A Breakthrough in Gadolinum-based Contrast Agent Hypersensitivity Reactions

HomeRadiologyVol. 296, No. 2 PreviousNext Reviews and CommentaryFree AccessEditorialA Breakthrough in Gadolinum-based Contrast Agent Hypersensitivity ReactionsMartin R. Prince Martin R. Prince Author AffiliationsFrom the Department of Radiology of Weill Cornell Medicine, 416 E 55th St, New York, NY 10021; and Columbia University Medical Center, New York, NY.Address correspondence to the author (e-mail: [email protected]).Martin R. Prince Published Online:May 19 2020https://doi.org/10.1148/radiol.2020201644MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Walker et al in this issue.Dr Prince is a professor of radiology at Weill Cornell Imaging and Columbia University who specializes in body MRI. His research interests focus on optimizing body MRI and MR angiography techniques and on the safety of gadolinium-based contrast agents. Dr Prince received the International Society for Magnetic Resonance in Medicine (ISMRM) gold medal for developing contrast-enhanced MR angiography.Download as PowerPointOpen in Image Viewer When a patient needing gadolinium-based contrast agent (GBCA)-enhanced MRI reports a prior GBCA reaction, I can feel my heart racing as I ponder the best course of action. Can this examination be done without a GBCA? Shall I switch to a GBCA that is different from the GBCA that caused the reaction? Severe reactions to GBCAs are rare, occurring in only one per 20 000 administrations (1), but the risk increases substantially with a history of a prior reaction to gadolinium (2). Although the spotlight for GBCA risk has been focused on nephrogenic systemic fibrosis (3) and gadolinium retention in the brain (4), these issues are largely mitigated with use of macrocyclic and protein-binding GBCAs. Hypersensitivity reactions can be fatal. When the patient says they have already had their corticosteroid pretreatment, I think “Ah, what a relief.” I relax, thinking all is well. A repeat reaction with corticosteroid pretreatment, known as a breakthrough reaction, may be less likely. But the corticosteroid pretreatment protocol has been copied from that of iodinated contrast material and has never been validated for GBCAs (2). In addition, its utility with iodinated contrast agents has been seriously questioned (5).Thus, the article by Walker et al (6) in this issue of Radiology is a wake-up call on the importance of this aspect of GBCA safety. Walker et al analyzed how effective corticosteroids are at preventing repeat reactions (breakthrough reactions) when patients with a history of GBCA hypersensitivity reaction are re-exposed. Their systematic search identified 23 studies reporting on 120 patients with a history of hypersensitivity reaction to a GBCA undergoing 130 repeat administrations. Although the risk of patient selection bias was high because many of the articles were case reports and case series, the overall findings are impressive. The authors used meta-regression and estimated a 39% rate of breakthrough reactions to repeat GBCA administration in patients premedicated with corticosteroids with or without antihistamines. The breakthrough rate when the same GBCA was used was not significantly different from that after switching to a different GBCA with corticosteroid pretreatment. Walker et al also examined the utility of switching to a new GBCA without corticosteroid pretreatment. There were only five cases, however, which was too small for a meaningful comparison. Four of those five reported cases had reactions to the new GBCA.Finally, the effect of switching to a different GBCA guided by skin GBCA allergy testing showed no breakthrough reactions in 17 patients (15 without corticosteroid pretreatment). Although these numbers were too small to demonstrate a significant difference compared with the breakthrough rate with corticosteroid pretreatment without skin testing guidance (P = .1), this finding shows that more research on skin testing is needed. There may also have been a selection bias for skin testing, which may have occurred more frequently in patients with more severe initial reactions. This further adds to the promise of the skin testing approach.This new research brings up the question of how to approach a patient at risk for hypersensitivity reactions to GBCA—especially those with a known prior GBCA reaction. Many will continue to rely on corticosteroid pretreatments despite their limited utility. Since Walker et al found nearly all breakthrough reactions were of similar intensity as the original reaction (6), the use of corticosteroid treatment may work with mild reactions but is not a good strategy for patients reporting a severe prior reaction to a GBCA. If a GBCA is essential in a patient with a prior severe reaction to a GBCA and alternate tests are not available, use of skin testing to guide the choice of an alternative GBCA may be considered. However, this was not proven to be helpful in the meta-analysis by Walker et al. Another option this meta-analysis did not evaluate was the potential utility of switching to the nonionic linear class of GBCA, which has an order of magnitude lower rate of hypersensitivity reactions compared with macrocyclic and protein-binding GBCAs (1). Ferumoxytol, an intravenously administered iron supplement, has been used as an alternative MRI contrast agent off-label when gadolinium is contraindicated, but its reaction rate is controversial (7).It is useful to consider other preventive measures, some of which are based on anecdotes or common sense due to the rarity of GBCA hypersensitivity reactions, implementing as many measures as possible, so as not to rely solely on corticosteroid pretreatments. In reviewing reports of fatal gadolinium hypersensitivity reaction in the Food and Drug Administration adverse event report database obtained under the Freedom of Information Act (8), I was struck by how many of these described a hypersensitivity reaction to a GBCA administered at an outpatient imaging center, with death occurring in the ambulance on the way to a hospital. Patients at high risk for hypersensitivity reactions could be scheduled for examination with an MRI scanner located within a hospital that has code team support. It is nearly impossible for a radiologist with 2 days of advanced cardiac life support training to perform solo at the level of an entire code team, which is used to handling these events on a regular basis. Patients at high risk can be scheduled in the daytime hours when more staff are on site who can drop what they are doing and assist with managing a reaction. Of course, there must be a crash cart at every imaging facility. Periodic hypersensitivity reaction drills with MRI staff can help everyone learn where the oxygen and crash cart are located; how to operate the pulse oximeter, oxygen, and monitoring equipment; and what each person can do to support the goal of saving the patient. It is critical that the personnel present know how to diagnose and treat contrast material reactions; these drills can help get lifesaving inventions to occur more quickly when seconds can mean the difference between life and death.Staff must watch patients with high risk for an adverse reaction and must be alert to early signs of a reaction. More experienced technologists and nurses may have better outcomes with such patients. I reviewed a case of a fatal reaction in which the nurse hooked the patient’s intravenous canula up to a power injector and then left the MRI area. The nurse did not administer the contrast material. Instead, the technologist pushed the power injector start button and became frustrated when the patient could not cooperate with breathing instructions, repeating the breath-hold scan again and again. Eventually, the technologist entered the scanner room to see what was wrong and discovered too late that the patient was in the midst of a hypersensitivity reaction and was gasping for air. Pulse oximeter monitoring and a nurse in attendance at the time of GBCA administration might have resulted in an earlier intervention.Is a GBCA really necessary? A review of precontrast images may find that all clinical questions have been resolved, thereby obviating the need to challenge the patient with another GBCA injection. Many lessons from years of avoiding GBCAs in patients with renal failure to prevent nephrogenic systemic fibrosis can be applied to patients at high risk for severe hypersensitivity reactions. More research is needed on the more promising directions, including the potential for skin testing. One can imagine that in the future there will be a simple inexpensive skin test that can be applied when the patient arrives and that will reveal which GBCAs are well tolerated and which should be avoided.Disclosures of Conflicts of Interest: M.R.P. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: holds patent agreements with Bayer, Bracco, GE Healthcare, Guerbet/Mallinckrodt, and Lantheus for MR angiography patents. Other relationships: disclosed no relevant relationships.References1. Behzadi AH, Zhao Y, Farooq Z, Prince MR. Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2018;286(2):471–482. Link, Google Scholar2. ACR Contrast Media Manual version 10.3, page 79. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf. Accessed April 14, 2020. Google Scholar3. Attari H, Cao Y, Elmholdt TR, Zhao Y, Prince MR. A systematic review of 639 patients with biopsy-confirmed nephrogenic systemic fibrosis. Radiology 2019;292(2):376–386. Link, Google Scholar4. McDonald RJ, Levine D, Weinreb J, et al. Gadolinium retention: a research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology 2018;289(2):517–534. Link, Google Scholar5. Davenport MS, Cohan RH. The evidence for and against corticosteroid prophylaxis in at-risk patients. Radiol Clin North Am 2017;55(2):413–421. Crossref, Medline, Google Scholar6. Walker DT, Davenport MS, McGrath TA, McInnes MDF, Shankar T, Schieda N. Breakthrough hypersensitivity reactions to gadolinium-based contrast agents and strategies to decrease subsequent reaction rates: a systematic review and meta-analysis. Radiology 2020;296:312–321. Link, Google Scholar7. Nguyen KL, Yoshida T, Kathuria-Prakash N, et al. Multicenter safety and practice for off-label diagnostic use of ferumoxytol in MRI. Radiology 2019;293(3):554–564. Link, Google Scholar8. Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium contrast media reactions. AJR Am J Roentgenol 2011;196(2):W138–W143. Crossref, Medline, Google ScholarArticle HistoryReceived: Apr 16 2020Revision requested: Apr 28 2020Revision received: May 2 2020Accepted: May 5 2020Published online: May 19 2020Published in print: Aug 2020 FiguresReferencesRelatedDetailsCited BySafety of Off‐Label Use of Ferumoxtyol as a Contrast Agent for MRI : A Systematic Review and Meta‐Analysis of Adverse EventsFarazAhmad, LeeTreanor, Trevor A.McGrath, DanielWalker, Matthew D.F.McInnes, NicolaSchieda2021 | Journal of Magnetic Resonance Imaging, Vol. 53, No. 3Acute Chelation Therapy‐Associated Changes in Urine Gadolinium, Self-reported Flare Severity, and Serum Cytokines in Gadolinium Deposition DiseaseHolden T.Maecker, Janet C.Siebert, YaelRosenberg-Hasson, Lorrin M.Koran, MiguelRamalho, Richard C.Semelka2021 | Investigative Radiology, Vol. 56, No. 6Accompanying This ArticleBreakthrough Hypersensitivity Reactions to Gadolinium-based Contrast Agents and Strategies to Decrease Subsequent Reaction Rates: A Systematic Review and Meta-AnalysisMay 19 2020RadiologyRecommended Articles The Feasibility of Abbreviated MRI for Active Surveillance of Hepatocellular CarcinomaRadiology2023Volume: 307Issue: 2Gadolinium Retention: What Do We Know?Radiology2021Volume: 301Issue: 3pp. 643-644Quantitative Susceptibility Mapping Is Superior to T1-weighted Imaging for Detecting and Measuring GadoliniumRadiology2020Volume: 297Issue: 1pp. 151-153Contrast Agent Substitution to Prevent Repeat Adverse ReactionsRadiology2022Volume: 305Issue: 2pp. 350-352Notice of Withdrawal: MR Imaging and Gadolinium: Reassessing the Risk of Nephrogenic Systemic Fibrosis in Patients with Severe Renal DiseaseRadiology2018Volume: 286Issue: 1See More RSNA Education Exhibits Safe Use Of Contrast Media In Breast Imaging; A Practical GuideDigital Posters2021Just Say No to Gad: Focused Non-Contrast Body Protocols and Alternative Contrast AgentsDigital Posters2019Contrast Enhanced Mammography. 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