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[[Anaphylactoid reactions]] are rare, occurring in about 0.03–0.1%.<ref>{{cite journal |author=Murphy KJ, Brunberg JA, Cohan RH |title=Adverse reactions to gadolinium contrast media: A 1996 review of 36 cases |journal=AJR Am J Roentgenol |volume=167 |issue=4 |pages=847–49 |date=1 October 1996|pmid=8819369 |url=http://www.ajronline.org/cgi/pmidlookup?view=long&pmid=8819369 |doi=10.2214/ajr.167.4.8819369|last2=Brunberg |last3=Cohan |doi-access=free }}</ref>
[[Anaphylactoid reactions]] are rare, occurring in about 0.03–0.1%.<ref>{{cite journal |author=Murphy KJ, Brunberg JA, Cohan RH |title=Adverse reactions to gadolinium contrast media: A 1996 review of 36 cases |journal=AJR Am J Roentgenol |volume=167 |issue=4 |pages=847–49 |date=1 October 1996|pmid=8819369 |url=http://www.ajronline.org/cgi/pmidlookup?view=long&pmid=8819369 |doi=10.2214/ajr.167.4.8819369|last2=Brunberg |last3=Cohan |doi-access=free }}</ref>


As a free solubilized aqueous ion, gadolinium (III) is somewhat toxic, but was generally regarded as safe when administered as a [[chelation|chelated]] compound. In animals the free Gd (III) ion exhibits a 100–200&nbsp;mg/kg 50% lethal dose, but the [[LD50]] is increased by a factor of 100 when Gd (III) is chelated, so that its toxicity becomes comparable to iodinated X-ray contrast compounds.<ref>{{cite journal |doi=10.1038/ncpneph0660 |title=What nephrologists need to know about gadolinium |year=2007 |last1=Penfield |first1=Jeffrey G. |last2=Reilly |first2=Robert F. |journal=Nature Clinical Practice Nephrology |volume=3 |issue=12 |pages=654–68 |pmid=18033225}}</ref> The chelating carrier molecule for Gd for MRI contrast use may be classified by whether they are macro-cyclic or have linear [[Molecular geometry|geometry]] and whether they are ionic or not. Cyclical ionic Gd(III) compounds are considered the least likely to release the Gd(III) ion, and hence the safest.<ref>{{cite web |url=http://www.ismrm.org/special/EMEA2.pdf |title=Questions and Answers |publisher=International Society for Magnetic Resonance in Medicine}}</ref>
As a free solubilized aqueous ion, gadolinium (III) is reported to be highly toxic, but was generally regarded as safe enough to be administered as a [[chelation|chelated]] compound. In animals the free Gd (III) ion exhibits a 100–200&nbsp;mg/kg 50% lethal dose, but the [[LD50]] is increased by a factor of 100 when Gd (III) is chelated, so that its toxicity becomes comparable to iodinated X-ray contrast compounds.<ref>{{cite journal |doi=10.1038/ncpneph0660 |title=What nephrologists need to know about gadolinium |year=2007 |last1=Penfield |first1=Jeffrey G. |last2=Reilly |first2=Robert F. |journal=Nature Clinical Practice Nephrology |volume=3 |issue=12 |pages=654–68 |pmid=18033225}}</ref> The chelating carrier molecule for Gd for MRI contrast use may be classified by whether they are macro-cyclic or have linear [[Molecular geometry|geometry]] and whether they are ionic or not. Cyclical ionic Gd(III) compounds are considered the least likely to release the Gd(III) ion, and hence the safest.<ref>{{cite web |url=http://www.ismrm.org/special/EMEA2.pdf |title=Questions and Answers |publisher=International Society for Magnetic Resonance in Medicine}}</ref>


The use of some Gd(III) chelates in persons with kidney disease was linked to a rare but severe complication, ''nephrogenic fibrosing dermopathy'',{{old fact|2021|8|13}}<ref name="Doindtgfk">{{cite journal |doi=10.1093/ndt/gfk062 |title=Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? |year=2005 |last1=Grobner |first1=T. |journal=Nephrology Dialysis Transplantation |volume=21 |issue=4 |pages=1104–08 |pmid=16431890|doi-access=free }}</ref> also known as [[nephrogenic systemic fibrosis]] (NSF).{{old fact|2021|8|13}}<ref name="Doindtgfk" /><ref>{{Cite journal |doi=10.1681/ASN.2006060601 |title=Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging |year=2006 |last1=Marckmann |first1=P. |journal=Journal of the American Society of Nephrology |volume=17 |issue=9 |pages=2359–62 |pmid=16885403 |last2=Skov |first2=L. |last3=Rossen |first3=K. |last4=Dupont |first4=A. |last5=Damholt |first5=M.B. |last6=Heaf |first6=J.G. |last7=Thomsen |first7=H.S.|doi-access=free }}</ref><ref>{{cite journal |pmid=17318112 |year=2007 |author1=Centers for Disease Control and Prevention (CDC) |title=Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents|volume=56 |issue=7 |pages=137–41 |journal=MMWR. Morbidity and Mortality Weekly Report}}</ref> This systemic disease resembles [[scleromyxedema]] and to some extent [[scleroderma]]. It may occur months after contrast has been injected.<ref>{{cite journal |doi=10.1016/j.crad.2006.09.003 |title=Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? |year=2006 |last1=Thomsen |first1=H.S. |last2=Morcos |first2=S.K. |last3=Dawson |first3=P. |journal=Clinical Radiology |volume=61 |issue=11 |pages=905–06 |pmid=17018301}}</ref> Patients with poorer [[kidney function]] are more at risk for NSF, with dialysis patients being more at risk than patients with [[chronic kidney disease]].<ref>{{cite journal |doi=10.2214/AJR.06.1616 |title=ACR Guidance Document for Safe MR Practices: 2007 |year=2007 |last1=Kanal |first1=E. |last2=Barkovich |first2=A.J. |last3=Bell |first3=C. |last4=Borgstede |first4=J.P. |last5=Bradley |first5=W.G. |last6=Froelich |first6=J.W. |last7=Gilk |first7=T. |last8=Gimbel |first8=J.R. |last9=Gosbee |first9=J. |last10=Kuhni-Kaminski |first10=Ellisa |last11=Lester |first11=James W. |last12=Nyenhuis |first12=John |last13=Parag |first13=Yoav |last14=Schaefer |first14=Daniel J. |last15=Sebek-Scoumis |first15=Elizabeth A. |last16=Weinreb |first16=Jeffrey |last17=Zaremba |first17=Loren A. |last18=Wilcox |first18=Pamela |last19=Lucey |first19=Leonard |last20=Sass |first20=Nancy |journal=American Journal of Roentgenology |volume=188 |issue=6 |pages=1447–74 |pmid=17515363|display-authors=8 |author21=ACR Blue Ribbon Panel on MR Safety }}</ref><ref>{{cite web |url=http://www.c2i2.org/vol_vi_issue_2/Gadolinium_and_NSF%20-What_is_fact_and_what_is_theory.asp |title=Gadolinium and NSF What is fact and what is theory? |year=2008}}</ref> At present, NSF has been linked to the use of four gadolinium-containing MRI contrast agents. The [[World Health Organization]] issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents ([[Optimark]], [[Omniscan]], [[Magnevist]], [[Magnegita]], and [[Gado-MRT ratiopharm]]) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age."<ref>{{cite web |url=https://www.who.int/medicines/publications/Restricted_List_FINAL_2010.pdf |title=Pharmaceuticals: Restrictions in Use and Availability |publisher=[[World Health Organization]] |year=2010 |page=14}}</ref>
The use of some Gd(III) chelates in persons with acute or chronic kidney disease is linked to a rare but severe complication, [[nephrogenic systemic fibrosis]] (NSF).<ref name="Doindtgfk">{{cite journal|last1=Grobner|first1=T.|year=2005|title=Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?|journal=Nephrology Dialysis Transplantation|volume=21|issue=4|pages=1104–08|doi=10.1093/ndt/gfk062|pmid=16431890|doi-access=free}}</ref><ref>{{Cite journal |doi=10.1681/ASN.2006060601 |title=Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging |year=2006 |last1=Marckmann |first1=P. |journal=Journal of the American Society of Nephrology |volume=17 |issue=9 |pages=2359–62 |pmid=16885403 |last2=Skov |first2=L. |last3=Rossen |first3=K. |last4=Dupont |first4=A. |last5=Damholt |first5=M.B. |last6=Heaf |first6=J.G. |last7=Thomsen |first7=H.S.|doi-access=free }}</ref><ref>{{cite journal |pmid=17318112 |year=2007 |author1=Centers for Disease Control and Prevention (CDC) |title=Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents|volume=56 |issue=7 |pages=137–41 |journal=MMWR. Morbidity and Mortality Weekly Report}}</ref> This systemic disease resembles [[scleromyxedema]] and to some extent [[scleroderma]]. It may occur months after contrast has been injected.<ref>{{cite journal |doi=10.1016/j.crad.2006.09.003 |title=Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? |year=2006 |last1=Thomsen |first1=H.S. |last2=Morcos |first2=S.K. |last3=Dawson |first3=P. |journal=Clinical Radiology |volume=61 |issue=11 |pages=905–06 |pmid=17018301}}</ref> Patients with poorer [[kidney function]] are more at risk for NSF, with dialysis patients being more at risk than patients with [[chronic kidney disease]].<ref>{{cite journal |doi=10.2214/AJR.06.1616 |title=ACR Guidance Document for Safe MR Practices: 2007 |year=2007 |last1=Kanal |first1=E. |last2=Barkovich |first2=A.J. |last3=Bell |first3=C. |last4=Borgstede |first4=J.P. |last5=Bradley |first5=W.G. |last6=Froelich |first6=J.W. |last7=Gilk |first7=T. |last8=Gimbel |first8=J.R. |last9=Gosbee |first9=J. |last10=Kuhni-Kaminski |first10=Ellisa |last11=Lester |first11=James W. |last12=Nyenhuis |first12=John |last13=Parag |first13=Yoav |last14=Schaefer |first14=Daniel J. |last15=Sebek-Scoumis |first15=Elizabeth A. |last16=Weinreb |first16=Jeffrey |last17=Zaremba |first17=Loren A. |last18=Wilcox |first18=Pamela |last19=Lucey |first19=Leonard |last20=Sass |first20=Nancy |journal=American Journal of Roentgenology |volume=188 |issue=6 |pages=1447–74 |pmid=17515363|display-authors=8 |author21=ACR Blue Ribbon Panel on MR Safety }}</ref><ref>{{cite web |url=http://www.c2i2.org/vol_vi_issue_2/Gadolinium_and_NSF%20-What_is_fact_and_what_is_theory.asp |title=Gadolinium and NSF What is fact and what is theory? |year=2008}}</ref> NSF has been linked to the use of both linear and macrocyclic<ref>{{Cite journal|last=Lim|first=Yu Jeong|last2=Bang|first2=Jisun|last3=Ko|first3=Youngsun|last4=Seo|first4=Hyun Min|last5=Jung|first5=Woon Yong|last6=Yi|first6=Joo Hark|last7=Han|first7=Sang Woong|last8=Yu|first8=Mi Yeon|date=2020-09-07|title=Late Onset Nephrogenic Systemic Fibrosis in a Patient with Stage 3 Chronic Kidney Disease: a Case Report|url=https://pubmed.ncbi.nlm.nih.gov/32893521/|journal=Journal of Korean Medical Science|volume=35|issue=35|pages=e293|doi=10.3346/jkms.2020.35.e293|issn=1598-6357|pmc=7476800|pmid=32893521}}</ref><ref>{{Cite journal|last=Elmholdt|first=Tina Rask|last2=Jørgensen|first2=Bettina|last3=Ramsing|first3=Mette|last4=Pedersen|first4=Michael|last5=Olesen|first5=Anne Braae|date=2010-6|title=Two cases of nephrogenic systemic fibrosis after exposure to the macrocyclic compound gadobutrol|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477958/|journal=NDT Plus|volume=3|issue=3|pages=285–287|doi=10.1093/ndtplus/sfq028|issn=1753-0784|pmc=5477958|pmid=28657062}}</ref> gadolinium-containing MRI contrast agents but is more frequent with linear. The [[World Health Organization]] issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents ([[Optimark]], [[Omniscan]], [[Magnevist]], [[Magnegita]], and [[Gado-MRT ratiopharm]]) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age."<ref>{{cite web |url=https://www.who.int/medicines/publications/Restricted_List_FINAL_2010.pdf |title=Pharmaceuticals: Restrictions in Use and Availability |publisher=[[World Health Organization]] |year=2010 |page=14}}</ref>


Gadolinium has been found to remain in the brain, hearth muscle, kidney, liver and others organs after one or more injection of a linear or macrocyclic GBCA<ref>{{Cite journal|last=Stanescu|first=A. Luana|last2=Shaw|first2=Dennis W.|last3=Murata|first3=Nozomu|last4=Murata|first4=Kiyoko|last5=Rutledge|first5=Joe C.|last6=Maloney|first6=Ezekiel|last7=Maravilla|first7=Kenneth R.|date=2020-03|title=Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation|url=https://pubmed.ncbi.nlm.nih.gov/31989188/|journal=Pediatric Radiology|volume=50|issue=3|pages=388–396|doi=10.1007/s00247-019-04535-w|issn=1432-1998|pmid=31989188}}</ref><ref>{{Cite journal|last=Bussi|first=Simona|last2=Coppo|first2=Alessandra|last3=Celeste|first3=Roberto|last4=Fanizzi|first4=Antonello|last5=Fringuello Mingo|first5=Alberto|last6=Ferraris|first6=Andrea|last7=Botteron|first7=Catherine|last8=Kirchin|first8=Miles A.|last9=Tedoldi|first9=Fabio|last10=Maisano|first10=Federico|date=2020-02-04|title=Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000570/|journal=Insights into Imaging|volume=11|doi=10.1186/s13244-019-0824-5|issn=1869-4101|pmc=7000570|pmid=32020385}}</ref>, even after a prolonged period of time but the amount differs with the presence of kidney injury at the moment of injection, the structure of the ligand and the dose administered.
Gadolinium has been found to remain in the body after multiple MRIs, even after a prolonged period of time. Although gadolinium contrast agents have not been found to be harmful to the body, it is unknown whether these deposits can lead to adverse health effects. The FDA has asked doctors to limit the use of Gadolinium contrast agents to times when necessary information is made available through its use.<ref>https://www.fda.gov/Drugs/DrugSafety/ucm455386.htm</ref>


In vitro studies have found GBCAs to be [[Cytotoxicity|neurotoxic]],<ref name=":0">{{Cite journal|last=Bower|first=Danielle V.|last2=Richter|first2=Johannes K.|last3=von Tengg-Kobligk|first3=Hendrik|last4=Heverhagen|first4=Johannes T.|last5=Runge|first5=Val M.|date=2019-08|title=Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent|url=https://pubmed.ncbi.nlm.nih.gov/31265439/|journal=Investigative Radiology|volume=54|issue=8|pages=453–463|doi=10.1097/RLI.0000000000000567|issn=1536-0210|pmid=31265439}}</ref> and a study found signal intensity in the [[dentate nucleus]] of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency<ref>{{Cite journal|last=Forslin|first=Y.|last2=Martola|first2=J.|last3=Bergendal|first3=Å.|last4=Fredrikson|first4=S.|last5=Wiberg|first5=M.K.|last6=Granberg|first6=T.|date=2019-8|title=Gadolinium Retention in the Brain: An MRI Relaxometry Study of Linear and Macrocyclic Gadolinium-Based Contrast Agents in Multiple Sclerosis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048491/|journal=AJNR: American Journal of Neuroradiology|volume=40|issue=8|pages=1265–1273|doi=10.3174/ajnr.A6112|issn=0195-6108|pmc=7048491|pmid=31248867}}</ref>. [[Confusion]] is often reported as a possible clinical symptoms.<ref name=":0" /> The FDA has asked doctors to limit the use of Gadolinium contrast agents to times when necessary information is made available through its use.<ref>https://www.fda.gov/Drugs/DrugSafety/ucm455386.htm</ref>
⚫
Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, has led to a safety review by the European Medicines Agency (EMA and The Committee for Medicinal Products for Human Use (CHMP)).{{cn|date=August 2021}} Although not directly linked to adverse health effects in patients with normal kidney function, the possible risk of using intravenous linear chelated media, in which the gadolinium is shown to have a lower binding affinity, has led to a change in the market authorisation for all linear chelated gadolinium-based media.{{cn|date=August 2021}}

⚫
Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, has led to a safety review by the European Medicines Agency and The Committee for Medicinal Products for Human Use (CHMP)).{{cn|date=August 2021}} Although not directly linked to adverse health effects in patients with normal kidney function, the possible risk of using intravenous linear chelated media, in which the gadolinium is shown to have a lower binding affinity, has led th EMA to suspend the use of linear chelated gadolinium-based media.{{cn|date=August 2021}}


In the United States, the research has led the FDA (Food and Drug Administration) to revise its class warnings for all gadolinium-based contrast media. It is advised that the use of gadolinium-based media is based on careful consideration of the retention characteristics of the preferred medium. Extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.<ref>{{cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/UCM589442.pdf|title=FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings|date=2017-12-19|website=United States [[Food and Drug Administration]]}} {{PD-notice}}</ref>
In the United States, the research has led the FDA (Food and Drug Administration) to revise its class warnings for all gadolinium-based contrast media. It is advised that the use of gadolinium-based media is based on careful consideration of the retention characteristics of the preferred medium. Extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.<ref>{{cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/UCM589442.pdf|title=FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings|date=2017-12-19|website=United States [[Food and Drug Administration]]}} {{PD-notice}}</ref>
Line 92: Line 94:


In December 2017, the FDA announced in a drug safety communication it is requiring these new warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents.<ref>{{cite web|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body|title=fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body; requires new class warnings|date=2018-05-16|website=USA [[FDA]]}}</ref>
In December 2017, the FDA announced in a drug safety communication it is requiring these new warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents.<ref>{{cite web|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body|title=fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body; requires new class warnings|date=2018-05-16|website=USA [[FDA]]}}</ref>

The french [[:fr:Haute_Autorité_de_santé|health authority]] recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it.<ref>{{Cite web|title=GADOLINIUM PIC RI REEVAL RAPPORT ANNEXE|url=https://www.has-sante.fr/plugins/ModuleXitiKLEE/types/FileDocument/doXiti.jsp?id=c_2870309|access-date=2021-08-19|website=www.has-sante.fr}}</ref>


===Iron oxide: superparamagnetic===
===Iron oxide: superparamagnetic===

Revision as of 17:41, 19 August 2021

A bottle of Omniscan contrast agent

MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI).[1] The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten the relaxation times of nuclei within body tissues following oral or intravenous administration.

In MRI scanners, sections of the body are exposed to a very strong magnetic field causing primarily the hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intense radiofrequency pulse is applied that tips the magnetization generated by the hydrogen nuclei in the direction of the receiver coil where the spin polarization can be detected. Random molecular rotational oscillations matching the resonance frequency of the nuclear spins provide the "relaxation" mechanisms that bring the net magnetization back to its equilibrium position in alignment with the applied magnetic field. The magnitude of the spin polarization detected by the receiver is used to form the MR image but decays with a characteristic time constant known as the T1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons thereby altering the contrast in the image.

Types

Most clinically used MRI contrast agents work by shortening the T1 relaxation time of protons inside tissues via interactions with the nearby contrast agent. Thermally driven motion of the strongly paramagnetic metal ions in the contrast agent generate the oscillating magnetic fields that provide the relaxation mechanisms that enhance the rate of decay of the induced polarization. The systematic sampling of this polarization over the spatial region of the tissue being examined forms the basis for construction of the image.

MRI contrast agents may be administered by injection into the blood stream or orally, depending on the subject of interest. Oral administration is well suited to G.I. tract scans, while intravascular administration proves more useful for most other scans. A variety of agents of both types enhances scans routinely.

MRI contrast agents can be classified in many ways,[2] including by their:

  1. chemical composition
  2. administration route
  3. magnetic properties
  4. effect on the image
  5. presence and nature of metal atoms
  6. biodistribution and applications:
    1. Extracellular fluid agents (also known as intravenous contrast agents)
    2. Blood pool agents (also known as intravascular contrast agents)
    3. Organ specific agents (i.e. gastrointestinal contrast agents and hepatobiliary contrast agents)
    4. Active targeting/cell labeling agents (i.e. tumor-specific agents)
    5. Responsive (also known as smart or bioactivated) agents
    6. pH-sensitive agents

Gadolinium(III)

For other uses of the abbreviation "GAD" in medicine, see Gad.
Effect of contrast agent on images: Defect of the blood–brain barrier after stroke shown in MRI. T1-weighted images, left image without, right image with contrast medium administration

Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels in MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier.[3][4] For large vessels such as the aorta and its branches, the gadolinium(III) dose can be as low as 0.1 mmol per kg body mass. Higher concentrations are often used for finer vasculature.[5] Gd(III) chelates do not pass the intact blood–brain barrier because they are hydrophilic. Thus, these are useful in enhancing lesions and tumors where blood-brain barrier is compromised and the Gd(III) leaks out. In the rest of the body, the Gd(III) initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys.

Types by body compartment

Gadolinium(III) contrast agents can be categorized into:[citation needed]

Extracellular fluid agents
Blood pool agents
Hepatobiliary (liver) agents
  • gadoxetic acid (Primovist [EU] / Eovist [US]) is used as a hepatobiliary agent as 50% is taken up and excreted by the liver and 50% by the kidneys.

Agents approved for human use

The following gadolinium chelated contrast agents have been approved for human use by European Medicines Agency (EMA)[6] and/or the U.S. Food and Drug Administration (FDA):[7]

Safety of gadolinium contrast agents

Main article: Nephrogenic systemic fibrosis

Anaphylactoid reactions are rare, occurring in about 0.03–0.1%.[8]

As a free solubilized aqueous ion, gadolinium (III) is reported to be highly toxic, but was generally regarded as safe enough to be administered as a chelated compound. In animals the free Gd (III) ion exhibits a 100–200 mg/kg 50% lethal dose, but the LD50 is increased by a factor of 100 when Gd (III) is chelated, so that its toxicity becomes comparable to iodinated X-ray contrast compounds.[9] The chelating carrier molecule for Gd for MRI contrast use may be classified by whether they are macro-cyclic or have linear geometry and whether they are ionic or not. Cyclical ionic Gd(III) compounds are considered the least likely to release the Gd(III) ion, and hence the safest.[10]

The use of some Gd(III) chelates in persons with acute or chronic kidney disease is linked to a rare but severe complication, nephrogenic systemic fibrosis (NSF).[11][12][13] This systemic disease resembles scleromyxedema and to some extent scleroderma. It may occur months after contrast has been injected.[14] Patients with poorer kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with chronic kidney disease.[15][16] NSF has been linked to the use of both linear and macrocyclic[17][18] gadolinium-containing MRI contrast agents but is more frequent with linear. The World Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (Optimark, Omniscan, Magnevist, Magnegita, and Gado-MRT ratiopharm) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age."[19]

Gadolinium has been found to remain in the brain, hearth muscle, kidney, liver and others organs after one or more injection of a linear or macrocyclic GBCA[20][21], even after a prolonged period of time but the amount differs with the presence of kidney injury at the moment of injection, the structure of the ligand and the dose administered.

In vitro studies have found GBCAs to be neurotoxic,[22] and a study found signal intensity in the dentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency[23]. Confusion is often reported as a possible clinical symptoms.[22] The FDA has asked doctors to limit the use of Gadolinium contrast agents to times when necessary information is made available through its use.[24]

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, has led to a safety review by the European Medicines Agency and The Committee for Medicinal Products for Human Use (CHMP)).[citation needed] Although not directly linked to adverse health effects in patients with normal kidney function, the possible risk of using intravenous linear chelated media, in which the gadolinium is shown to have a lower binding affinity, has led th EMA to suspend the use of linear chelated gadolinium-based media.[citation needed]

In the United States, the research has led the FDA (Food and Drug Administration) to revise its class warnings for all gadolinium-based contrast media. It is advised that the use of gadolinium-based media is based on careful consideration of the retention characteristics of the preferred medium. Extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.[25]

In magnetic resonance imaging in pregnancy, gadolinium contrast agents in the first trimester is associated with a slightly increased risk of a childhood diagnosis of several forms of rheumatism, inflammatory disorders, or infiltrative skin conditions, according to a retrospective study including 397 infants prenatally exposed to gadolinium contrast.[26] In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study.[26]

In December 2017, the FDA announced in a drug safety communication it is requiring these new warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents.[27]

The french health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it.[28]

Iron oxide: superparamagnetic

Main article: Superparamagnetic relaxometry

Two types of iron oxide contrast agents exist: superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspended colloids of iron oxide nanoparticles and when injected during imaging reduce the T2 signals of absorbing tissues. SPIO and USPIO contrast agents have been used successfully in some instances for liver tumor enhancement.[29]

  • Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.[30]
  • Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.[31]
  • Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.[32]
  • Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996[33] and was discontinued by its manufacturer in 2012.[34][35]
  • Clariscan (also known as PEG-fero, Feruglose, and NC100150). This iron based contrast agent was never commercially launched and its development was discontinued in early 2000s due to safety concerns.[36] In 2017 GE Healthcare launched a macrocyclic extracellular gadolinium based contrast agent containing gadoteric acid as gadoterate meglumine under the trade name Clariscan.[37]

Iron platinum: superparamagnetic

Superparamagnetic iron–platinum particles (SIPPs) have been reported and had significantly better T2 relaxivities compared with the more common iron oxide nanoparticles. SIPPs were also encapsulated with phospholipids to create multifunctional SIPP stealth immunomicelles that specifically targeted human prostate cancer cells.[38] These are, however, investigational agents which have not yet been tried in humans. In a recent study, multifunctional SIPP micelles were synthesized and conjugated to a monoclonal antibody against prostate-specific membrane antigen.[38] The complex specifically targeted human prostate cancer cells in vitro, and these results suggest that SIPPs may have a role in the future as tumor-specific contrast agents.

Manganese

Manganese(II) chelates such as Mn-DPDP (Mangafodipir) enhance the T1 signal.[39] The chelate dissociates in vivo into manganese and DPDP where the former is absorbed intra-cellularly and excreted in bile, while the latter is eliminated via the kidney filtration.[40] Mangafodipir has been used in human neuroimaging clinical trials, with relevance to neurodegenerative diseases such as Multiple sclerosis. [41][42] Manganese(II) ions are often used as a contrast agent in animal studies, usually referred to as MEMRI (Manganese Enhanced MRI).[43] Due to the ability of Mn2+ to enter cells through calcium transport channels it has been used for functional brain imaging.[44]

Manganese(III) chelates with porphyrins and phthalocyanines and have also be studied.[39]

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage.[45]

Oral administration of contrast agents

A wide variety of oral contrast agents can enhance images of the gastrointestinal tract. They include gadolinium and manganese chelates, or iron salts for T1 signal enhancement. SPIO, barium sulfate, air and clay have been used to lower T2 signal. Natural products with high manganese concentration such as blueberry and green tea can also be used for T1 increasing contrast enhancement.[46]

Perflubron, a type of perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.[47] This contrast agent works by reducing the number of hydrogen ions in a body cavity, thus causing it to appear dark in the images.

Protein-based MRI contrast agents

See also: Enzyme-activated MR contrast agents

Newer research suggests the possibility of protein based contrast agents, based on the abilities of some amino acids to bind with gadolinium.[48][49][50][51]

See also

References

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