NEUROIMAGING / MAGNETIC RESONANCE

Gadolinium-based contrast agents (GBCAs)

Created 11/04/2022, last revision 02/05/2023

2020 – Consensus Guidelines of the French Society of Neuroradiology (SFNR) on the use of Gadolinium-Based Contrast agents (GBCAs) and related MRI protocols in Neuroradiology

  • contrast agents facilitate the relaxation of hydrogen protons in water, thus shortening the T1 and T2 relaxation times. Shortening the T1 relaxation time leads to signal enhancement (tissue voxels become hyperintense), whereas T2 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 are enhanced after contrast agent injection   Gadolinium-based contrast agents enhance pathological lesions on MRI
    • MR angiography or MR venography (not for all sequences, mostly it can be replaced by TOF)
    • MR perfusion (can be replaced by ASL)
  • in clinical practice, mainly paramagnetic agents containing gadolinium are used – Gadolinium-Based Contrast Agents (GBCAs)
    • e.g. Magnevist (gadopentetate), Omniscan (gadodiamide), Dotarem (Gd-DOTA, gadoteric acid)
    • GBCAs are most commonly 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; unmetabolized complexes are excreted by the kidneys
  • the GBCAs are commonly very well tolerated; however, two concerns on their biological safety profile emerged – the risk of NSF and the deposition and retention of gadolinium in the brain and other organs

    • in some indications, advances in MRI technology and the development of new MRI sequences have made GBCAs injection avoidable

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 lower 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 reaction to GBCAs is low (0.04-0.3% of administrations); the risk is higher in patients with a previous hypersensitivity reaction to GBCAs, bronchial asthma, or 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 (pain, swelling, later accompanied by joint immobility)
    • internal organs involvement (muscles, lungs, liver, and myocardium)
  • no causal treatment for NSF
  • in 2006, an association between NFS and gadolinium contrast agent administration was demonstrated
    • most cases were reported after Omniscan and OptiMark administration, a small number after Magnevist
  • 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
    • 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 in small amounts in various organ
    • brain (especially in globus pallidus and dentate nuclei)
    • bones
    • liver
    • skin
  • more common after repeated examinations
  • less marked with macrocyclic agents, it occurs even in patients with normal renal functions
  • the clinical significance is unknown,  no clear evidence of health issues

Post-contrast acute kidney injury (AKI)

  • rare, if standard doses of GBCAs are used
  • AKI is associated with an increased risk of 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: 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)
  • in suspicion of the possibility of renal insufficiency, it is advisable to investigate the serum creatinine levels and determine the eGFR
    • for patients with eGFR below 30ml/min/1.73m², weigh the risk-benefit of GBCA injection
    • in patients with acute kidney injury, delaying GBCA injection until renal function recovers is recommended
    • in patients with no residual renal function (anuric), enhanced computed tomography (CT) is preferred to enhanced MRI if diagnostic performances are similar

Hemodialysis

  • GBCAs can be removed by hemodialysis (HD) or peritoneal dialysis
  • for patients under 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
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 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 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]

GBCAs and pregnancy/lactation

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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

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