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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 Children’s Hospital of Philadelphia. Gad MRI in CHD.

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contrast enhanced pediatric cardiac magnetic resonance imaging fda advisory committee meeting 04

Contrast Enhanced Pediatric Cardiac Magnetic Resonance ImagingFDA Advisory Committee Meeting ‘04

Mark A Fogel, MD, FACC, FAAP

Associate Prof Cardiology/Radiology

Director of Cardiac MRI

The Children’s Hospital of Philadelphia

slide2

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
slide3

Gad MRI in CHD

  • 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]
    • 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

MAJOR

slide4

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
        • T½is is 1.5 hours
    • dissociation from chelated agent- toxicity
      • Theory: Competing moeity – copper and zinc
    • time of gad in the body- toxicity
slide5

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
slide6

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
  • Temp bili
  • Temp Fe
  • Local burning
  • Cool sensation
  • Hives
slide7

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
slide8

Gad MRI in CHD - Marketed Products

Gadolinium based

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

slide9

Gad MRI in CHD - Marketed Products

  • 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)
slide10

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
slide11

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
slide12

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
slide13

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:
    • First pass
    • Delayed enhancement
  • Time resolved
  • “Freeze Frame”
slide19

Gad MRI for Anatomy – How does it help?

Gadolinium

Enhanced

Multiplanar

Reconstruction

  • Curved Cut
slide21

Gad MRI for Anatomy – How does it help?

Time-Resolved

Gadolinium

Injection

slide22

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
slide23

Gad MRI for Anatomy – Types of Patients

  • 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
slide24

Gad MRI for Anatomy – Types of Patients

  • Great Vessels: PA
    • PA stenosis TOF
    • PA dilation TOF-absent pulm valve
    • PA origins Truncus/Hemitruncus
    • PA conduits Heterotaxy
    • Reconstructed PAs Fontan
slide25

Gad MRI for Anatomy – Types of Patients

  • Pulmonary Veins
    • Anomalous PV connections
    • PV stenosis
    • Repaired PVs
  • Systemic Veins
    • Anomalous SV connections
slide26

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

slide27

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.
slide28

Gad for Blood Flow – Myocardial Perfusion

AVV APEX SPAMM

TGA S/P ASO

  • Regional myocardial blood flow
slide29

Gad for Blood Flow – Lung Perfusion

Normal

LPA Stenosis

  • Regional lung perfusion
  • Qualitative
slide30

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
slide31

Tissue Characterization – Delayed Enhancement

Normal Myocardium

contrast

injection

Infarcted Myocardium

Ischemic Myocardium

> 5 min

< 1 min

Delayed Enhancement

First-Pass

time

slide32

Tissue Characterization – Delayed Enhancement

Segmented Inversion Recovery TurboFLASH

R

R

R

ECG

Trigger

Mz Infarct

Non-selective

180o inversion

Non-selective

180o inversion

  12 13 23

  ... | | ... 

 1 2 12 23

Mz Normal

. . .

trigger

delay

TI

200 - 300 msecs

slide33

Tissue Characterization – Delayed Enhancement

Endocardial Cushion Defect After Repair

  • Regional myocardial scarring
slide35

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
    • Rhabdomyoma
  • Not published
    • Liposarcoma
    • Leiomyosarcoma
slide36

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
slide37

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
slide38

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

slide39

Gad MRI – The Future

….Yogi Berra

“It’s hard to make predictions, especially about the future.”

slide40

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