MR Contrast Agents

Kristan Harrington, MBA, RT (R) (MR) (ARRT)

Understanding and Embracing Change

Why Use Contrast Agents in MRI?• Improve disease detection and characterization

• Increase sensitivity to extent of disease

• Increase differentiation between normal and abnormal tissues

• Track enhancement patterns

• Demonstrate pathophysiology

• Perfusion

• Clearance

Why Use Contrast Agents in MRI?

US Agents

Generic Name Trade NameGadopentetate dimeglumine Gadoteridol Gadodiamide Gadoversetamide Gadobutrol Gadoterate meglumine

Magnevist ProHance Omniscan OptiMARK Gadavist Dotarem

Gadobenate dimeglumine MultiHance

Gadoxetate disodium Eovist

Gadofosveset trisodium Ablavar

Gd-Based Contrast Media

Chelate design -Clinical Safety

Ionic/Non-Ionic - Clinical Safety

Excretion- Renal or Biliary

Molar concentration- Volume Delivery in ml based on Dose

Relaxivity- Effectiveness based on Dose

Variable PropertiesMechanism of Action

Question....... TR (Time of Repetition)

TR

Signal(“brightness”)

TimeTR

T1-Relaxation T1-Relaxation

Signal(“brightness”)

TimeTR

Gadolinium Agent

Water Molecule

∆ 1T1

= r1 [Gd]

Relaxivity (r1) is a measure of the effect on the T1-relaxation rate

Molecular tumbling-rate slows

T1-relaxation time shortens

With contrast

Without contrast

Signal intensity vs TR

Courtesy Dr. E. Kanal

Contrast

T1=1/(R10 + r1Ct)

Brain

Intra-axial Extra-axialPre Post

Low-Grade Lesion

*p<.05

*Lesion contrast significantly higher after MultiHance administration (N = 24) Data from Essig M. Appl Radiol 2003; April (suppl):92-100

Med

ian

incr

ease

in tu

mor

si

gnal

inte

nsity

(nor

mal

ized

)

200

250

300

350

400

1 3 5 7 9

Time post-injection (min)

Intraindividual Crossover Comparison Gadopentetate vs Gadobenate: Timecourse

Gadobenate (MultiHance)Gadopentetate (Magnevist)

*p<.01

*p<.001 *p <.01 Pre Post

Low-Grade LesionTake another look…..

Increasing Signal (Contrast)

Reduce background (MTC)

Increase doseIncrease concentration(1.0 molar vs 0.5 molar)

Increase Relaxivity

Concentration

1.0 Molar 0.5 Molar

Macrocylic Agents

DosingDose is determined by amount of gadolinium

not volume of the agent

ProHance0.5 molar concentration

Standard dose: 0.1 mmol/kg

Patient weight: 80 Kg (approx 180 lbs)

80 x 0.1 = 8

Same for: - Magnevist - MultiHance - Omniscan - Optimark

8 x 2 =16 ml

DosingDose is determined by amount of gadolinium

not volume of the agent

Gadavist1.0 molar concentration

Standard dose: 0.1 mmol/kg

Patient weight: 80 Kg (approx 180 lbs)

80 x 0.1 = 8 ml

No data to support increased safety due to reduced volume but same dose

Increased concentration in the bottle does not translate to increased concentration in

tissues

Increasing Relaxivity

Gd-BOPTAStandard

Gd+3 & H20

ProteinWeak / TransientInteraction w/Proteins

2-fold increasein relaxivity (r1, r2)

Benzyloxymethylchain

effectivness

Standard Gd

Without contrast

With MultiHance

Signal intensity vs TR

Courtesy Dr. E. Kanal

Higher Signal from the lesion = more contrast

Seeing it betteris seeing it better

T1=1/(R10 + r1Ct)

0.1 mmol

Dotarem MultiHance

0.1 mmol

Colosimo C et al: Detection of intracranial metastases. A multicenter, intrapatient comparison of gadobenate dimeglumine-enhanced MRI with routinely used

contrast agents at equal dosage. Invest Radiol 36-2: 72-81, 2001

Magnevist 0.1 MultiHance 0.1

Maravilla K et al: Contrast Enhancement of Central Nervous System Lesions: Multicenter Intraindividual Crossover Comparative Study of Two MR Contrast

Agents . Radiology Volume 240: Number 2 - August 2006

Courtesy Dr. Ken Maravilla

Qualitative Measures

All Readers, All MeasuresCourtesy Dr. Ken Maravilla

Lesion Border Delineation

Extent of Lesion

Internal Morphology

Degree of Enhancement

Radiology Volume 240: Number 2 - August 2006

Quantitative Measures

Mean % Signal EnhancementCourtesy Dr. Ken Maravilla Radiology Volume 240: Number 2 - August 2006

Colosimo C, et al, Comparison of gadobenate dimeglumine (Gd-BOPTA) with gadopentetate dimeglumine (Gd-DTPA) for enhanced MR imaging of brain and spine tumors in children., Pediatr Radiol. 2005 May;35(5):501-10.

Additional References (partial list)

Essig M, et al, Enhancing lesions of the brain: intraindividual crossover comparison of contrast enhancement after gadobenate dimeglumine versus established gadoliniumcomparators., Acad Radiol. 2006 Jun;13(6):744-51.

Rowley HA, et al, Contrast-Enhanced MR Imaging of Brain Lesions: A Large-Scale Intraindividual Crossover Comparison of Gadobenate Dimeglumine versus Gadodiamide., AJNR Am J Neuroradiol. 2008 Jul 3.

Kuhn MJ, et al, Evaluation of intraaxial enhancing brain tumors on magnetic resonance imaging: intraindividual crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine for visualization and assessment, and implications for surgical intervention., J Neurosurg. 2007 Apr;106(4):557-66.

Knopp MV, Gadobenate dimeglumine-enhanced MRI of the breast: analysis of dose response and comparison with gadopentetate dimeglumine., AJR Am J Roentgenol. 2003 Sep;181(3):663-76.

Schneider G et al. Invest Radiol. 2003;38:85-94

• 41 patients with primary or secondary liver lesions

• Images evaluated for ̶ Confidence in lesion detection ̶ Lesion number, character, and diagnosis ̶ Enhancement pattern ̶ Lesion-to-liver contrast ̶ Benefit of dynamic and delayed scans

• Overall, compared with 0.1 mmol/kg Magnevist, 0.05 mmol/kg MultiHance was ̶ Equivalent for dynamic imaging ̶ Superior for delayed imaging

MRA MRA

0.1 mmol/kgMultiHance

0.2 mmol/kgMagnevist

Clinical Safety

Adverse Events Stability

Clinical Safety

Adverse Events

Gadolinium

Rare Earth Metal

Toxic to Mammals if delivered alone

Paramagnetic

http://en.wikipedia.org/wiki/Gadolinium

Adverse Events

No difference between any of the agentsavailable in the US today

Runge VM: Top Magn Reson Imaging 2001 Aug:12(4):309-13

Rare and most are mild (Idiosyncratic)

Sites should be prepared to treat a reaction just as they would with iodinated contrast media

Dillman, et. al.: AJR:189 Dec 2007Murphy, et. al.: AJR:196 Oct 1996

Runge VM: Invest Rad 2001 Vol 36, Num 2, 65-71

Shellock FG, et. al.: Invest Rad 2006 Vol 41, Num 6, 65-71Bleicher, A, Kanal, E AJR: 191, December 2008

Contrast Media Adverse Events

Then Now

Contrast Media Adverse Events

Then NowHappened every dayWe expected itWe were prepared

Ammonia capsulesBenedrylEpinepherineAtropineO2

BP cuffIV sets

Rarely happensWe don’t expect itWe are not prepared

Patients not well monitoredDrugs locked upWhere’s the key?Physician available?Just call 911

Andrew Bleicher, Emanuel KanalAJR: 191, December 2008

13 hospitals and associated imaging centers13 months and 23,553 doses of MultiHance

Data recorded by technologists included dose, related adverse reactions (type and treatment)

178 Reactions (0.76% of CE examinations)22 Required treatment (13% of reactions)8 (5%) qualified as serious

13 months and 23,553 doses of MultiHance

Bleicher, A, Kanal, E AJR: 191, December 2008

Stability

Any of a class of coordination or complex compounds consisting of a central metal atom attached to a large molecule, called a Ligand

http://www.britannica.com/EBchecked/topic/108427/chelate

Gd+3

Chelate

Linear Ionic

Linear Non-Ionic

Macrocyclic

GBCM Make-up

Non-Ionic

Non-Ionic

Non-Ionic

Ionic

Ionic

IonicFundam Clin Pharmacol. 2006 Dec;20(6):563-76

Linear Non-Ionic Least Stable Agents

Stability and Transmetalation

Desreux JF, Barthélemy PP Int J Rad Appl Instrum B. 1988;15(1):9-15

Corot C, et al. J Magn Reson Imaging. 1998 May-Jun;8(3):695-702

Laurent S, Elst LV, Muller RN Contrast Media Mol Imaging. 2006 May;1(3):128-37

Idée JM, et al. Fundam Clin Pharmacol. 2006 Dec;20(6):563-76

Puttagunta NR, Gibby WA, Puttagunta VL Invest Radiol. 1996 Oct;31(10):619-24

Gibby WA Invest Radiol. 2004 Mar;39(3):138-42

Concerns regarding stability of chelates are NOT NEW..

Sadowski, E. A. et al. Radiology 2007;0:2431062144

Broome DR et al. AJR:188, Feb 2007 586-92

NSF

Nephrogenic Systemic Fibrosis

Nephrogenic Systemic Fibrosis

Syndrome: -Skin-Joints-Eyes-Internal Organs

http://www.renal.org/eGFRcalc/GFR.pl ACR: Manual on Contrast Media – Version 7, 2010

Nephrogenic Systemic Fibrosis

Screening Questions: -Kidney Disease-Acute Kidney Trauma-Sickle Cell -Chemotherapy recently-Liver Transplant-Kidney Transplant

http://www.renal.org/eGFRcalc/GFR.pl

Glomerular Filtration Rate

Estimation Calculation Based On:-Serum Creatine Level-Age-Sex-Race

http://www.renal.org/eGFRcalc/GFR.pl

Glomerular Filtration Rate

http://www.renal.org/eGFRcalc/GFR.pl ACR: Manual on Contrast Media – Version 7, 2010

ACR: Manual on Contrast Media – Version 7, 2010 ACR: Manual on Contrast Media – Version 7, 2010

ACR: Manual on Contrast Media – Version 7, 2010

Stability Measurements

Contrast Agent

Thermodynamic Stability Constant (log Keq)

Conditional Stability

Constant at pH 7.4

ProHance 23.8 17.1

Magnevist 22.1 18.1

MultiHance 22.6 18.4

Optimark 16.6 15

Omniscan 16.9 14.9

Kirchin MA et al. Top Magn Reson Imaging. 2003;14:426-435.

Linearno molecular charge

MR contrast agents are an integral part of MR exams

Gadolinium-based agents act by altering relaxation parameters

“Enhancement” based on technique, field strength, dose, concentration and rexlaxivity of the agent

Summary

Faster imaging techniques require more efficient MR contrast agents

Adverse events associated with GBMCAs are rare but occur equally among all agents

The risk of NSF in patients with poor renal function again demonstrates differences between agents

Summary

Thank You!Kristan Harrington, MBA, RT (R) (MR) (ARRT)