NEUROIMAGING / MAGNETIC RESONANCE

Gadolinium-based contrast agents (GBCAs)

David Goldemund M.D.
Updated on 12/02/2024, published on 11/04/2022

contrast agents facilitate the relaxation of hydrogen protons in water, thereby shortening the T1 and T2 relaxation times. Shortening the T1 relaxation time leads to signal enhancement (tissue voxels become hyperintense), while shortening the T2 relaxation time leads to signal attenuation ⇒ therefore, T1 sequences are used for contrast-enhanced examination
usage:
- detection of focal lesions (e.g., tumor, abscess, metastasis) – structures that are not well defined in the standard images become enhanced after contrast agent injection
- MR angiography or MR venography (contrast agent is not required for all sequences, mostly replaceable by TOF)
- MR perfusion (can be replaced by ASL in some cases)
in clinical practice, paramagnetic agents containing gadolinium are predominantly used – Gadolinium-Based Contrast Agents (GBCAs)
- e.g. Magnevist (gadopentetate), Omniscan (gadodiamide), Dotarem (Gd-DOTA, gadoteric acid)
- GBCAs are typically administered intravenously
- thanks to chelation, acute toxicity is reduced, and the elimination rate is increased ⇒ the chance of long-term toxicity is reduced
- all agents have low osmolarity and unmetabolized complexes are excreted by the kidneys
whole GBCAs are generally well tolerated, two concerns have emerged regarding their biological safety profile: the risk of Nephrogenic Systemic Fibrosis (NSF) and the deposition and retention of gadolinium in the brain and other organs

Classification of contrast agents

according to physical properties
- paramagnetic
  - gadolinium-based contrast agents (GBCAs)
  - manganese-based contrast agents
- superparamagnetic – iron oxide or iron platinum particles
according to the net charge in the solution
- ionic
- non-ionic
according to carrier ligand structure
- linear (lower risk of allergic reaction than macrocyclic agents)
- macrocyclic (lower instability, resulting in a reduced risk of NSF and gadolinium deposition)
according to the method of administration
- intravenous (neuroimaging) – ionic x non-ionic
- oral (GIT imaging)
according to distribution in the body
- extracellular
  - low molecular weight (typically in neuroimaging – GADOVIST, MAGNEVIST)
  - high molecular weight (e.g., VASOVIST)
- intracellular

→ MRI contrast agents: classification and application

linear ionic
- Gd-DTPA, gadopentetate dimeglumine (MAGNEVIST)
- Gd-BOPTA, gadobenate dimeglumine (MULTIHANCE)
- Gd-EOB-DTPA, gadoxetate disodium (PRIMOVIST, EOVIST)
linear non-ionic
- Gd-DTPA-BMA, gadodiamide (OMNISCAN)
- Gd-DTPA-BMEA, gadoversetamide (OPTIMARK)
macrocyclic ionic
- Gd-DOTA, gadoterate meglumine (DOTAREM, CLARISCAN)
macrocyclic non-ionic
- Gd-HP-DO3A, gadoteridol (PROHANCE)
- Gd-BT-DO3A, gadobutrol (GADOVIST, GADAVIST)

Adverse events

GBCAs are, in general, associated with an excellent safety profile

Allergic reaction

risk of a reaction to GBCAs is generally low (0.04-0.3% of administrations); the risk is higher in patients with a history of hypersensitivity reaction to GBCAs, bronchial asthma, or a known allergy to iodine-based contrast media
reactions can be acute or chronic

Nephrogenic systemic fibrosis (NSF)

a rare disease with a severe prognosis
clinical manifestations:
- deposition of connective tissue in the skin, which becomes rough and stiff (accompanied by pain, swelling, and later joint immobility)
- internal organs involvement (muscles, lungs, liver, and myocardium)
no causal treatment
in 2006, an association between NFS and gadolinium contrast agent administration was demonstrated
- most cases were reported after the administration of Omniscan and OptiMark, less after Magnevist use
NSF is caused by a significantly prolonged elimination of contrast agents from the body
- patients with a significant renal insufficiency (eGFR < 30ml/min/1.73m²) are particularly at risk; NSF has not yet been reported in people with normal or mildly reduced renal function
- the risk is dose-dependent (including cumulative dose)
onset: from the day of exposure for up to 2-3 months
etiopathogenesis
- instability of GBCAs associated with the release of toxic gadolinium from the detoxifying chelate molecule
- redundant chelate binds important metal ions (zinc, copper) in the body

Gadolinium deposition and retention

gadolinium deposits occur in small amounts in various organ
- brain (especially in the globus pallidus and dentate nuclei)
- bones
- liver
- skin
more common after repeated examinations
less marked with macrocyclic agents, it may occur even in patients with normal renal functions
the clinical significance is unknown and there is no clear evidence of of associated health issues

Post-contrast acute kidney injury (AKI)

rare if standard doses of GBCAs are used
AKI is associated with an increased risk of developing NSF

Overview of GBCAs with regard to adverse events

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Guidelines for the application of GBCAs

consider whether the administration of GBCAs is necessary
respect the ALARA principle
ensure adequate hydration before and after the examination
GBCAs administration may rarely provoke an acute allergic reaction, especially in persons with a history of allergy; the treatment is identical to that for allergic reactions to iodine contrast agents

use only low-risk agents (GADOVIST, DOTREM, PROHANCE) in neuroimaging [Lersy, 2020]
a standard dose is 0.1 mmol/kg body weight
- there is no indication in neuroradiology to use higher doses

eGFR assessing before MRI examination

eGFR assessment is not mandatory in patients with no suspicion of renal dysfunction (e.g., in individuals < 60 years of age with good general health and no history of renal disease)
renal function tests (serum creatinine levels, CrCl or eGFR) are recommended for individuals at higher risk of possible renal insufficiency
- for patients with eGFR < 30mL/min/1.73m², weigh the risk-benefit of GBCA injection
- in patients with acute kidney injury, it is recommended to delay GBCA injection until renal function recovers
- in patients with no residual renal function (anuric), contrast-enhanced computed tomography (CT) is preferred over enhanced MRI if diagnostic performances are similar

Hemodialysis

GBCAs can be removed by hemodialysis (HD) or peritoneal dialysis
for patients undergoing chronic HD or peritoneal dialysis, it is recommended to schedule an extra dialysis session as soon as possible after the injection to optimize gadolinium clearance
it is not recommended to perform preventive HD in patients without chronic HD

Repeated injections

do not repeat the GBCAs application in less than 4 hours [Lersy, 2020]
extend the interval to 7 days in patients with renal failure (with eGFR <30 mL/min/1.73m²)

GBCAs and acute stroke

in acute stroke/TIA, GBCAs can be used for:
- perfusion–weighted imaging (PWI) to determine PWI/DWI mismatch
  - DWI/FLAIR mismatch can be used instead
- supra–aortic (extracranial) MRA
  - non-contrast TOF should be used to evaluate intracranial vessels
standard dose of 0.1mmol/kg BW
- a double dose (0.2mmol/kg BW) is required if PWI + supra-aortic MRA are performed simultaneously!

Patients treated with metformin

no specific precautions are needed

GBCAs and pregnancy/lactation

Pregnancy

gadolinium contrast agents should be avoided (particularly during the period of organogenesis) unless essential to address a relevant clinical question
- gadolinium crosses the placenta and has a significantly prolonged elimination from the fetal circulation with a risk of deposition in fetal tissues
- animal studies indicate teratogenicity with high and repeated doses of IV gadolinium
- analyze the risk-benefit; the patient must give informed consent after a discussion of risks and benefits
- in vascular neurology, contrast administration can be avoided by using time-of-flight (TOF) sequences
- if contrast agent administration is necessary, prefer macrocyclic GBCAs with the lowest feasible dose [Copel, 2017]

Lactation

there is a limited excretion of GBCAs into breast milk (< 0.04% in the first 24 hours, and the infant absorbs < 1%) [Copel, 2017]
GBCAs should only be used when clinically necessary and non-postponable
there is no proven benefit of interrupting breastfeeding after GBCAs administration

GBCAs and renal insuficiency

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Classification of renal insufficiency

		ACR ( albumin/creatinine ratio)
		<3	3-30	> 30
mL/min/1,73m²	CKD	A1	A2	A3
> 90	G1
60–89	G2
45–59	G3a
30–44	G3b
15–29	G4
< 15	G5

→ see here

Patients with an eGFR of >60 ml/min/1.73m2 should not be classified as having CKD unless they have other markers of kidney disease

Serum creatinine levels for GFR = 30 mL/min
age (years)	serum creatinine – men (μmol/L)	serum creatinine – women (μmol/L)
20	250	200
30	235	190
40	225	175
50	210	160
60	205	155
70	200	150
80	195	145

CKD stage 1 (eGFR > 90 ml/min/1.73m2)

CKD stage 2 (eGFR 60–89 ml/min/1.73m2)

CKD stage 3 (eGFR 30–59 ml/min/1.73m2)

the risk of NSF is very low
use low-risk GBCAs

CKD stage 4 (eGFR 15–29 ml/min/1.73m2)

low-risk GBCAs only
do not exceed the standard dose (or use a low dose of 0.05 mmol/kg)) and do not repeat injection in less than 7 days

CKD stage 5 (eGFR < 15 ml/min/1.73m2)

low-risk GBCAs only
do not exceed the standard dose (or use a low dose of 0.05 mmol/kg) and repeat testing only after > 7 days
at least 9 hours of hemodialysis (3 cycles) are required to remove GBCAs from the body – schedule hemodialysis as soon as possible after the contrast-enhanced MRI scan
if possible, use contrast-enhanced CT [Lersy, 2020]