Contrast Enhanced Pediatric Cardiac

Magnetic Resonance Imaging

FDA Advisory Committee Meeting 04

Mark A Fogel, MD, FACC, FAAP

Associate Prof Cardiology/Radiology
Director of Cardiac MRI
The Childrens 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) doesnt
diffuse thru capillary membrane (blood pool agent)
Not yet FDA approved

Gad MRI in CHD

Extracellular agent
extravasation
Rapid vascular equilibration
into extravascular tissue
relaxation rate of surrounding protons:

Dose dependent
T1 - constant which signal intensity
100ms at 1.5T
T1 of blood 1200ms
1/T1 = 1/1200 ms + R1 [Gd]
T2 - rate of decay

MAJOR

Benefit-Target T1 value similar to background

but target takes up gad and background doesnt
Short TR, mod short TE, high flip angle studies

Gad MRI in CHD

Pharmacokinetics:
Free gad T 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
T 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 Local burning Temp
bili
Nausea
Fe
Cool sensation Temp
Vomiting
Hives

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

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

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

Gad MRI in CHD - Marketed Products

Similarities within the gadolinium agents:
AEs (frequency <5%, types)
Dose:
In general 0.1 mmol/kg
Packaging:
0.2 cc/kg
0.1 mmol/kg, 0.5 M solutions
Relaxivities (amount of T1, T2 relaxation given field
strength and concentration)
Cannot tell difference between gadolinium agents
when examining the images
Nephrotoxicity (none)

Gad MRI in CHD - Marketed Products

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

Gad MRI Monitoring During Study

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 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

Gad Enhanced MRI in CHD Peds

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:
Time resolved
First pass
Freeze Frame
Delayed enhancement

Gad Enhanced MRI in CHD - Anatomy

Gad Enhanced MRI in CHD Blood Flow

Gad MRI in CHD Tissue Characterization

Gad MRI for Anatomy How does it help?

R Ao Arch / L DAo / Coarct

Gad MRI for Anatomy How does it help?

Gadolinium
Enhanced

3D MIP
MPR

Gad MRI for Anatomy How does it help?

Gadolinium
Enhanced
Multiplanar
Reconstruction
Curved Cut

Gad MRI for Anatomy How does it help?

3D SSD

Gad MRI for Anatomy How does it help?

Time-Resolved
Gadolinium
Injection

Gad MRI for Anatomy Types of Patients

Great Vessels: Aorta
Coarctation of the Ao
Supravalvar Ao stenosis
Dilated Ao
Ao aneurysms/dissection
Vascular Rings

Williams Syndrome
Marfans Syndrome
Double Ao Arch

Gad MRI for Anatomy Types of Patients

Great Vessels: Aorta
Anomalies of Ao branches
Relationship of Ao to PAs
Collaterals from the Ao
Ao conduits for complex CHD
Reconstructed Aortas

Isolated LSCA
TGA after ASO
TOF/PA
Jump graft-Coa
Ao-PA anastomosis

Gad MRI for Anatomy Types of Patients

Great Vessels: PA
PA stenosis
PA dilation
PA origins
PA conduits
Reconstructed PAs

TOF
TOF-absent pulm valve
Truncus/Hemitruncus
Heterotaxy
Fontan

Gad MRI for Anatomy Types of Patients

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
Coiling
ID small/large collaterals
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
signal
Abnormal localized regions of relative

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

Images @ each slice position taken at different

part of the cardiac cycle.

Gad for Blood Flow Myocardial Perfusion

AVV

APEX

TGA S/P ASO

Regional myocardial blood flow

SPAMM

Gad for Blood Flow Lung Perfusion

Normal

LPA Stenosis

Regional lung perfusion

Qualitative

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

Normal Myocardium
contrast
injection

Infarcted Myocardium

Ischemic Myocardium
< 1 min
First-Pass

> 5 min
Delayed
Enhancement

time

Tissue Characterization Delayed Enhancement

Segmented Inversion Recovery TurboFLASH
R

ECG
Trigger

Non-selective
180o inversion

Mz Infarct

trigger
delay

23

1 2

TI

12

200 - 300 msecs

Non-selective
180o inversion

Mz Normal

...

Tissue Characterization Delayed Enhancement

Endocardial Cushion Defect After Repair

Regional myocardial scarring

Tissue Characterization Cardiac Masses

Tissue Characterization Cardiac Masses

Types of cardiac masses:
Hyperenhancement:

Non-specific:

Myxoma
Hemangioma
Angiosarcoma
Fibroma (slight/heterogeneous)
Pericardial cysts

Lymphoma (heterogenous)

No enhancement
Thrombus

Lipoma
Lipomatous
hypertrophy
Rhabdomyoma

Not published
Liposarcoma
Leiomyosarcoma

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: - dose gad as a minimum

Blood Flow:
Myocardial/Lung perfusion: 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:

Protein interaction
Inherent

relaxivity

Remains in intravascular space

More robust imaging of blood vessels - coronaries

Superparamagnetic Fe oxide agents:

Long intravascular T - coronaries

Molecular imaging:
Gadolinium tagged antibodies/agents directed against
receptors, antigens, etc

3T systems:
Improved SNR, resolution

Gad MRI The Future

Its hard to make

predictions, especially
about the future.

.Yogi Berra

Other types of MRI Contrast Agents

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