4021S1_06_Fogel

Contrast Enhanced Pediatric Cardiac Magnetic Resonance

ImagingFDA Advisory Committee Meeting

‘04

Mark A Fogel, MD, FACC, FAAPAssociate Prof

Cardiology/RadiologyDirector of Cardiac MRI

The Children’s Hospital of Philadelphia

Gad MRI in CHD

• MRI: differentiates tissue by magnetic properties– Hydrogen/proton density– T1 (longitudinal/vertical/spin-lattice) recovery rates– T2(*) (horizontal/transverse/spin-spin) recovery rates– Motion/flow properties (if any)

• Gadolinium:– 7 unpaired electrons in outer shell– Paramagnetic – large magnetic moment in magnetic

field!– Toxic - Must be bound to a chelator!

• Diethylenetriamine pentaaccetic acid (DPTA)• Can be bound to large molecules (eg albumin) –

doesn’t diffuse thru capillary membrane (“blood pool agent”)

– Not yet FDA approved

Gad MRI in CHD

– T2 - rate of decay

• Benefit-Target T1 value similar to background but target takes up gad and background doesn’t

• Short TR, mod short TE, high flip angle studies

• Extracellular agent• Rapid vascular equilibration extravasation

into extravascular tissue• relaxation rate of surrounding protons:

– Dose dependent– T1 - constant which signal intensity

• T1 of blood 1200ms 100ms at 1.5T

– 1/T1 = 1/1200 ms + R1 [Gd]

MAJOR

Gad MRI in CHD

• Pharmacokinetics:

– Free gad – T½ is several weeks

– Chelation is a tradeoff:• efficiency of T1 relaxation rate• toxicity by affecting pharmacokinetics

– When chelated, 500 X in the rate of renal excretion relative to pre-chelation

– T½ is is 1.5 hours

– dissociation from chelated agent- toxicity• Theory: Competing moeity – copper and zinc

– time of gad in the body- toxicity

Gad Enhanced MRI in CHD - Safety

• Median lethal dose (Gd-DTPA): 10 mmol/kg– 60-300 x diagnostic dose

• LD50: Highest Ominiscan, lowest Magnevist

• Safety profile better than conventional iodinated contrast agents:– Goldstein et al. Radiology 1990;164:17– Niendorf HP et al. Magn Reson Med 1991;22:222– Niendorf HP et al. Invest Radiol 1991;26(suppl

1):S221

• Few reported fatalities temporally related to Gad administration - ? Association

• No known contraindications

Gad Enhanced MRI in CHD - Safety

• AEs: Very low, idiosyncratic Rx rare– Runge VM. J Magn Reson Imaging. 2000;12:205 – <5% with vast majority being minor

• Transient HA• Nausea• Vomiting

• Anaphylactoid Rx – 1 / 200,000-400,000 doses

• Safe in renal patients – even at 0.3 mmol/kg:– Renal failure, dialysis, renal A stenosis, renal

tumors– Numerous reports – small numbers

• Haustein J et al. Invest Radiol 1992;27:153• Prince MR et al. J Magn Reson Imaging

1996;6:162• Rofsky NM et al. Radiology 1991;180:85

• Local burning• Cool sensation• Hives

• Temp bili• Temp Fe

Gad Enhanced MRI in CHD – Peds

• Multiple safety studies – use in Peds w/o danger:– Marti-Bonmati L, et al. Invest Radiol. 2000;35:141

• Abnormalities in lab values or vital signs:– 51% contrast group (N=39)– 80% non-contrast group (N=20)

– Lundby B, et al. Eu J Radiol. 1996;23:190– Hanquinet S, et al. Peds Radiol. 1996;26:806.– Ball WS, et al. Radiology. 1993;186:769.– Niendorf HP, et al. Mag Resonan Med. 1991;22:229

• All 5 studies taken together:– Dose 0.1-0.2 mmol/kg– 1368 children from 15 days – 21 years of age– AEs – 2-5%, none which were serious

Gad MRI in CHD - Marketed Products

From Cardiovascular Magnetic Resonance Imaging – 2004, Martin Dunitz, Chapter 2, page 20

Gadolinium based


• Similarities within the gadolinium agents: – AEs (frequency <5%, types)– Dose:

• In general 0.1 mmol/kg• Packaging:

– 0.1 mmol/kg, 0.5 M solutions 0.2 cc/kg– Relaxivities (amount of T1, T2 relaxation given

field strength and concentration)• Cannot tell difference between gadolinium

agents when examining the images– Nephrotoxicity (none)


• Differences between selected gadolinium agents:– Magnevist has >4 more yrs on market than others

• Magnevist approved-1988• Prohance-1992, Omniscan-1993

– Ionic vs. Non-ionic• Ionic – Magnevist (-2)• Non-ionic – Prohance, Omniscan, Optimark

– Osmolality (mmol/kg of water) (plasma is 285):• Magnevist (1,960), Optimark (1110)• Omniscan (789), ProHance (630)

– Upper dosage: Omniscan/Prohance approved - 0.3 mmol/kg

• Personnel:– Cardiologist/Radiologist, sedation nurse, MRI

technician

• Monitoring equipment:– Direct visualization via video link– Direct audio feed from scanner– ECG– Pulse oximetry– In addition, during sedation:

•ETCO2

•BP monitor

Gad MRI – Monitoring During Study

Gad Enhanced MRI in CHD

• Frequency of Use:– On vast majority of cardiovascular cases

• ~ 70-90%• Out of ~400 cases in 2003-2004, will do ~330

cases with gadolinium

– Exceptions:• NLs• RV dysplasia• Strictly ventricular function (no perfusion)

• Uses:• Anatomy• Blood Flow• Tissue Characterization

• Multiple studies in CHD for anatomy (efficacy):– Examples:

• Kondo C, et al. Am J Cardiol 2001;87:420– 73 pts, PA size and anatomy, w/ and w/o BH

• Masui T, et al. J Magn Reson Imaging 2000;12:1034

– 38 pts, various types of CHD.

• Studies investigating blood flow, perfusion & tissue characterization still underway.

• Imaging:– First pass – Delayed enhancement

Gad Enhanced MRI in CHD – Peds

• Time resolved• “Freeze Frame”

Gad Enhanced MRI in CHD - Anatomy

Gad Enhanced MRI in CHD – Blood Flow

Gad MRI in CHD – Tissue Characterization

R Ao Arch / L DAo / Coarct

Gad MRI for Anatomy – How does it help?

GadoliniumEnhanced

• 3D MIP• MPR


GadoliniumEnhanced

MultiplanarReconstruction

• Curved Cut


3D SSD


Time-ResolvedGadolinium

Injection


Gad MRI for Anatomy – Types of Patients

• Great Vessels: Aorta– Coarctation of the Ao– Supravalvar Ao stenosis William’s Syndrome

– Dilated Ao Marfan’s Syndrome

– Ao aneurysms/dissection– Vascular Rings Double Ao Arch

• Great Vessels: Aorta– Anomalies of Ao branches Isolated LSCA

– Relationship of Ao to PAs TGA after ASO

– Collaterals from the Ao TOF/PA

– Ao conduits for complex CHD Jump graft-Coa

– Reconstructed Aortas Ao-PA anastomosis



• Great Vessels: PA– PA stenosis TOF

– PA dilation TOF-absent pulm valve

– PA origins Truncus/Hemitruncus

– PA conduits Heterotaxy

– Reconstructed PAs Fontan


• Pulmonary Veins– Anomalous PV connections– PV stenosis– Repaired PVs

• Systemic Veins– Anomalous SV connections

Gad MRI for Anatomy – How It Helps

• 3D nature to study– Freeze frame

• MPR• MIP• SSD

– Time Resolved• Similar to cardiac angiography in cath lab

• “Labels” blood– Can visualize 3-5 generation branching of

blood vessels– ID small/large collaterals

Coiling

Unifocalization

Gad for Blood Flow – Myocardial Perfusion

• Gadolinium injection followed by time-resolved imaging of myocardium in region of interest.– Chamber “lights up” followed by myocardium

• Normally – uniform signal intensity• Abnormal – localized regions of relative

signal

– Analyzed:• Qualitatively• Semiquantitative (time intensity curves)• Quantitative (mathematical modeling)

• Images @ each slice position taken at different part of the cardiac cycle.

• Regional myocardial blood flow

TGA S/P ASO

AVV APEX SPAMM

Gad for Blood Flow – Myocardial Perfusion

Gad for Blood Flow – Lung Perfusion

• Regional lung perfusion• Qualitative

Normal LPA Stenosis

Gad for Blood Flow – Perfusion

• Types of Patients:– Coronary artery

• ALCA• Other pts with coronary artery anomalies• HCM• Post op: TGA after ASO, Ross procedure

– Pulmonary artery/vein stenosis pts (eg TOF)

• How it helps:– ID myocardium at risk– Contribute physiologic information for

branch PA stenosis & decreased lung perfusion

Tissue Characterization – Delayed Enhancement

time

Normal Myocardiumcontrastinjection

Infarcted Myocardium

Ischemic Myocardium

First-Pass Delayed Enhancement

< 1 min > 5 min

Segmented Inversion Recovery TurboFLASH

R

ECG

Trigger

R R

Non-selective180o inversion

triggerdelay

11 22 12 12 2323

TI TI 200 - 300 msecs200 - 300 msecs

Non-selective180o inversion

. . .

Mz Infarct

Mz Normal


• Regional myocardial scarring

Endocardial Cushion Defect After Repair


Tissue Characterization – Cardiac Masses

Tissue Characterization – Cardiac Masses

• Types of cardiac masses:– Hyperenhancement:

• Myxoma• Hemangioma• Angiosarcoma• Fibroma (slight/heterogeneous)• Pericardial cysts• Lymphoma (heterogenous)

– No enhancement• Thrombus

– Non-specific:• Lipoma• Lipomatous

hypertrophy• Rhabdomyom

a

– Not published• Liposarcoma• Leiomyosarco

ma

Tissue Characterization

• Types of Patients:– Coronary artery

• ALCA• Other pts with coronary artery anomalies• HCM• Post op patients, especially after CPB and DHCA

– Myocardial tumors/masses• How it helps:

– ID scarred myocardium– Contribute to prognosis in patients with

tumors

Gad MRI – Dosing & Administration

• Anatomy of Great Vessels:– Freeze frame: single - double dose of gad

• Neimatallah MA et al. JMRI. 1999:10:758-770.

– Time resolved: ¼ - ½ dose gad as a minimum

• Blood Flow:– Myocardial/Lung perfusion: ½ dose of gad

(minimum)• Tissue Characterization:

– Single dose of gadolinium• Administration:

– Power injector– Hand

Gad MRI – The Future

• New first pass agents:– Higher relaxivity

• Blood pool agents:– Remains in intravascular space

– More robust imaging of blood vessels - coronaries • Superparamagnetic Fe oxide agents:

– Long intravascular T½ - coronaries

• Molecular imaging:– Gadolinium tagged antibodies/agents directed

against receptors, antigens, etc

• 3T systems:– Improved SNR, resolution

Protein interaction

Inherent relaxivity

“It’s hard to make predictions,

especially about the future.”

….Yogi Berra

Gad MRI – The Future

• Other gadolinium preparations:– Gadoterate Meglumine (GD DOTA, Dotarem) non-

ionic– Gadoxetic Acid Disodium (GD EOB-DTPA, Eovist)

• Manganese ion:– Mangadodipir Trisodium (MN DPDP, Telscan),

Nycomed– Non-ionic, Osm 298 mOsmol/kg– Used for liver imaging

• Ferumoxides (large superparamagnetic iron oxide):– Feridex, Endorem– Large T2 effect, less T1 effect– Liver imaging

Other types of MRI Contrast Agents

Documents

4021S1_06_Fogel