Practical Messages from Large Database Studies of Contrast Media Reactions

See also the article by Ahn and Kang et al in this issue.

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Gadolinium-based contrast agents (GBCAs) are an essential component of MRI, providing critical diagnostic information that is otherwise undetectable with unenhanced MRI. Contrast-enhanced MRI examinations are ubiquitous in diagnostic medicine, with over 40 million GBCA doses administered in the United States in 2019 (1). The most common complications of GBCA exposure are acute adverse events, subdivided by presentation into allergiclike (ie, pruritus, urticaria, anaphylaxis) and physiologic (ie, nausea and vomiting, vasovagal response) reactions. Acute events are defined as those occurring within 1 hour of intravenous GBCA administration and are reported to occur at a rate of one to two events per 100 administrations (2). Allergic-like reactions to GBCAs occur far less frequently, at rates of 0.004%–0.7%. Their infrequent occurrence makes them difficult to tabulate and study.

To further complicate matters, so-called allergic reactions to contrast material do not fit the standard canonical definitions of an immunoglobulin E–mediated hypersensitivity reaction: Most GBCA allergic reactions do not involve immunoglobulin E–mediated mast cell degranulation (3). Some remaining fraction of reactions have all the other hallmarks of a hypersensitivity reaction but appear to occur through noncanonical mechanisms; hence, these reactions are now termed allergic-like.

As a manifestation of these noncanonical mechanisms, patients can receive several doses of contrast material before they experience an acute reaction, or they can have a reaction after their first GBCA exposure. Most patients who have a reaction never have a subsequent reaction when re-exposed. Further, premedication protocols that traditionally have been used to prevent allergic reactions to drugs, including corticosteroid and antihistamine prophylaxis, have questionable effectiveness when used to prevent allergic-like reactions to contrast material (4). Cumulatively, the unpredictable nature of these reactions results in challenges to identify risk factors that predispose patients to these reactions. In turn, it has been difficult to elucidate a mechanism of action and to develop prophylactic therapies to avoid reactions.

Delayed allergic-like reactions to contrast material are reactions that are reported to occur from 1 hour up to 1 week after contrast material exposure. Even less is known about these delayed reactions, which are typically cutaneous and mild in nature (5). Delayed reactions are less likely to be identified and reported after the patient leaves the imaging center. Confounding factors, such as the patient’s underlying medical condition, complicates analysis of delayed reaction and their causal connection to gadolinium-containing contrast material. The mechanism or mechanisms of delayed reactions and potential measures to prevent them remain largely unknown.

In this issue of Radiology, Ahn and Kang et al performed a single-center retrospective study encompassing an 8-year period involving 331070 GBCA exposures in 154539 patients to study acute and delayed reactions to GBCAs (6). The authors observed a rate of 0.4% acute reactions (n = 1178) and 0.04% (n = 126) delayed reactions. Most of these reactions were mild (92% of acute reactions, 75% of delayed reactions). Only 12 severe acute reactions were observed (0.004%). Consistent with prior studies, the authors found that patient demographics, including sex, age, and a history of a prior allergic-like reaction to GBCAs, affected reaction rates (2).

To evaluate the effectiveness of preventative therapies against GBCA acute reactions, the authors examined 487 patients with a history of acute or delayed allergic-like reactions to GBCAs who had a total of 1445 subsequent GBCA exposures. Patients with a prior acute reaction had a higher repeat reaction rate than did patients with a prior delayed reaction (16% vs 8%). Overall, premedication decreased the repeat reaction rate from 20% to 14%, and switching GBCAs decreased the repeat reaction rate from 21% to 5%. These findings corroborate those from other recent studies, indicating that using a different contrast agent may be more effective at preventing repeat reactions than premedication in patients with a history of an allergic-like reaction to contrast material (7–9).

The premedication strategy used by Ahn and Kang et al differed substantially from that recommended by the American College of Radiology (ACR). The ACR recommends an oral steroid preparation premedication protocol be administered to patients with a prior reaction to contrast material either 13, 7, and 1 hour (prednisone) or 12 and 2 hours (methylprednisolone) prior to contrast material administration (2). In the study by Ahn and Kang et al, patients with a mild prior reaction (the presumed majority) instead received the antihistamine chlorpheniramine 30 minutes before MRI, while patients with moderate or severe prior reactions received chlorpheniramine and steroids 1 and 4 hours, respectively, before MRI. Current ACR guidelines recommend antihistamine administration only as a supplement to steroid preparation and note that "premedication regimens less than 4–5 hours in duration…have not been shown to be effective" (2). While use of steroid preparations is widespread, there is weak evidence supporting their effectiveness in patients with a prior reaction; further, they are time consuming and have known side effects and contraindications (10). The findings of Ahn and Kang et al suggest that shorter antihistamine-only regimens may indeed be effective at preventing repeat allergic-like reactions in patients with a history of prior reaction. Such a regimen could be completed faster and could lead to far less delay in imaging than the 12–13-hour pre-examination steroid preparation standard. However, additional studies focused on these regimens are needed before changing clinical practice.

Interestingly, Ahn and Kang et al reported that the effectiveness of their prophylactic measures varied depending on whether the patient had a prior acute or delayed reaction. Both premedication and switching GBCA strategies were effective in preventing repeat reactions in patients with prior acute reactions, while only premedication was effective in preventing repeat reactions in patients with prior delayed reactions. This finding suggests that acute and delayed reactions to contrast material may have different underlying mechanisms. Future studies should include patients with a history of delayed reactions to further compare them with patients with a history of acute reactions.

Ahn and Kang et al also reported that patients who had a prior reaction to iodinated contrast material (ICM) also had an increased rate of a subsequent reaction to GBCAs (3% vs 0.7% with no prior ICM reaction). This finding is surprising considering the different molecular structures of ICMs and GBCAs and conflicts with current ACR guidelines that note that “There is no cross-reactivity between different classes of contrast medium…a prior reaction to [GBCAs] does not predict a future reaction to [ICM], or vice versa, more than any other unrelated allergy” (2). Ahn and Kang et al recommend careful use of ICMs in patients with a prior reaction to GBCAs and vice versa, which again is incongruent with current ACR guidelines that note that “routine premedication or avoidance of contrast medium for other indications, such as allergic reactions to other substances (including…contrast media from another class [e.g. gadolinium-based – iodinated])…is not recommended.” While Ahn and Kang et al note that the potential mechanism for this increased risk is unknown, they state that a genetic predisposition to hypersensitivity reactions may be responsible. Are patients who had a prior allergic-like reaction to ICMs truly at increased risk of also having a reaction to GBCAs? Another possible explanation for these findings is that patients who had a prior reaction to any contrast material may be more likely to report allergic-like symptoms at any future imaging, regardless of the contrast material class used. Again, additional research is warranted before changing current guidelines and clinical practice.

In conclusion, Ahn and Kang et al have provided intriguing new data about potential risk factors and preventative measures for acute and delayed reactions to gadolinium-based contrast agents. Such findings merit further investigation to improve contrast material safety and patient care.

Disclosures of Conflicts of Interest: D.F.K. institutional grants from GE Healthcare; consultant to the Editor-in-Chief of Radiology. J.S.M. investigator- and sponsor-initiated institutional research grants from GE Healthcare; institutional consulting fees regarding contrast media safety research from GE Healthcare; member of the America College of Radiology Committee on Drugs and Contrast Safety.