2025 Volume 48 Issue 3 Pages 241-245
Iodine-based contrast agents can induce various acute hypersensitivity reactions ranging from mild itching or vomiting shortly after administration to severe hypotension or loss of consciousness. In Japan, steroid premedication is commonly used to prevent acute hypersensitivity reactions. However, little clear evidence supporting its efficacy is available. In this study, we evaluated the effectiveness of premedication for acute hypersensitivity reactions induced by nonionic iodine contrast agents using propensity score matching. The participants included patients who were administered nonionic iodine contrast agents at Yokohama City Minato Red Cross Hospital between April 1, 2016 and March 31, 2022. Only first-time patients with no history of hypersensitivity reactions to contrast agents were included. The patients were classified into premedication and non-premedication groups, and the incidence proportions of acute hypersensitivity reactions were compared after matching. Of the 19976 patients, 422 (211 in each group) were matched. In the premedication group, 7 cases (3.32%) of hypersensitivity reactions occurred. In contrast, only 2 cases (0.95%) were observed in the non-premedication group. The odds ratio for the occurrence of hypersensitivity reactions in the premedication group was 3.500 (95% confidence interval, 0.727–16.848), with no significant difference. Therefore, premedication did not demonstrate the efficacy in preventing acute hypersensitivity reactions induced by nonionic iodine contrast agents. Based on the results of this study and guidelines, a recommendation for premedication was not reached for patients with a history of allergies, including asthma and atopy, as well as those with a history of drug or food allergies.
Contrast agents that enhance the visibility of lesions and tissues play a crucial role in medical diagnostics and are widely used. However, numerous side effects may occur immediately after administering contrast agents, ranging from mild symptoms such as itching and vomiting to life-threatening conditions such as hypotension and loss of consciousness.1) Allergic-like reactions to modern iodine contrast agents are rare; however, they occur at a rate of approximately 0.6%. Given the high frequency of use of iodine contrast agents, such reactions are commonly encountered in routine clinical practice and require safer preventive measures.
A history of allergy to contrast agents has been cited as a prominent risk factor for adverse reactions to contrast agents, with reports indicating that the risk of developing allergy-like reactions upon re-exposure is approximately 5 times higher.2) The European Society of Urogenital Radiology (ESUR) guidelines3) state that a history of allergy to contrast agents, active bronchial asthma, and active atopy are risk factors for the development of acute adverse reactions; however, there is no statement in the guidelines supporting the recommendation of premedication with intravenous or oral steroids, or antihistamines, in any of these cases. The American College of Radiology (ACR) guidelines4) indicate that premedication may be considered for patients with a history of allergy to contrast agents. However, premedication is not recommended for those with a history of asthma, other drug allergies, or food allergies. Neither guideline generally recommends the administration of premedication in most cases. One reason is that the effectiveness of premedication for moderate and severe allergic reactions has not yet been demonstrated.5,6) However, these guidelines are primarily based on Western patient data and may not adequately account for the unique risk profiles of Japanese patients. Some studies suggest that premedication may have a preventive effect; however, others have concluded with recommendations to change the contrast agent.7) Additionally, reports indicated that while premedication may mitigate symptoms, it cannot prevent recurrent reactions.8) However, these reports have limitations in generalizing the current understanding of the efficacy of premedication, as they were confined to patients with a history of allergy to iodine contrast agents7) or included ionic iodine contrast agents rather than the currently prevalent nonionic iodine contrast agents.7,8) Additionally, the fact that the exact mechanisms underlying hypersensitivity reactions to contrast agents have not yet been fully elucidated highlights the need for further investigations into the efficacy of premedication. Moreover, many of these studies have failed to consider the bias introduced by the presence of specific risk factors in patient groups receiving premedication, and the adjustment for confounding factors required to accurately assess its true efficacy has been inadequate.
Currently, some experts believe that premedication reduces the likelihood of allergic reactions in high-risk patients receiving iodine contrast agents.6) According to a nationwide survey conducted in Japan,9) premedication was used for a wide range of risk factors, including a history of allergy to contrast agents (40%), active bronchial asthma (24%), asthma (25%), anaphylactic shock due to substances other than contrast agents (20%), drug allergies (21%), and food allergies (6%). Furthermore, in a study analyzing risk factors for hypersensitivity reactions to iodine contrast agents,10) the administration of premedication was not identified as a factor influencing the occurrence of hypersensitivity reactions. However, as this study did not adjust for background factors influencing premedication use, limitations in interpreting these results exist.
This study aimed to address these challenges by employing propensity score (PS) matching that accounts for patient backgrounds and risk factors specific to Japan, enabling an accurate evaluation of the effectiveness of premedication.
The study targeted patients who were administered nonionic iodine contrast agents at Yokohama City Minato Red Cross Hospital between April 1, 2016 and March 31, 2022. This study focused on those who received nonionic iodine contrast agents for the first time at the facility during this period and those who had no history of contrast agent allergies to exclude patients with a history of hypersensitivity reactions to contrast agents. A list of nonionic iodine contrast agents is provided in Supplementary Table S1.
Data CollectionHypersensitivity reactions to nonionic iodine contrast agents were defined as those that occurred at the time of administration and were reported as adverse reactions to the pharmacy department by radiologists, radiologic technologists, or nurses. Data were collected on basic information (including age, sex, and weight), allergy history (food and drugs), comorbidities (atopic dermatitis, urticaria, asthma, hypertension, diabetes, and dyslipidemia), laboratory values (blood urea nitrogen, serum creatinine (SCr), serum sodium, serum potassium, serum chloride, total bilirubin (T-Bil), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), blood glucose, glycosylated hemoglobin, white blood cell count, hemoglobin, platelet count (Plt), estimated glomerular filtration rate calculated using the Japanese formula for estimated glomerular filtration rate,11) nonionic iodine contrast agent information (contrast agent name and iodine dose), concomitant medications (steroids, antihistamines, and immunosuppressants), and the presence or absence of premedication to evaluate patient characteristics.
For each clinical item, data obtained within 30 d before the administration of the contrast agent were used. The iodine dose of the contrast agent was calculated based on the dose recorded in the electronic medical records. Concomitant medications were defined as those prescribed on the same day as those with overlapping prescription durations, prescribed on the day of contrast agent administration. For concomitant use of steroids, only those with a prescription duration exceeding 10 d were included to exclude premedication prescriptions. The computed tomography examination order manual at Yokohama City Minato Red Cross Hospital recommends that in cases with a history of mild hypersensitivity reactions to contrast agents, a different contrast agent should be used, and steroids should be administered before contrast agent administration. Premedication was defined as the administration of intravenous or oral steroids on the day of or before contrast agent administration.
AnalysisStatistical analyses were performed using the statistical software SAS version 9.4 (SAS Institute Inc., Cary, NC, U.S.A.). For comparisons between the premedication and non-premedication groups, the chi-square test or Fisher’s exact test was used for nominal variables, and the Wilcoxon rank-sum test was used for continuous variables. The statistical significance level was defined as a p-value <0.05. Additionally, PSs were calculated using logistic regression, and 1 : 1 nearest-neighbor matching with a caliper (caliper 0.2) was performed between the premedication and non-premedication groups. Subsequently, the odds ratio (OR) for hypersensitivity reactions in the premedication group was estimated using conditional logistic regression, with the non-premedication group as the reference. The variability of each variable after matching was evaluated using standardized differences, and a |standardized difference of less than 0.1 was considered to indicate minimal variability.12) Covariates for calculating the PS were selected based on previous reports10) and included age, sex, total iodine dose, history of atopic dermatitis, history of asthma, history of hypertension, history of diabetes, history of dyslipidemia, AST, ALT, SCr, use of steroids, antihistamines, immunosuppressants, history of food allergies, history of drug allergies, and outpatient or inpatient status.
Ethical ConsiderationsThis study adhered to the “Ethical Guidelines for Life Science and Medical Research Involving Human Subjects” and was approved by the Keio University Faculty of Pharmacy Ethics Committee (Approval No. 220518-2) and the Yokohama City Minato Red Cross Hospital Medical Ethics Committee (Approval No. 2022-11).
The comparison of patient characteristics between the premedication and non-premedication groups is listed in Supplementary Table S2, and the premedication drugs and their usage amounts are shown in Supplementary Table S3. In the premedication group, female sex, inpatient status, total iodine dose, LDH, Plt, history of drug allergies, history of food allergies, history of asthma, history of hypertension, history of diabetes, history of dyslipidemia, use of steroids, antihistamines, and immunosuppressants were significantly higher. In contrast, in the non-premedication group, male sex, outpatient status, and T-Bil were significantly higher.
Efficacy of Premedication after PS MatchingThe median values (minimum–maximum) and standardized differences in the covariates before and after PS matching are presented in Table 1. After PS matching, the patients were classified into the premedication (n = 211) and non-premedication groups (n = 211) (Fig. 1). Following PS matching, the standardized differences for 15 of the 17 variables were less than 0.1, confirming that the statistical balance of the covariates was achieved. In the premedication group, 7 cases of hypersensitivity reactions (3.32%) occurred, whereas in the non-premedication group, 2 cases (0.95%) were observed. The OR for hypersensitivity reaction incidence in the premedication group was 3.500 (95% confidence interval: 0.727–16.848), and no significant difference was observed.
| Description | Before propensity score matching | Std diff | After propensity score matching | Std diff | ||
|---|---|---|---|---|---|---|
| Premedication group (n = 211) |
Non-premedication group (n = 19765) |
Premedication group (n = 211) |
Non-premedication group (n = 211) |
|||
| Age (years), median (range) | 68 (13–93) | 64 (0–107) | 0.120 | 68 (13–93) | 70 (0–93) | 0.039 |
| Sex (male), n (%) | 95 (45.0) | 11169 (56.5) | 0.232 | 95 (45.0) | 89 (42.2) | 0.057 |
| Sex (female), n (%) | 116 (55.0) | 8596 (43.5) | 116 (55.0) | 122 (57.8) | ||
| Number of people using contrast media, n (%) | ||||||
| Outpatient | 79 (37.4) | 14121 (71.4) | 0.752 | 79 (37.4) | 76 (36.0) | 0.030 |
| Inpatient | 132 (62.6) | 5644 (28.6) | 132 (62.6) | 135 (64.0) | ||
| Iodine content, median (range) | ||||||
| Contrast medium iodine content (g) | 30.9 (0–101) | 30.0 (0–128) | 0.139 | 30.9 (0–101) | 30.0 (2–70) | 0.072 |
| Clinical laboratory test, median (range) | ||||||
| Aspartate aminotransferase (U/L) | 23 (10–3079) | 24 (5–9533) | 0.027 | 23 (10–3079) | 24 (7–465) | 0.029 |
| Alanine aminotransferase (U/L) | 20 (6–975) | 19 (1–5664) | 0.053 | 20 (6–975) | 18 (3–476) | 0.040 |
| Serum creatinine (mg/dL) | 0.72 (0.26–10.6) | 0.74 (0.13–24.1) | 0.074 | 0.72 (0.26–10.6) | 0.76 (0.21–9.11) | 0.060 |
| Allergy, n (%) | ||||||
| Drug allergy | 43 (20.4) | 1246 (6.30) | 0.574 | 43 (20.4) | 46 (21.8) | 0.043 |
| Food allergy | 17 (8.06) | 828 (4.19) | 0.192 | 17 (8.06) | 18 (8.53) | 0.020 |
| Comorbidity, n (%) | ||||||
| Atopic dermatitis | 5 (2.37) | 253 (1.28) | 0.097 | 5 (2.37) | 7 (3.32) | 0.071 |
| Asthma | 85 (40.3) | 1183 (5.99) | 1.421 | 85 (40.3) | 84 (39.8) | 0.012 |
| High blood pressure | 114 (54.0) | 7485 (37.9) | 0.333 | 114 (54.0) | 99 (46.9) | 0.144 |
| Diabetes | 73 (34.6) | 5132 (26.0) | 0.197 | 73 (34.6) | 67 (31.8) | 0.062 |
| Dyslipidemia | 64 (30.3) | 4043 (20.5) | 0.244 | 64 (30.3) | 63 (29.9) | 0.011 |
| Concomitant medication, n (%) | ||||||
| Steroid medicine | 7 (3.32) | 232 (1.17) | 0.197 | 7 (3.32) | 7 (3.32) | 0.000 |
| Anti-allergic medicine | 22 (10.4) | 426 (2.16) | 0.560 | 22 (10.4) | 24 (11.4) | 0.040 |
| Immunosuppressant | 6 (2.84) | 136 (0.69) | 0.257 | 6 (2.84) | 2 (0.95) | 0.144 |
Std diff: standardized difference.
Our previous study9) demonstrated that the situation in Japan differs from the ESUR and ACR guidelines, which generally do not recommend the use of premedication to prevent hypersensitivity reactions to iodinated contrast agents. Building on this, we focused on evaluating the effectiveness of premedication specifically for the Japanese population, recognizing it as an urgent issue. This study evaluated the effectiveness of premedication after adjusting for the covariates considered to influence its implementation. As a result, a conclusion that supports the recommendation for premedication was not obtained.
Premedication is often administered to groups with a higher risk of hypersensitivity. PS matching was performed in our study to address this bias. The standardized differences for 15 of the 17 variables were less than 0.1 between the 2 groups. While no significant difference was identified, a tendency toward a higher incidence of hypersensitivity in the premedication group was observed, suggesting that unmeasured confounding factors that could not be fully evaluated in this study may have influenced the results. However, considering the mechanisms of hypersensitivity and the existing evidence, the findings of this study, which indicate no effectiveness of premedication, are believed to be valid. Furthermore, in our previous analysis of risk factors for hypersensitivity reactions to iodinated contrast agents,10) premedication was not identified as a factor influencing the onset of reactions, which is consistent with the findings of this study.
It is considered that approximately 90% of hypersensitivity reactions caused by iodinated contrast agents are not mediated by the typical immunoglobulin E (IgE) antibody-mediated immediate-type reactions. Instead, these reactions occur through a mechanism in which the contrast agent acts directly on basophils and eosinophils, causing the release of histamine and other mediators without IgE antibodies.5) As a result, antihistamines and corticosteroids may not be fully effective against this mechanism, making it difficult to explain the effectiveness of premedication from this perspective.
In this study, before adjusting for confounding factors using PS matching, 13 of the 17 factors had a standardized difference greater than 0.1, suggesting that these factors may influence the choice of premedication. A comparison of patient backgrounds between the premedication and non-premedication groups (Supplementary Table S2) revealed that the premedication group had significantly higher rates for the following factors: female sex, inpatient status, total iodine dose, LDH, Plt, drug allergies, food allergies, history of asthma, hypertension, diabetes, dyslipidemia, use of corticosteroids, anti-allergic medications, and immunosuppressive drugs. These results are consistent with those of a nationwide survey that was previously conducted,9) which reported the use of premedication for a wide range of risk factors, including a history of asthma, anaphylactic shock, drug allergies, and food allergies. Furthermore, the tendency for premedication to be administered to patients with risk factors for acute hypersensitivity reactions to iodinated contrast agents aligns with the findings of our previous report,10) in which factors such as age, total iodine dose, history of drug allergies, and asthma were identified as independent risk factors for the onset of hypersensitivity reactions. The OR for hypersensitivity reaction onset in the premedication group was 3.500 (95% confidence interval, 0.727–16.848), and no significant difference was observed. Therefore, evidence that premedication is effective in preventing hypersensitivity reactions was not obtained. In contrast, the result showed that the odds of hypersensitivity reaction onset were 3.5 times higher in the premedication group than in the non-premedication group, suggesting low precision due to the wide 95% confidence interval. Further investigations are necessary to draw definitive conclusions from these results.
This study had some limitations. First, the study was conducted at a single institution with a limited sample size, which may result in biases arising from institution-specific patient populations or prescribing practices, making it challenging to generalize the findings. However, the premedication group in this study consisted of patients without a history of contrast media allergy, and the approximately 1% premedication implementation rate is considered a reasonable result. Second, the severity of hypersensitivity reactions was not assessed, and neither the classification into mild, moderate, or severe reactions nor the categorization of the observed symptoms was clearly defined, including the possible influence of the severity of the patient’s history, particularly asthma and atopy.
Based on the results of this study and various guidelines, a conclusion that supports the recommendation for premedication was not reached for patients with a history of allergies, including asthma and atopy, as well as those with a history of drug or food allergies.
This work was supported by the Grant for Research Project of the Japanese Society of Drug Informatics in 2023. We sincerely appreciate the substantial support provided to this study.
The authors declare no conflict of interest.
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