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Contrast Enhanced Pediatric Cardiac Magnetic Resonance Imaging FDA Advisory Committee Meeting ‘04

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

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. Gad MRI in CHD - Marketed Products Gadolinium based From Cardiovascular Magnetic Resonance Imaging – 2004, Martin Dunitz, Chapter 2, page 20

  9. 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)

  10. 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

  11. 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

  12. 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

  13. 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”

  14. Gad Enhanced MRI in CHD - Anatomy

  15. Gad Enhanced MRI in CHD – Blood Flow

  16. Gad MRI in CHD – Tissue Characterization

  17. Gad MRI for Anatomy – How does it help? R Ao Arch / L DAo / Coarct

  18. Gad MRI for Anatomy – How does it help? Gadolinium Enhanced • 3D MIP • MPR

  19. Gad MRI for Anatomy – How does it help? Gadolinium Enhanced Multiplanar Reconstruction • Curved Cut

  20. Gad MRI for Anatomy – How does it help? 3D SSD

  21. Gad MRI for Anatomy – How does it help? Time-Resolved Gadolinium Injection

  22. 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

  23. 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

  24. 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

  25. Gad MRI for Anatomy – Types of Patients • Pulmonary Veins • Anomalous PV connections • PV stenosis • Repaired PVs • Systemic Veins • Anomalous SV connections

  26. 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

  27. 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.

  28. Gad for Blood Flow – Myocardial Perfusion AVV APEX SPAMM TGA S/P ASO • Regional myocardial blood flow

  29. Gad for Blood Flow – Lung Perfusion Normal LPA Stenosis • Regional lung perfusion • Qualitative

  30. 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

  31. Tissue Characterization – Delayed Enhancement Normal Myocardium contrast injection Infarcted Myocardium Ischemic Myocardium > 5 min < 1 min Delayed Enhancement First-Pass time

  32. 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

  33. Tissue Characterization – Delayed Enhancement Endocardial Cushion Defect After Repair • Regional myocardial scarring

  34. Tissue Characterization – Cardiac Masses

  35. 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

  36. 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

  37. 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

  38. 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

  39. Gad MRI – The Future ….Yogi Berra “It’s hard to make predictions, especially about the future.”

  40. 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

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