Gadolinium Deposition in the Brain: A Systematic Review of Existing Guidelines and Policy Statement Issued by the Canadian Association of Radiologists

Abstract

Emerging evidence has confirmed that, following administration of a gadolinium-based contrast agent (GBCA), very small amounts of gadolinium will deposit in the brain of humans with intact blood-brain barriers. The literature is evolving rapidly and the degree to which gadolinium will deposit for a particular GBCA or class of GBCAs remains undetermined. Several studies suggest that linear GBCAs deposit more gadolinium in the brain compared with macrocyclic GBCAs; however, our understanding of the molecular composition of deposited gadolinium is preliminary, and the clinical significance of gadolinium deposition remains unknown. To date, there is no conclusive evidence linking gadolinium deposition in the brain with any adverse patient outcome. A panel of radiologists representing the Canadian Association of Radiologists was assembled to assist the Canadian medical imaging community in making informed decisions regarding the issue of gadolinium deposition in the brain. The objectives of the working group were: 1) to review the evidence from animal and human studies; 2) to systematically review existing guidelines and position statements issued by other organizations and health agencies; and 3) to formulate an evidence-based position statement on behalf of the Canadian Association of Radiologists. Based on our appraisal of the evidence and systematic review of 9 guidelines issued by other organizations, the working group established the following consensus statement. GBCA administration should be considered carefully with respect to potential risks and benefits, and only used when required. Standard dosing should be used and repeat administrations should be avoided unless necessary. Gadolinium deposition is one of several issues to consider when prescribing a particular GBCA. Currently there is insufficient evidence to recommend one class of GBCA over another. The panel considered it inappropriate to withhold a linear GBCA if a macrocyclic agent is unavailable, if hepatobiliary phase imaging is required, or if there is a history of severe allergic reaction to a macrocyclic GBCA. Further study in this area is required, and the evidence should be monitored regularly with policy statements updated accordingly.

Analysis of retention of gadolinium by brain, bone, and blood following linear gadolinium‐based contrast agent administration in rats with experimental sepsis

“…No adverse clinical or pathological consequences of Gd deposition in the brain have thus far been confirmed . However, precautionary recommendations have been made in the use of linear GBCA by professional organizations and the Food and Drug Administration . At a recent international workshop of experts held at the National Institutes of Health, the current state of knowledge regarding Gd deposition from GBCA was reviewed and the importance of identifying populations of patients who may be vulnerable to deposition of Gd from GBCA was acknowledged …”

“…[12][13][14][15] However, precautionary recommendations have been made in the use of linear GBCA by professional organizations and the Food and Drug Administration. [16][17][18][19][20] At a recent international workshop of experts held at the National Institutes of Health, the current state of knowledge regarding Gd deposition from F I G U R E 3 Gadolinium content in bone at various intervals from 24 hours to 6 weeks following the intravenous administration of a single dose of 0.2 mmol/kg gadobenate dimeglumine (MultiHance) MRI contrast medium. Per equal weight of tissue, Gd content in the bone was much higher than brain levels.…”

“…The Food and Drug Administration has issued warnings regarding the use of GBCA in potentially vulnerable populations, such as children and those with blood–brain barrier (BBB) disruption . The Canadian government and Canadian Association of Radiologists have also issued advisory statements regarding the use of linear GBCA . However, linear GBCA remain in wide clinical use in many countries, including the United States and Canada.…”

Increased signal intensity in the unenhanced T1-weighted magnetic resonance in the brain after repeated administrations of a macrocyclic-ionic gadolinium-based contrast agent

“…Subsequent autopsy studies showing the accumulation of Gd in many tissues, including brain have prompted a review of the safety of GBCAs [16][17][18]. It is still unclear why, to what extent, and in which organs does Gd accumulate and how important is this accumulation [19]. Although brain Gd accumulation is considered not to cause asymptomatic clinical presentation, the heavy-metal family (manganese, iron, and copper) to which Gd belongs has been implicated in the development of parkinsonism by accumulating in the brain [19,20].…”

Practical recommendations for the safe use of gadolinium in magnetic resonance imaging: a Delphi expert panel study

“…Free gadolinium is highly toxic, and the amount of gadolinium accumulated in tissues is greater for agents with lower stability (7) . However, to date, there is no evidence of any damage caused by gadolinium deposition in the brain, and there is no evidence to recommend one class of GBCA over another based on this aspect (2) .…”