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Breakthrough Adverse Reactions to Low-Osmolar Contrast Media After Steroid Premedication

¹ Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710.
² Present address: Department of Radiology, Lehigh Valley Hospital, Allentown, PA 18105.

Received April 19, 2000; accepted after revision November 17, 2000.

 
Address correspondence to R. A. Leder.

Abstract

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OBJECTIVE. The purpose of this study was to review the nature of adverse reactions, or "breakthrough reactions," experienced by patients who received steroid premedication and low-osmolar contrast media. We compared the demographics of patients having these breakthrough reactions with those of patients who did not develop these reactions.

MATERIALS AND METHODS. We retrospectively reviewed our radiology quality improvement database to identify patients with breakthrough reactions that occurred from January 1, 1994, through October 1, 1999, and we reviewed their medical records. We compared these patients with a control cohort of patients who had a history of prior adverse reaction to contrast media but no breakthrough reaction after administration of low-osmolar contrast media and premedication with corticosteroids.

RESULTS. Over the 6-year period, 52 patients experienced 61 breakthrough reactions. The breakthrough reaction was mild in 76% of the patients. The breakthrough reaction was similar to the patient's initial adverse reaction in 85% of the patients. A history of seafood allergy or hay fever was statistically more likely to be identified in the breakthrough group than the control group.

CONCLUSION. Breakthrough reactions occur in a substantial number of patients despite premedication with steroids and use of low-osmolar contrast agents. Typically the breakthrough reaction is of similar severity to the patient's initial reaction. Severe or life-threatening reactions are seen in 24% of patients.

Introduction

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Since their advent in the 1950s, radiologic contrast media have revolutionized diagnostic imaging. Although the diagnostic value of contrast media is enormous, other less desirable side effects also occur. Radiologists routinely grapple with the issue of how to treat patients who are at high risk for contrast media reaction and require a contrast-enhanced study. The combination of low-osmolar contrast media (LOCM) and a steroid premedication regimen has been advocated to reduce the likelihood of an adverse reaction [1, 2]. It has not been determined how a patient who has experienced an adverse reaction (i.e., a breakthrough reaction) after LOCM use and steroid premedication should be treated.

The purpose of this study was to review the nature of adverse reactions experienced by patients who received steroid premedication and LOCM. We compared the demographics of patients having these breakthrough reactions with patients who did not develop these reactions.

Materials and Methods

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The radiology quality improvement database at our institution was reviewed to identify patients who experienced adverse reactions to LOCM after steroid premedication from January 1, 1994, through October 1, 1999. All patients who experienced a breakthrough reaction were included regardless of the route of contrast media administration and regardless of the indication for steroid premedication. The patients' medical and radiology records were reviewed, and the patients were contacted by telephone when possible. Institutional review board approval was not deemed necessary because of the nature of the follow-up. Radiology nurses or technologists questioned all patients about risk factors before the procedure and assessed all patients with breakthrough reactions. Parameters recorded included age; sex; severity of initial adverse reaction; number and severity of breakthrough reactions; route of contrast media administration; presence of individual risk factors including drug allergy, food or seafood allergy, asthma, or hay fever; presence of multiple risk factors (>1 of the listed risk factors); the type of premedication regimen; and treatment if any for the breakthrough reaction. A history of drug allergy was classified as negative or positive; no differentiation was made of the number or severity of drug allergies. In the patients premedicated because of prior adverse reactions it was not known if the initial adverse reaction was in response to LOCM or high-osmolar contrast media (HOCM). At our institution, we universally administered LOCM for CT and excretory urography examinations from 1994 through 1999 with the exception of a 6-month period in 1999 when we selectively administered HOCM.

Adverse reactions were classified into three groups. Cutaneous reactions such as hives, erythema, rash, pruritus, and sneezing were considered class 1 reactions. Dyspnea, bronchospasm, laryngeal edema, and facial edema were classified as class 2 reactions. Hypotension, loss of consciousness, and cardiopulmonary arrest were considered class 3 reactions. If a patient experienced more than one class of reaction, only the more severe or higher class reaction was recorded. Nausea and vomiting were not considered adverse reactions for the purpose of this study.

For the purpose of statistical analysis, comparison was made with a control cohort of patients selected from the CT database of patients who underwent CT examination from January 1, 1999, through October 1, 1999. All patients who had had a prior adverse reaction but experienced no breakthrough reaction after the peripheral IV administration of LOCM and steroid premedication were included. These patients' medical and radiology records were reviewed. The patients were contacted by telephone when possible; 28 (54%) of 52 patients in the breakthrough group and 30 (79%) of 38 patients in the control group were successfully contacted by telephone. Similar parameters to those of the breakthrough group were recorded.

Statistical analysis was performed using Kendall's tau with results considered statistically significant for p values less than 0.05. Despite the fact that multiple comparisons were made, we did not reduce the p value because we believed that valid differences would still be identified. Analysis involved determining whether there were any statistically significant differences in risk factors for the patients with breakthrough reactions compared with those for the control group. Additionally, in an attempt to maximize similarity between the groups, the breakthrough group was subdivided into the patients whose breakthrough reaction followed the peripheral IV administration of contrast media and who had had a prior adverse contrast media reaction. This subset was also compared with the control group.

Results

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Over the 6-year period investigated, 52 patients experienced a total of 61 breakthrough reactions (46 patients had one reaction, five patients had two reactions, and one patient had five reactions). The patients included 31 women and 21 men ranging in age from 21 to 81 years with a mean age of 53 years. The route of LOCM administration was via a peripheral IV (n = 47 patients [56 reactions]), a central IV route for a transjugular intrahepatic portosystemic shunt procedure (n = 1), into the bowel (n = 1), into the cerebrospinal fluid (n = 1), into an intervertebral disk (n = 1), and intraarterial (n = 1). Forty-nine of the 52 patients had experienced a prior adverse reaction to contrast media; three had received steroid premedication because of other risk factors (e.g., asthma or food, drug, or seasonal allergy). During this time period, 120,100 patients received IV contrast media. The most common breakthrough reaction was class 1 in 46 (75%) of 61 cases, followed by class 2 reaction (13/61 cases or 21%), and uncommonly a class 3 reaction (2/61 cases or 3%).

Initial Versus Breakthrough Reaction
In comparing the initial and breakthrough reactions, the initial reaction was not known in five cases, and in three cases the patients received LOCM and steroid premedication on the basis of risk factors other than prior adverse reaction. Of the remaining 53 cases, the initial and breakthrough reactions were of similar severity in 45 (85%) of 53 cases (Table 1). Interestingly, three patients stated they developed the same number of hives in the same location during the initial and breakthrough reactions. However, in six (11%) of 53 cases, the breakthrough reaction was more severe than the initial reaction, changing from a class 1 to class 2 reaction. In two (4%) of 53 cases, the breakthrough reaction was less severe than the initial reaction switching from a class 2 to a class 1. We did not investigate changes in severity within a class (e.g., if a patient had one or numerous hives).

Multiple Breakthrough Reactions
Ten patients who had at least one breakthrough reaction underwent subsequent LOCM-enhanced imaging studies with steroid premedication. Of these 10 patients, six patients had multiple breakthrough reactions and four patients had no documented subsequent breakthrough reaction. Of the six patients with multiple breakthrough reactions, the subsequent breakthrough reaction remained class 1 in three patients and changed from class 1 to class 2 in three patients. The patient with five breakthrough reactions stated that each reaction became progressively more severe. Her initial reaction and first breakthrough reaction were one hive progressing to diffuse hives by the third and fourth breakthrough reactions; her fifth breakthrough reaction consisted of dyspnea and laryngeal edema in addition to diffuse hives. The decision to administer contrast media in patients with a history of prior breakthrough reaction at our institution was made on an individual basis.

Severe Reactions to LOCM
No cases of death from LOCM administration were recorded in our database during the time period studied. In both cases of class 3 breakthrough reaction, the initial reaction was also class 3 to LOCM. Interestingly, neither class 3 breakthrough reaction resulted from a peripheral IV injection of LOCM. In one case the LOCM was administered into the bowel, in the form of a urinary diversion; in the other, into the central venous system during a transjugular intrahepatic portosystemic shunt procedure. In both patients, a code was called because of unresponsiveness and severe hypotension. Both patients survived without long-term sequelae. One patient in the control group experienced no breakthrough reaction after receiving LOCM and steroid premedication. The patient had experienced a class 3 initial adverse reaction in the past, presumably to HOCM.

Of the 13 patients who experienced a class 2 breakthrough reaction, six experienced laryngeal edema, four had dyspnea, and three had bronchospasm.

Comparison of Breakthrough Group and Control Group
The control group consisted of 28 women and 10 men ranging in age from 30 to 79 years with a mean age of 55 years. The initial adverse reaction was class 1 (n = 30), class 2 (n = 6), class 3 (n = 1), and unknown (n = 1).

Table 2 summarizes the statistical analysis results for the breakthrough group and the control group. Statistical analysis revealed no significant difference between the groups in patient age or sex. No statistical significance was seen between the groups with respect to a history of drug allergy, asthma, or multiple risk factors. The risk factors that were statistically significantly more likely to be identified in the group of patients with breakthrough reactions than in the control cohort included seafood allergy (p = 0.017) and a history of hay fever (p = 0.048). Food allergy (p = 0.048) was also statistically significant if seafood allergy was included.

In patients with a prior adverse reaction to contrast media, the frequency of a breakthrough reaction to peripheral IV LOCM injection is calculated to be five of 43, or 12%. The numerator is the number of patients who had a breakthrough reaction to peripheral IV LOCM administration from January 1, 1999, through October 1, 1999. The denominator is the total number of patients with a history of prior adverse reaction who received peripheral IV LOCM injection after steroid premedication during that time period (i.e., the 38 patients in the control group and the five patients in the breakthrough group who received their contrast injection during the same time period). The denominator was not known for the time period of January 1, 1994, to December 31, 1998, to allow the frequency to be calculated over the 6-year period studied.

The subset of patients whose breakthrough reaction was to peripheral IV LOCM injection from January 1, 1994, through October 1, 1999, and who experienced an initial adverse reaction included 44 patients (26 women, 18 men) ranging in age from 21 to 81 years with a mean of 52 years. The patients excluded from this subset included those five patients whose route of LOCM was not a peripheral IV and three patients who were premedicated on the basis of risk factors other than prior adverse reaction. A history of seafood allergy (p = 0.031) was the only statistically significant risk factor more likely to be identified in this subset than in the control group.

Our standard steroid premedication regimen consists of oral prednisone (20 mg) given every 6 hr before the imaging study for a total of five doses. In most breakthrough reactions (49/61 or 80%), the patient had complied with our steroid premedication regimen. In four (7%) of 61 cases, only four doses of prednisone were completed, and in eight (13%) of 61 cases only three prednisone doses were completed. A small number of patients received diphenhydramine or the combination of diphenhydramine and cimetidine in addition to the prednisone. Forty (66%) of the 61 breakthrough reactions were treated; medications that were administered included diphenhydramine, epinephrine, oxygen, and IV fluids.

Discussion

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Little research has focused on the patient who has experienced a breakthrough reaction or adverse reaction to LOCM after steroid premedication. Past investigations have addressed the selective use of LOCM versus HOCM, the economic impact of adverse reaction to HOCM, and the risk profile of patients at risk for an adverse reaction [3,4,5,6,7,8]. Radiologists can expect to deal with the dilemma of whether to administer LOCM to a patient who has a history of breakthrough reaction.

The reported incidence of recurrent reactions is as low as 6-9% and as high as 40% [7, 9,10,11,12,13,14]. These estimates, however, were based on studies in which patients either received HOCM or no premedication or both [2, 9,10,11,12,13,14]. To our knowledge, our study is the first to examine the risk of a breakthrough reaction when all patients were treated to ensure the greatest possible safety, specifically with LOCM and steroid premedication. It seems likely that the safest approach would be embraced in this context by most radiologists, but there have not yet been estimates of risk to guide and counsel patients.

In our study, in patients with a history of prior adverse reaction to contrast media, the overall risk of having a breakthrough reaction despite LOCM and steroid premedication is approximately 10%. Some of these breakthrough reactions will be severe despite use of optimal precautionary measures. Patients whose initial contrast media reaction was anaphylactoid are at particularly high risk. If the initial reaction was mild (class 1), then the breakthrough reaction is also frequently mild (in our series occurring in more than two thirds of these patients). However, the subsequent reaction may be more severe in this same patient group (occurring in 11% of patients in our series). If the initial reaction was severe (class 2 or 3), then a significant minority (17% in our series) will again experience a severe reaction, and in our series 4% of the patients experienced a lifethreatening reaction (class 3).

A recent article investigating the mechanisms of reactions to iodinated contrast material suggested that "most severe reactions may be IgE-mediated" [15]. This research suggests that patients with a history of anaphylactoid contrast media reaction should not be reinjected with LOCM regardless of whether they receive steroid premedication. Research about the issue of severe reactions is widely disparate, probably because the total number of cases is small [2, 9,10,11, 16,17,18].

Shehadi [11] concluded that "previous major reactions are seldom repeated," whereas Ansell et al. [10] reported an 11-fold increased risk of a severe reaction in a patient with a prior history of adverse reaction. Greenberger [17] reported a 35-60% incidence of repeated severe reactions, which was reduced to 3-9% with premedication [16].

The use of LOCM has been reported to reduce the incidence of adverse reactions as compared with HOCM [2, 5,6,7,8, 15]. The value of steroid premedication is less clear, espoused by some authors as effective and others as useless in preventing recurrent reactions [2, 11, 16,17,18]. However some of the authors who questioned the efficacy of premedication compared HOCM use after premedication with LOCM use. The composition of the recommended premedication regimens also varies from those that include only steroids as in our institution to those that also incorporate diphenhydramine and ephedrine or cimetidine (or both) [2, 19,20,21].

We found that the risk factors significantly more likely to be identified in the breakthrough group than in the control group were a history of seafood allergy or hay fever. Shehadi [22] reported that of patients with a history of seafood allergy, 15% had an adverse contrast media reaction, whereas Enright et al. [3] did not find it a statistically significant risk factor. In the same article, Shehadi reported that of the patients who had a history of hay fever, 10% experienced an adverse reaction [22]. No article to date has specifically studied at-risk factors in patients with breakthrough reactions.

Additional studies will be necessary to validate our results. A limitation of this study is the small number of patients who experienced breakthrough reactions. A multiinstitutional investigation may be necessary to obtain a large number of patients. Despite our best efforts with screening by nurses, chart perusal, and telephoning patients, some data were missing as shown in Table 2. It is also possible that some patients who had breakthrough reactions were not entered into our quality improvement database. In addition, data about whether a patient's initial reaction was to HOCM or LOCM were not always available. Another deficiency is that not all patients complied with our steroid premedication regimen. Finally, our control group included only patients who received IV contrast media rather than those who also received contrast media enterically or by other routes.

In conclusion, breakthrough reactions are likely to occur in radiology practice. Typically this breakthrough reaction is of similar severity to the patient's initial reaction, although it may be more severe. Contrast media should be given with caution in patients who have had prior reactions despite having received a steroid premedication. This is particularly true if the patient has a history of seafood allergy or hay fever. Further experience may allow us to conclude that contrast media use in this subgroup should be reserved for emergency situations or only in a controlled setting (immediate availability of cardiopulmonary support or a code team). Careful assessment must be made about the necessity of contrast media for future examinations. If alternative studies provide similar information, strong consideration should be given to performing these alternative examinations. In select cases, sonography or MR imaging may be substituted for contrast-enhanced CT. As a result of our study, we make the following recommendations. If after careful assessment it is deemed necessary to give IV contrast media, a full steroid premedication should be given in addition to premedication with 50 mg of diphenhydramine given 1 hr before the administration of IV contrast media. In addition, because of the potential for a respiratory reaction possibly requiring intubation, requiring individuals trained in intubation to be present outside the examination room is prudent. This is a logical and safe approach to the difficult problem of administrating contrast media in this patient population.

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