MRIF: Guidance on the use of gadolinium based contrast agents

Author: Professor Alan Jackson

Gadolinium based contrast agents are widely used in clinical studies. On the whole they are extremely safe when administered within standard dosage guidelines. Investigators should be aware of two potential groups of complications, which should be addressed in protocol design and ethics committee submissions: allergic reactions and late development of Nephrogenic Systemic Fibrosis (NSF)

MRIF Policy

Gadolinium containing contrast media should be given only where clear scientific need.
Contrast media should not be administered to patients with a previous history of allergic response to gadolinium containing agents.
Administration of gadolinium contrast agents to patients with a severe atopic history unless there is clear clinical need. In this case prophylactic therapy should be considered and medical support must be immediately available on site.
Wherever possible contrast media with a low rate of gadolinium release recommended. Consequently, the standard contrast media within MRIF is Dotarem.
Patients receiving contrast should have an eGFR and contrast media should not be administered if this is below 15 ml/min.
Subjects with any evidence of renal impairment eGFR < 50 mls/min should receive only Dotarem unless there is pressing scientific justification to do otherwise.
If the patient has been stable pre MR scan then an eGFR obtained up to 3 months before will suffice; any hint of clinical illness should prompt a more up to date assessment of eGFR.

Allergic Reactions to Gadolinium-Based Contrast Agents Are Rare

Allergic-like reactions to gadolinium containing contrast injections in adults and pediatric patients (those younger than 19 years of age) are rare. When these reactions do occur, most of them are mild.

A Seminal Recent Study is Dillman, J.R., J.H. Ellis, R.H. Cohan, P.J. Strouse, and S.C. Jan, Frequency and severity of acute allergic-like reactions to gadolinium-containing i.v. contrast media in children and adults. AJR Am J Roentgenol, 2007. 189(6): p. 1533-8.

The study included 78,353 (65,009 adult and 13,344 pediatric) IV administrations of gadolinium-containing contrast material were performed during the study period. Acute allergic-like reactions were documented after 54 injections (reaction frequency, 0.07%). Forty-eight reactions involved adult patients (adult reaction frequency, 0.07%), and six reactions occurred in pediatric patients (pediatric reaction frequency, 0.04%). Forty (74%) acute allergic-like reactions were mild, 10 (19%) were moderate, and four (7%) were severe. No gadolinium-containing contrast material–related death occurred during the study period. Twenty- six (50%) of 52 patients had one or more presumed risk factors for contrast material reaction.

The following tables from that study show the severity classification and treatment for typical reactions:

Table 2: Manifestations of mild acute allergic-like reaction to Gadolinium-containing contrast media (n=40)

Manifestation	No. of Reactions
Urticaria (hives)	23^a
Mild throat symptoms (e.g. itching, tightening) requiring no treatment	4^a
Rash (away from injection site)	3^b
Mild difficulty breathing requiring no treatment	3
Sneezing and nasal congestion (muscosal edema)	3
Mild perioral or periorbital edema	2^a
Mild facial edema and urticaria	2

^aIncluding a single pediatric patient

^bIncluding two pediatric patients

Table 3: Manifestations of moderate acute allergic-like reaction to Gadolinium-containing contrast media (n=10)

Manifestation	Management
Difficulty breathing, urticaria^a	Diphenhydramine, transfer to emergency department
Difficulty breathing, throat symptoms, rash^a	Diphenhydramine, epinephrine, transfer to emergency department
Difficulty breathing, chest pain^b	Transfer to emergency department
Difficulty breathing, facial angioedema, urticaria^a	Transfer to emergency department
Difficulty breathing, facial angioedema, hypotension^b	Diphenhydramine, epinephrine, transfer to emergency department
Difficulty swallowing, bronchospasm^b	Epinephrine, inhaled albuterol
Facial angioedema, rash^b	Diphenhydramine, transfer to emergency department
Throat symptoms, facial angioedema, urticaria^c	Epinephrine, transfer to emergency department
Throat symptoms, rash, urticaria^a	Diphenhydramine, methylprednisolone, transfer to emergency department
Throat symptoms, nasal congestion^a	Transfer to emergency department

NOTE - All patients in table are adults. Those transferred to emergency department were all subsequently discharged without being admitted to hospital.

^aReaction for which exact gadolinium-containing contrast agent is unknown

^bReaction to gadopentetate dimeglumine

^cReaction to gadobenate dimeglumine

Table 4: Manifestations of severe acute allergic-like reaction to Gadolinium-containing contrast media (n=4)

Manifestation	Management
Laryngeal edema, urticaria, sneezing, nasal congestion^a	Diphenhydramine, epinephrine, hospital admission via emergency department
Difficulty breathing, hypoxia^a	Diphenhydramine, epinephrine, methylprednisolone, (hospital admission via emergency department)
Difficulty breathing, hypoxia^a	Hospital admission via emergency department
Difficulty breathing, facial angioedema, urticaria	Diphenhydramine, epinephrine, methylprednisolone, (hospital admission via emergency department)

^aReaction for which exact gadolinium-containing contrast agent is unknown

^bPediatric patient

Gadolinium-containing MRI contrast agents and Nephrogenic Systemic Fibrosis (NSF)

Eight gadolinium-containing contrast agents are authorised in the UK: gadodiamide (Omniscan®), gadopentetic acid (Magnevist®), gadobenic acid (MultiHance®), gadobutrol (Gadovist®), gadofosveset (Vasovist®), gadoteric acid (Dotarem®), gadoteridol (ProHance®) and gadoxetic acid (Primovist®).

Some gadolinium-based contrast media are more likely than others to release free Gd3+ through a process called transmetallation with endogenous ions from the body. These agents have the largest amount of excess chelate. Gadodiamide differs from other gadolinium-based contrast media, with the exception of gadoversetamide,2 because it has an excess of chelate and is more likely to release free Gd3+ compared with other agents. Cases of NSF in association with gadoversetamide have been reported in the USA.

Table 1: Currently marketed gadolinium contrast agents

Brand Name	Generic Name	Acronym	Chemical Structure	Charge	Cases of NSF
Omniscan	gadodiamide	Gd-DTPA-BMA	Linear	Non-ionic	Yes
OptiMARK^a	gadoversetamide	Gd-DTPA-BMEA	Linear	Non-ionic	Yes
Magnevist	gadopentetate dimeglumine	Gd-DTPA	Linear	Ionic	Yes
MultiHance	gadopentetate dimeglumine	Gd-BOPTA	Linear	Ionic	No
Primovist	gadoxetic acid disodium salt	Gd-EOB-DTPA	Linear	Ionic	No
Vasovist	gadofosveset trisodium	Gd-DTPA	Linear	Ionic	No
ProHance	gadoteridol	Gd-HP-DO3A	Cyclic	Non-ionic	No
Gadovist	gadoteridol	Gd-BT-DO3A	Cyclic	Non-ionic	No
Dotarem	gadoterate meglumine	Gd-DOTA	Cyclic	Ionic	No

^aOptiMARK is not licensed in Europe, but is available in the USA

Nephrogenic systemic fibrosis (NSF)

NSF, also known as nephrogenic fibrosing dermopathy (NFD), is a rare condition characterised by the formation of connective tissue in the skin which becomes thickened, coarse and hard, sometimes leading to contractures and joint immobility. Patients with NSF can have systemic involvement of other organs including the lungs, liver, muscles, and heart. Five per cent of patients have a rapidly progressive fulminant clinical course. NSF has been reported only in patients with renal insufficiency. Although most affected patients have advanced or end-stage renal disease, a few cases have been reported in patients with only moderate renal dysfunction.

In early 2006, a possible causal link between NSF and gadolinium-containing MRI contrast agents was first identified. In an article, five of nine patients with end-stage renal failure (ESRF) who had received gadodiamide developed NSF 2–4 weeks later. Shortly after this publication, a separate study reported that 13 patients with ESRF who had NSF had all received gadodiamide (median time from exposure 25 days [range 2–75]).

Approximately 200 worldwide cases of NSF in those with renal impairment have now been reported with gadolinium-containing MRI contrast agents, most of which are associated with the least-stable agentsOmniscan and OptiMARK (the latter is not authorised in the EU). A small number of cases have been associated with Magnevist, one of which was considered directly attributable to Magnevist in a patient given multiple high doses of this contrast agent. We are not aware of reports of NSF with the other gadolinium-containing contrast agents.

The mechanism by which some gadolinium-containing contrast agents are more likely to trigger NSF than other agents is not understood fully, but is thought to be related to their different physicochemical properties that affect the extent to which they release free gadolinium ions. Deposition of free gadolinium ions in tissues and organs might stimulate NSF through induction of fibrosis. Patients with severe renal impairment are at increased risk of NSF because they take longer to eliminate the contrast agent from the body—the half-life of gadodiamide increases from 1–3 hours in healthy volunteers to 34·3 hours in patients with ESRF. Cases of NSF have also been reported in patients who have had or are awaiting liver transplantation. There are no known cases of NSF in patients with normal renal function.

Continuing investigation

Suspected adverse drug reactions should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) by use of a Yellow Card, which is available from MHRA, CHM Freepost, London SW8 5BR or electronically via the MHRA website (http://www.mhra.gov.uk).

Further information about NSF and gadolinium-containing MRI contrast agents can be found at the websites of Medicines and Healthcare products Regulatory Agency (MHRA); the European Society of Urogenital Radiology (ESUR); and the International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR).

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