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Faculty Disclosures
Vincent B. Ho, M.D., M.B.A.
MR Contrast Agents: Safety
Financ ial Disclosure:
Grant/Research Support: General Electric Healthcare
Off-Label/Investigational Drug Use:
Dr. Ho will discuss the “off-label” use of contrast agents for
cardiac MRI/MRA and various investigational contrast
agents.
Dr. Ho will be discussing investigational pulse sequences.
Vincent B. Ho, M.D., M.B.A.
Interim Chair and Professor
Department of Radiology
Uniformed Services University
Bethesda, Maryland
The opinions or assertions contained herein are the private
views of Dr. Ho and are not to be construed as official or
reflecting the views of USUHS or the Dept. of Defense.
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MR Contrast Agents
Extracellular Agents
General Classification
1) Extracellular Gd-chelate Agents
Traditional (1 st generation); also, 1M concentration
Weak Protein Interaction
Blood Pool Agents
Super
Paramagnetic
Iron Oxides
(SPIO/USPIO)
Other Macromolecular
Agents
MS-325
Ferumoxide
Gadofluorine-8
SPIO/USPIOlabeled agents
B-22956
NC100150
Gadomeritol
Gd-labeled
agents
AMI-7228
Gd-DTPA-17,24
Weak Protein
Interaction
Gd-DTPA
Gd-BOPTA
(MultiHance)
(Ablavar)
Gadodiamide
Gd-EOB-DTPA
(Omniscan)
Gadoteridol
(Primovist)
Mn-DPDP
(ProHance)
Strong Protein Interaction
Superparamagnetic Iron Oxides (SPIO) and Ultra
superparamagnetic Iron Oxides (USIO)
Other Macrom olecular Agents
(Clariscan)
(Vistarem)
(Gadomer-17)
SHU 555
Gd-DTPA-PEG
Gadobutrol (1M)
SHU555C
NMS60
(Gadovist)
(Supravist)
Gd-DOTA
AMI 227
(Dotarem)
(Sinerem)
(OptiMARK)
3) Tissue-specific MR Imaging (“Smart” or “Molecular”)
(Feridex)
(Ferumoxytol)
Gadoversetamide
Tissuespecific
Agents
Strong
Protein
Interaction
Gd-chelate
Agents
(“Traditional”)
(Magnevist)
2) Blood Pool Agents (intravascular >30 minute to hours)
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MR Contrast Agents
MP-2269
(Resovist)
Modif ied f rom Hood MN and Ho V. MRI Clinics N Am 2005
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MR Contrast Agents
Current Cardiovascular MR Practice
• Cardiac MRI:
• No contrast agent FDA approved for cardiac
imaging
• Vascular MRA:
• Gadofosveset Trisodium (Ablavar; “to evaluate
aortoiliac occlusive disease (AIOD) in adults with
known or suspected peripheral vascular disease”)
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Safety of MR Contrast Agents
• Most common agents used are traditional Gadoliniumbased contrast media (GBCM; “gadolinium-chelates”)
• Typically cleared through glom erular filtration
• Excellent safety profile
• Non-nephrotoxic at clinical doses and when given
intravenously (Prince MR et al JMRI 1991; Rofsky NM
et al Radiology 1991; Runge VM MRI 2001)
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Safety of MR Contrast Agents
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GBCM Extravasation*
• Incidence of extravasation: 0.5% (but this is site
specific… education of staff, patient population)
• Extravasation
• Serum Calcium Determinations
• Adverse Reactions
• GBCM generally less toxic to skin and
subcutaneous tissues than equal volumes of
iodinated contrast
• Low volumes are generally required for MRI
• Nephrogenic Systemic Fibrosis
(relative to iodinated contrast CT studies)… less
likely for compartment syndrom e.
• Non-ionic GBCM less likely to cause symptoms or
adverse outcom e.
*ACR Manual on Contrast Media (Version 7) 2010
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Pseudohypocalcemia*
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GBCM Adverse Reactions*
• Artifact of calorimetric assay for serum calcium measurement.
• Incidence of acute adverse event: 0.07% to 2.4% (for
• Reagent also binds gadolinium ions freeing chelate that then
binds calcium… thereby lowering detected calcium by assay
0.1-0.2 mmol/kg)
• Majority are m ild (96%, Li et al. Br J Rad 2006; e.g.
coldness/warmth/pain at injection site, headache,
nausea/vomiting, paresthesias, dizziness and itching)
• Alternative calcium testing: atomic emission spectroscopy and
ion-specific electrode method… expensive and less widely used
• Gadodiamide and gadoversetamide (but not gadopentetate
dimeglumine, gadoteridol, gadobenate dimeglumine, gadobutrol)
• “Allergic” response (rash, hives, urticaria …
bronchospasm) are uncommon (0.004%-0.7%)
• Severe, life-threatening anaphylactoid or non-allergic
• Solution: 1) postpone calcium testing; 2) use different calcium
assay; or 3) choosing a GBCM that does not interfere with
calorimetric assay
anaphylactic reactions are rare (0.001%-0.01%)… fatal
occur but are extremely rare.
*Prince MR et al. Radiology 2003; Prince MR et al. N Engl J Med 2004;
Doorenbos CJ et al N Engl J Med 2004
*ACR Manual on Contrast Media (Version 7) 2010
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GBCM Adverse Reactions*
Risk Factors:
• Previous reaction to Gd-based contrast media (8x higher)
and 2nd reaction can be much more severe (Li et al Br J Rad
2006)
• Patients with asthma and allergies to various other allergies
(rates up to 3.7%)
Solutions:
• Perform MRI without a GBCM
• Premedication with corticosteroids and antihistamines
• Use different brand of GBCM
*ACR Manual on Contrast Media (Version 7) 2010
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Nephrogenic Systemic Fibrosis
• First recognized a decade ago as a skin disorder resembling
scleromyxedema predominantly in patients with end stage
chronic kidney disease on dialysis (Cowper SE et al. Lancet
2000; Juluru K et al. RadioGraphics 2008)
• Fibrosing dermopathy of dialysis, nephrogenic fibrosing
dermopathy… nephrogenic systemic fibrosis (2005)
• Rare debilitating fibrosing condition most often affecting skin
and subcutaneous tissues but also lungs, esophagus, heart
and skeletal muscle
• Signs and symptoms develop and progress rapidly and can
cause death (visceral involvement)
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Nephrogenic Systemic Fibrosis
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Nephrogenic Systemic Fibrosis
Risk Factors:
• Chronic Kidney Disase (stage 4, eGFR 15-29 ml/min/1.73m2;
and stage 5, eGFR <15 ml/min/1.73m2) has 1-7% chance of
NSF after GBCM
• Acute Kidney Injury (up to 20%; Prince MR Radiology 2008)
• High dose or multiple dose of GBCM (e.g. Gd-enhanced
MRA)
NSF: Hardened and thickened skin, hyperpigmentation and papules
and subcutaneous nodules in extremities.
Postulated mechanism: transmetallation of agent whereby
gadolinium ion dissociates from the ligand.
From Cowper SE. Nephrogenic Fibrosing Dermopathy [ICNSFR Website]. 20012009. Available at http://www.icnsfr.org. Accessed 09/23/2011.
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Nephrogenic Systemic Fibrosis*
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Nephrogenic Systemic Fibrosis*
Highest Risk: Severe Chronic Kidney Disease (eGFR
<30ml/min/1.73m2 ) or Acute Kidney Injury
Group I. Agents associated with greatest # of NSF cases:
Gadodiamide; Gadopentetate dimeglum ine;
Gadoversetamide
Screening: ACR Subcommittee on MR Safety recommends eGFR
obtained within 6 weeks of GBCM injection in patients who might
have reduced renal function:
Group II. Agents associated with few, if any,
unconfounded cases of NSF: Gadoteridol; Gadobenate
• Prior history of renal disease (including solitary kidney, renal
neoplasm, renal transplant): eGFR within 6 weeks of GBCM
dimeglumine; Gadobutrol
Group III. Agents which have only recently appeared on
• Adult over age 60 years
the market in the US: Gadofosveset, Gadoxetic acid
• Patients with history of hypertension or diabetes mellitus
*ACR Manual on Contrast Media (Version 7) 2010
*ACR Manual on Contrast Media (Version 7) 2010
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Nephrogenic Systemic Fibrosis*
Additional ACR Recommendations for high risk patients:
• Consider alternate studies (US,CT or non-contrast MRI)
• Discussion with patient and referring clinician concerning options
and risks (risk-benefit assessment and discussion)
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Nephrogenic Systemic Fibrosis*
Patients with Chronic Kidney Disease stage 4 or 5 (eGFR <30
ml/min/1.73m2 ):
• Avoid any contrast administration (including iodinated contrast)
• No proof that any GBCM is safe but avoid Group I
• Avoid those GBCM with higher frequency of NSF (Group I)
Patients with Chronic Kidney Disease stage 3 (eGFR = 45-59
ml/min/1.73m2 )
Patients with end-stage renal disease on chronic dialysis:
• 3b (eGFR = 30-44 ml/min/1.73m2 ): evaluate eGFR trend
• Using lowest possible dose of GBCM
• Consider iodinated contrast enhanced CT
• Perform GBCM-enhanced MRI just before hemodialysis (but can
still get NSF)
*ACR Manual on Contrast Media (Version 7) 2010
• 3a (eGFR = 45-59 ml/min/1.73m2 ): low dose; non Group I GBCM
Patients with Chronic Kidney Disease stage 1 or 2 (eGFR 60-119
ml/min/1.73m2 ): All GBCM can be administered safely
*ACR Manual on Contrast Media (Version 7) 2010
Thank You