A patient was referred to urology after having several episodes of gross hematuria. The urologist thought that the patient might have a renal mass and sent him to radiology for a CT scan. The patient stated that he was not allergic to x-ray dye. Therefore, the resident radiologist told the technologist to proceed with contrast material administration for contrast enhancement. Soon after the injection, the patient went into anaphylactic shock on the CT table. Luckily, the patient was rapidly resuscitated and suffered no permanent harm. On later questioning, the patient stated that he was "very allergic" to shellfish. On further inquiry, including an exhaustive review of all of the patient's allergies, he stated that he was extremely allergic to iodine in all forms.

by Richard Cohan, MD

Allergic-Like Reactions to Radiographic Contrast Media

Although the near-universal replacement of conventional high-osmolality ionic radiographic contrast agents with low-osmolality nonionic agents (for intravascular use) has led to a marked (four to five-fold) decrease in the incidence of contrast reactions, such reactions will still be encountered by nearly all radiologists. Approximately 3% of patients will experience some type of reaction to these safer (but more expensive) agents.(1) Fortunately, the vast majority of adverse reactions are mild, self-limited, and do not require any treatment. For example, severe reactions, defined as reactions that require treatment, including dyspnea, hypotension, loss of consciousness, or even cardiac arrest, are encountered much less commonly. Such reactions were seen in only 0.04%, or one in 2500 patients, in one large study.(1) Fatal contrast reactions are exceedingly rare. This is at least partially due to the fact that if a severe reaction is aggressively and appropriately treated, most patients will recover, and almost always do so without any adverse long-term sequelae.

High-Risk Patients
It is essential to ask patients about any potential risk factors prior to intravascular injection of iodinated radiographic contrast material, so that high-risk patients can be prospectively identified. The three most commonly encountered risk groups include patients who have had a previous adverse reaction to an intravascular iodinated contrast material injection, patients with asthma, and patients who have any allergies.(1) Older studies have also shown that patients with cardiac arrhythmias (2), myasthenia gravis of the central type (3), pheochromocytomas (4), sickle cell anemia (5), and hyperthyroidism (6) are at risk of having acute exacerbations of these diseases after ionic contrast injection. Unfortunately, the risks of nonionic contrast material injection in these patients are not well studied; however, the risks, if there are any at all, are likely much smaller.(5,7)

When interviewing patients prior to contrast material injection, many health care providers, including radiologists, technologists, nurses, and physicians, continue to ask patients about seafood or "iodine" allergies. Specific concern about iodine or seafood allergies is probably unjustified. The iodine atom, present in every human being (since the thyroid gland requires iodine to function), is too small to elicit an antigen-antibody response; thus, patients cannot be allergic to iodine by itself. Additionally, most adverse reactions to iodinated contrast material do not represent true allergic reactions, as has been demonstrated by the finding that anti-contrast material antibodies are not consistently found in patients having adverse allergic-like reactions.(8) The exact mechanism of allergic-like contrast reactions is not known. Since such reactions are not truly allergic, most researchers term these as anaphylactoid rather than anaphylactic reactions.

The literature does not support the widespread belief that patients with seafood allergies are particularly at risk for an adverse reaction to iodinated contrast material.(9) For example, in one study, patients with shellfish/seafood allergies were no more likely to react to an intravascular injection of ionic contrast material than were patients with allergies to eggs, milk, or chocolate.(10) Accordingly, it is recommended that patients not be questioned specifically about shellfish or iodine allergies. Instead, patients should be asked about any allergies. Patients with multiple or severe allergies to any substances, as well as those with histories of severe or poorly controlled asthma (particularly if the asthma is currently active), should be treated with the same caution.(9)

Pretreatment
Iodinated contrast material injection should be avoided, whenever possible, in any patient who has had a previous moderate or severe anaphylactoid reaction to iodinated contrast material. If contrast material injection must be performed (because imaging with contrast material is necessary and no alternative imaging study will provide the desired information), corticosteroid premedication must be provided, if at all feasible. It is also suggested that steroid premedication be given to patients who have had previous mild allergic-like contrast reactions, such as hives, although there is no uniformity of opinion on this issue. Steroid premedication should also be strongly considered in patients with multiple or severe allergies to other agents, and in patients with symptomatic or poorly controlled asthma. Two pretreatment regimens have been widely researched. The first utilizes two oral 32 mg doses of methylprednisolone administered 12 hours and 2 hours before contrast material injection (11), while the second requires administration of 50 mg of prednisone 13 hours, 7 hours, and 1 hour prior to contrast media injection.(12) The latter regimen also usually includes a 1-hour pre-procedural oral dose of 50 mg of diphenhydramine.

There are two important issues concerning premedication. First, premedication is known to be effective only if the first dose of corticosteroids is administered at least 12 hours prior to intravascular contrast media injection.(11) While the minimum duration of an effective steroid regimen has not been determined, a single oral dose of steroids 2 hours prior to injection is definitely of no benefit.(11) Second, corticosteroid premedication reduces the number of adverse reactions, but does not completely prevent them from occurring. For example, in one study, total adverse reactions to ionic contrast media in both high-risk and low-risk patients decreased from about 9% to 6% with a 12-hour steroid "prep."(11) Adverse reactions requiring therapy decreased from 2.0%-2.2% to 1.2%. In another study, which included only high-risk patients, premedication had a more pronounced effect, reducing the number of reactions to ionic contrast material by two-thirds (from 9% to 3%).(12) In a more recent study of both high-risk and low-risk patients, 6 to 24 hour steroid regimens reduced the number of total reactions to nonionic contrast material by a similar amount (from 4.9% to 1.7%).(13)

Treating Acute Contrast Reactions
Treatment of acute allergic-like reactions to contrast material is discussed in more detail elsewhere (14), but is summarized in the Table.

Identifying and Communicating with High-Risk Patients
It is exceedingly important that radiology departments have a system in place to identify all patients at an increased risk of developing an adverse reaction to radiographic contrast material. At the least, the individual injecting the contrast material must specifically ask patients whether they have had contrast material before and, if so, how well they tolerated the injection. They must also inquire about any "allergies" (including to contrast material) and about the nature of such allergies. Since some patients will not be able to distinguish a non-allergic reaction from an allergic one, the interviewer must try to make such a distinction. Asking patients who are to receive contrast material to fill out a brief questionnaire adds another layer of safety.

If a patient does react to iodinated contrast material, the radiologist must subsequently educate the patient about the nature of the reaction and what future precautions are necessary. The physician must also include a description of the reaction in the official report. Finally, the patient should be "flagged" as being at high-risk, so that if he or she returns to the radiology department, the patient's risk can be easily recognized. A contrast "alert" should be programmed into the radiology information system, or the patient's name recorded on an appropriate list in the radiology department. The more formalized the process, the less likely that patient will receive a contrast injection in the future without any advance awareness of the increased risks of such an injection.

In the case presented here, it would have been very helpful to know of the patient's being "very allergic" to shellfish and to "iodine in all forms" prior to the administration of contrast. However, as has been described, the term "iodine allergy" is not accurate. This patient probably has multiple, severe allergies. Upon obtaining such a history, the CT examination should have been deferred and premedication with corticosteroids instituted prior to imaging.

Take-Home Points

• Every patient must be asked about prior contrast reactions, asthma, allergies, and other underlying diseases/medical problems. Specific questions with respect to seafood/shellfish or to iodine allergies are not necessary and can lead to confusion.
• Contrast material injection should be avoided, if at all possible, in any patient who has had a previous moderate or severe allergic-like reaction to contrast material. Should re-injection be needed, steroid premedication should be provided for such patients, if at all possible.
• Steroid premedication should be considered even in patients who have had previous mild allergic-like reactions.
• Steroid premedication should also be considered in patients with multiple or severe true allergies to other substances or severe, poorly controlled, or currently symptomatic asthma.
• Every radiologist must be aware of the appropriate ways to treat the various encountered acute contrast reactions.
• After a reaction has occurred, the radiologist must educate the patient about the nature of the reaction and necessary future precautions. The reaction should be documented in the radiology report. Finally, the patient should be "flagged" as being at high-risk, so that if he or she returns to the radiology department, this risk can be recognized easily.

Richard Cohan, MD
Professor, Department of Radiology
University of Michigan School of Medicine

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2. Lawton G, Phillips T, Davies R. Alterations in heart rate and rhythm at urography with sodium diatrizoate. Acta Radiol Diagn (Stockh). 1982;23:107-10.
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3. Chagnac Y, Hadani M, Goldhammer Y. Myasthenic crisis after intravenous administration of iodinated contrast agent. Neurology. 1985;35:1219-20.
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4. Raisanen J, Shapiro B, Glazer GM, Desai S, Sisson JC. Plasma catecholamines in pheochromocytoma: effect of urographic contrast media. AJR Am J Roentgenol. 1984;143:43-6.
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5. Rao VM, Rao AK, Steiner RM, Burka ER, Grainger RG, Ballas SK. The effect of ionic and nonionic contrast media on the sickling phenomenon. Radiology. 1982;144:291-3.
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6. Lorberboym M, Mechanick JI. Accelerated thyrotoxicosis induced by iodinated contrast media in metastatic differentiated thyroid carcinoma. J Nucl Med. 1996;37:1532-5.
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7. Mukherjee JJ, Peppercorn PD, Reznek RH, et al. Pheochromocytoma: effect of nonionic contrast medium in CT on circulating catecholamine levels. Radiology. 1997;202:227-31.
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8. Almen T. The etiology of contrast medium reactions. Invest Radiol. 1994;29 Suppl 1:S37-45.
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10. Shehadi WH. Adverse reactions to intravascularly administered contrast media. A comprehensive study based on a prospective survey. Am J Roentgenol Radium Ther Nucl Med. 1975;124:145-52.
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11. Lasser EC, Berry CC, Talner LB, et al. Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. N Engl J Med. 1987;317:845-9.
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12. Greenberger PA, Patterson R, Radin RC. Two pretreatment regimens for high-risk patients receiving radiographic contrast media. J Allergy Clin Immunol. 1984;74:540-3.
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13. Lasser EC, Berry CC, Mishkin MM, Williamson B, Zheutlin N, Silverman JM. Pretreatment with corticosteroids to prevent adverse reactions to nonionic contrast media. AJR Am J Roentgenol. 1994;162:523-6.
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14. Cohan RH, Leder RA, Ellis JH. Treatment of adverse reactions to radiographic contrast media in adults. Radiol Clin North Am. 1996;34:1055-76.
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Table. Principles in Treating Acute Contrast Reactions