist

Relaxivity (pH 7, 40°C)

– R1 = 3.6 mM-1 L s-1

– R2 = 4.0 mM-1 L s-1


MultiHance

MultiHance Magnevist

Gd-BOPTA (Bracco)

Weak transient interaction with serum proteins

Shortened relaxation timesHigher relaxivity

– R1 = 9.7 mM-1 L s-1


Hepatobiliary-specific ECS agents

MultiHance – Bracco (Gd-BOPTA)Primovist – Schering (Gd-EOB-DTPA)

ECS paramagnetic agents with ECS properties but also actively taken up by hepatocytes.

ECS properties permit dynamic phase imaging and delayed hepatocyte specific imaging


Hepatocyte-targeted agents

Teslascan – Nycomed (Mn-DPDP)

Taken up by hepatocytes and eliminated at least in part through the biliary system

Administered by slow intravenous infusion over 1-2 mins which precludes dynamic phase imaging


T1w Pre contrast Arterial

Portal-venous 3 hours post injection

Graziolo L et al. JMJI 17:593-602 (2003)

MultiHance: FNH


Primovist

Ionic, highly water soluble Gd-chelate modified with lipophilic Ethyl-Oxy-Benzyl group (EOB). [Eovist]

T1 relaxivity 8.7 mmol -1 L s -1 in plasma at 39°C, 0.47T

2 x relaxivity of Magnevist. Equals dose of 0.025 mmol/kg

50% liver specific up take by hepatocytes (after 20 mins) lasting approx 2 hours

Dual excretion pathway, 50% biliary 50% renal (cf. Biliary imaging [MRCP + tumour])


Arterial Portal-venous

Equilibrium Hepatocyte phase (20 min)

Primovist: FNH


Resovist

Particle size range 45 – 60 nm

Small bolus injection allows T2 dynamic acquisition for phase information

Accumulation in Kupffer cells allows imaging window of 5 mins –8 hours

Not licensed in UK – prescribed on a named patient basis


Superparamagnetic Iron Oxides (SPIO)

Phagocytosed by the RES of the live

Small percentage of particles ending up in spleen and bone marrow

Particle size nm range, as large as proteins such as ferritin

Apparent size in blood is 30-100nm because of hydration of coating material and association with other particles or biological substances

Long range disturbance of B0 homogeneityT2 shortening of normal liver as accumulates in kupffer cells

Endorem - infusedResovist - bolus


Resovist

T1 VIBE post Gd Portal-Venous phase

T2* Resovist


Ultra small SPIO (USPIO)

Particle coating, size and electrical charge influence their pharmaco-dynamic properties

Larger particles target the kupffer cells of the RES system

Smaller particles circulate longer in blood, finally accumulating in macrophages of lymph nodes, liver, spleen and lungs

Inhomogeneous distribution within lymph nodes increases their susceptibility effect (T2*)

Significant reduction in MR signal intensity 24 hours after injectionDose of approx 50 µmol kg-1 is effective in detecting metastaticinvolvement of lymph nodes


Sinerem

mn

T2* Gradient Echo Pre USPIO Post USPIO


Blood Pool Agents

AngioMARK (Courtesy of EPIX Medical)

Clariscan (Courtesy of GE/Amersham)

5.0mg Fe/kg

BB22956 (Courtesy of Bracco)


Vasovist (Gd-DTPA +Gadofosveset)

Gadolinium based vascular blood pool agent

0.12 ml/kg body weight (equivalent to 0.03 mmol/kg)Reversible Albumen binding permits latent steady state high resolution imaging (up to 1 hour)

Molecular tumbling rate of:– Unbound 1010 s-1

– Albumen bound 108 s-1

Relaxivity:–– 6.6 mM-1 L s-1 for unbound– 19.0 mM-1 L s-1 in steady state


Dynamic first pass Steady state high res 3D T1


Flow Artifacts


Small Bowel Imaging

TrueFISP (Polyethylene Glycol) – 600mls 40mins prior to exam


Small Bowel Imaging

TrueFISP (WATER) – 1.4L 20mins prior to exam


Introduction to MRCM

MRCM (MR Contrast Media)– Are paramagnetic, i.e. contain a paramagnetic ion Gadolinium (Gd)– Gadolinium is toxic– Gd is encapsulated by chelates to detoxify it– Gd has a net positive magnetic susceptibility, i.e. becomes magnetic if placed in

an external magnetic field– The presence of a paramagnetic substance affects water proton in tissues, which

change the tissue contrast– Gd agents are positive T1 relaxation contrast agents– OptiMARK is one of the non-specific extracellular gadolinium agents


Gd-based MRCM

There are 7 Gd based MRCM available

– Gadopentate dimeglumine (Gd-DPTA) – Magnevist®

– Gadoterate meglumine (Gd-DOTA) – Dotarem®

– Gadodiamide (Gd-DPTA-BMA) – Omniscan®

– Gadoteriodol (Gd-HP-DO3A) – Prohance®

– Gadobenate dimeglumine (Gd-BOPTA) – Multihance®

– Gadobutrol (Gd-BT-DO3a) – Gadovist®

– Gadoverstamide (Gd-DTPA-BMEA) – Optimark®


Changing SI and Contrast T1w vs. T2w

T1-weighted Image (Short TR, Short TE)

One way to change signal intensity is by changing the pulse sequence (TR and TE)

Tissues with a short T1 are brighter

Tissues with a long T2 are brighter

T2-weighted Image (Long TR, Long TE)


Contrast Agents – T1 Images

MR contrast agents work by decreasing T1 and T2 valuesThe more an agent decreases tissue T1, the brighter that tissue will appear on a T1 weighted image. (Short TR, Short TE)Contrast agents containing paramagnetic metals (Gadolinium and Manganese) are used to shorten tissue T1


Changing SI and ContrastT1 Contrast Agent

T1-weighted Image (Pre-contrast)

Decreasing the T1 of a tissue using a Gadolinium contrast agent

Tissues with a short T1 are brighter

The meningioma takes up contrast which shortens T1 and makes it brighter than surrounding tissue

T1-weighted Image (Post-contrast)


Contrast Agents – T2 Images

MR contrast agents work by decreasing T1 and T2 valuesThe more an agent decreases tissue T2, the darker that tissue will appear on a T2 weighted image. (Long TR, Long TE)Contrast agents containing the ferromagnetic metal, Iron are used to shorten tissue T2


Changing SI and ContrastT2 Contrast Agent

T2-weighted pre-contrast Liver (Long TR, Long TE)

Decreasing the T2 of tissues (liver & spleen) using a iron contrast agent

Tissues with a long T2 are brighter

The Liver and Spleen take up contrast which shortens T2s and makes them

darker than surrounding tissue (including now bright lesion)

T2-weighted post-contrast Liver (Long TR, Long TE)

Paley, M. R., et al. (2000). "Characterization of focal hepatic lesions with ferumoxides-enhanced T2- weighted MR imaging." AJR Am J Roentgenol 175(1): 159-63.

mrh1

mrh1 This slide needs to add a citation for these images. We may want to write author and ask permission to use them.michael.hynes, 28/09/2006


Gadoversetamide

NNN

O

O

O O OO

HN

O

HN

OGd

OH2

O O


NNN

O

O

O O OO

O

O

O

OGd

OH2

2-

NNN

O

O

O O OO

HN

O

HN

OGd

OH2

NNN

O

O

O O OO

HN

O

HN

OGd

OH2

O O

N N

NN

O O

O

O

OO

OHGd

OH2

N N

NN

O O

O

O

OO

O

OGd

OH21-

NNN

O

O

O O OO

O

O

O

OGd

OH2

OP

OO

O

3-

NNN

O

O

O O OO

O

O

O

OGd

OH2

2-

N N

NN

O O

O

O

OO

OHGd

OH2

OH

OH

NNN

O

O

O O OO

O

O

O

OGd

OH2

2-

Magnevist Omniscan Optimark

Dotarem Prohance Gadovist

Primovist Multihance Vasovist

O

O


Molecular Structure

NNN

O

O

O O OO

O

O

O

OGd

OH2

2-

NNN

O

O

O O OO

HN

O

HN

OGd

OH2

O O

N N

NN

OO

O

O

OO

O

OGd

OH21-

N N

NN

OO

O

O

OO

OHGd

OH2

OH

OH

Linear, Ionic Linear, Nonionic

Cyclic, Ionic Cyclic, Nonionic


CharacteristicsMag Dota Omni Proh Multih Gado OptiM

Manufacturer Schering Guerbet GE Bracco Bracco Schering Mallinckrodt

Thermostability

Conditional Stability

22.1

17.9

25.8

n/a

16.9

14.9

23.8

17.1

22.6

18.4

21.8

n/a

16.6

15

1.5T

3 T 3.7 3.5 4.0 3.7 5.5 5.0 4.5

Yr of launch 1988 1989 1993 1994 1998 1998 2000

Linear,

Non-ionic

1110

2.0

4.7

Cyclic,

Non-ionic

1600

4.96

5.2

Linear,

ionic

1970

5.3

6.3

Cyclic,

Non-ionic

630

1.3

4.1

Linear,

Non-ionic

650

1.4

4.3

Cyclic,

ionic

1350

2.0

3.6

Linear,

ionic

1960

2.9

4.1

Molecular

structure

Osmolality

(mosm/kg H2O)

Viscosity

mPas @ 37ºC

T1 relaxitivity

(L/mmols-1)

Plasma #


What makes a difference (1)

Molecular structure:– Ionic vs. non-ionic: No real difference with slow hand injection of low doses. Non-

ionics are safer when larger dose (double or triple dose) or bolus injections are applied.

– Linear vs. cyclic: linear structures are slightly less stable compared with cyclicones. This instability is believed to be responsible for free Gd that can be hard to eliminate in renal impaired patients.

Osmolality:– The osmotic load of all Gd agents is low (due to the low amount of Gd

administered). So no real difference in clinical terms.– The osmolality becomes important in cases of extravasation.


Thermostability– It is thought that low thermostability favours the release Gd molecule in blood.– Thermostability constant of various MRCM is not a true measure of their

molecular stability; the in-vitro conditions under which these experiments are carried out are very different from in-vivo conditions.

Viscosity– MRCM have low viscosity compared to RXCM. – Except for Multihance and Gadovist, the viscosity of these agents are very similar.– The lower the viscosity, the easier the hand / power injection is to administer.

What makes a difference (2)


Injection of MRCM

Average volume: 15 ml (0.02 ml / kg of body weight)

Elimination: by the kidneys, 95% within 24hr

Side effects:– Less than 5% of cases: Headache, nausea, vomiting, rash and altered tastes– Anaphylactic reactions can occur but their incidence is very low, 1:100,000– Very rarely and at high dose: ventricular arrhythmia– Very very rarely: NSF (Nephrogenic systemic fibrosis)


Renal Safety

Although on an equimolar-basis MRCM are more nephrotoxic than iodinated CM, due to low quantity injected, Gd-based agents do not significantly affect GFR (glomerular filtration rate) or serum creatinine level

However, contrast-induced nephropathy (CIN) may occur after administration of Gdagent to patients with severe renal function impairment

“Caution” with patients with GFR of under 60 ml / min“Contra-indication” if GFR under 30 ml /min


Renal safety: MRCM vs. XRCM

From the perspective of hyperosmolar stress, the lowest available osmolality for MRCM is 630 for Prohance. In contrast Optiray 320 is 700 mOsm / kg.

With regards to viscosity, MRCM are at about 1/3 of viscosity compared with XRCM.Regarding the chemotoxicity, the number of potentially toxic molecules of MR contrast is 0.5 mol /L. for Optiray 320, which has three atoms of iodine per molecule it is 0.84 mol/l.

Therefore, at the doses that MRCM are used i.e. 0.2 mmol / kg of body weight, they have very little renal toxicity, unless for patients with kidney diseases or for children under 1 yr (kidneys still immature)


Extravasation

The effect of extravasation is usually mild and transient.

The effects are predominantly swelling and discoloration of the skin

Resolution within one week

Studies have shown that the extravasation effect of MR agents is directly linked to their osmolality (Runge et al. Investigative Radiol – 2002), i.e. Magnevist > OPTIMARK > Omniscan > Prohance > Saline.


NSF

Rare cases of severe reaction to Gd+ injection. Skin becomes very thick, and progressively other organs will be affected. Patient may die of multi-organ failure.The disease is due to the failure of kidneys to extract free circulating Gd, that could appear.Up until July 2007, more 250 cases of post-Gd NSF have been identified. Three, maybe four, agents have been involved: Omniscan, Magnevist and OptiMARK (Multihance may have been too – under investigations)Mechanism is unknown. The most believed hypothesis at this stage refers to “conditional instability” of MRCM with linear molecular structure, which is the case with these four agents.Official Guidelines: do not administer Gd to patients with severe to very severe renal impairment (Stage 4 and 5), unless absolutely necessaryWill be fully reviewed at another lecture.


Incidence

More than 300 cases have now been reported and, given the fact that reporting systems are voluntary, this must surely be an underestimate.


Conclusion-?


Optimark images

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