Retrospective Analysis of Acute Adverse Reactions of 4 Iodine Contrast Agents


 Objective Incidence of acute adverse reactions (ADR) of 4 kinds of iodine contrast agents were retrospective analyzed in 10532 cases of CT enhanced scan and 6130 cases of arteriography in our hospital, and to investigate the safety of these 4 types agents in clinical application.Materials and Methods The occurrence of ADR to Iohexol, Ioversol, Iopromide and Iodixanol (expressed as I1, I2, I3 and I4) were recorded in detail from August,2007. 36 months' data were analyzed by Fisher's `Exact Test. The incidences of ADR were calculated, and medicine information and features of adverse reactions induced by these 4 types agents are analyzed. Results: CT enhanced scan and arteriography was performed in 16662 cases, including body enhanced scan, CTA ，CTU and arteriography. Acute adverse reactions occurred in 25 cases, and the incidence of ADR was 0.15%. Among them, 18 cases had mild ADR (0.10%), 7 cases had moderate ADR (0.04%) and 0 cases had severe acute adverse reaction. There was a difference in the incidence of acute adverse reaction between the 4 contrast agents used (X2=5.854, p=0.022). I4 had the highest incidence of ADR, it was 0.32%, and the lowest incidence of ADR occurred in I2, it`s 0.08%. The incidence of ADR with I1 and I3 was 0.14% and 0.18%, respectively. The incidence of ADR in intravenous administration was significantly higher than that in arterial administration（X2=4.655，p=0.036）. Conclusion In this study, the incidence of acute adverse reaction to Iodixanol was the highest, and Ioversol was the lowest. The incidence of ADR in arteriography was significantly lower than that in patients with intravenous administration enhanced CT.


Introduction
Medical imaging plays an important role in clinical diagnosis and medical research. CT imaging is widely used in clinic, while arteriography not only plays a role in clinical diagnosis, but also is an important means of treatment. Among them, the application of iodine contrast agent is an indispensable part of CT enhanced scanning technology and arteriography, and the adverse reactions caused by iodine contrast agent are one of the most concerned problems in the clinical application of radiology, especially the most common acute adverse reactions (ADR), even death in severe cases. Suh et al. published a meta-analysis in 2019 to analyze the incidence of adverse reactions in 1,360,488 subjects using seven different types of iodine contrast agents. According to the report in this paper, the incidence of acute adverse reactions and severe adverse reactions of 7 kinds of iodine contrast agents were 1.03% and 0.0141% respectively. The incidence of ADR from high to low respectively Iomeprol, Iohexol, Iopamidol, ioversol, iodixanol, iopromide, iobitridol [1] Among them, iodixanol is a new type of non-ionic dimer iso-osmolar contrast agent, which is well tolerated and has a low incidence of adverse reactions according to some studies on Visipaque, the original agent of iodixanol [2] [3]. Aidixian is the generics of iodixanol in China rstly produced by Jiangsu Hengrui Pharmaceutical Co. LTD. For its clinical application, there is still a lack of corresponding clinical data. In this study, we retrospectively analyzed the incidence of ADR of 4 types iodine contrast agents( Iohexol (I 1 ), Ioversol (I 2 ), Iopromide (I 3 ) and Iodixanol (I 4 ) )in 16,662 persons of CT enhanced scan and angiography in our hospital during the past three years from May 2017 to April 2020.

Ethic statement
All experimental protocols were approved by the Institutional Review Board (IRB) for clinical study of Beijing Aerospace General Hospital (Beijing, China). All methods were carried out in accordance with the Guide for International Ethical Guidelines for Biomedical Research Involving Human Subjects, CIOMS and for Ethical review of biomedical research involving people in China. Informed consents of patients were exempted from IRB because this study only used retrospective chart review data and all personal data was eliminated and code as arbitrary number which were not personally-identi able.

Study subjects
We recruited all the patients who had enhanced CT scan and arteriography at the department of Radiology in our hospital From May 1, 2017 to April 30, 2020. The informed consent was obtained before enhanced CT scans and arteriography. There were 8948 male patients, with an average age of 63.80 ± 12.64 years. There were 7714 female patients with an average age of 63.50 ± 12.50 years.72% of the subjects were the rst time with iodine-contrast agent (11997/16662), and 28% were administration for iodine-contrast agent before (4665/16662), including 10,532 cases of intravenous administration and 6,130 cases of arterial administration.
The subjects underwent enhanced CT scanning or arteriography. The equipment parameters, examination types, and administration methods are described below.All subjects were given adequate hydration before and after the examination. They were visited once 0.5 hours before and 0.5 hours after the examination. If acute adverse reactions were found, they should be treated in time.

Equipment
We used Siemens SOMATOM De nition AS 64-Slice spiral CT scanner for the enhanced CT scan, and Siemens Artis Zee III Floor digital angiography for arteriography. We used Medrad Stellant VHU600 CT dual head injection system for the injection of the contrast media.
The arteriography included whole cerebral arteriography, selective coronary angiography, selective peripheral arteriography and aorta angiography.

Types of Examination
The parameters for the types of examinations are as follows: 1)Enhanced visceral CT scan with automatic tube current, 120kV tube voltage and 5 mm slice thickness.
2) Coronary CTA with automatic tube current, 120kV tube voltage and 0.75 mm slice thickness.
3) CTA of the head and neck with automatic tube current, 120kV tube voltage and 0.6 mm slice thickness.  Statistical Analysis: IBM SPSS23.0 software was used for row statistical analysis, and the normal distribution of quantitative data was expressed by X ± s.Two independent sample T test was used for comparison between the two groups.Fisher Exact test was used to determine the incidence of adverse reactions among 4 different contrast agents.The difference in the number of cases between the groups was statistically signi cant with χ2 difference or correlation.

Results
Characteristics of the study subjects with acute adverse reactions  Among the 16662 patients, 25 cases of acute adverse reactions occurred, with an incidence of 0.15%. Among them, 18 cases were mild, with an incidence of 0.10%.Moderate 7 cases, the incidence of 0.04%; There were 0 cases of severe. The incidence of acute adverse reactions was different among the four contrast agents used (Fisher's Exact Test X2 = 5.854 P = 0.022). The incidence of I4 was the highest, 0.32%. Seven of the 25 cases (28.0%) were from patients using I4, of which 4 were moderate.

Discussion
1. The mechanism of ADR of iodine contrast agent: Safety is a major concern in the use of iodine contrast agents, and all clinical strategies are used to avoid or reduce the ADR to iodine contrast agents which was initially thought to be an allergy-like reactions rather than a true immunoglobulin E (IgE) mediated hypersensitivity. These reactions are thought to result from the activation of complement, brinolytic system, and kinin system, as well as the release of histamine, prostaglandin, bradykinin, and other mediators [4].However, studies have shown that because of the release of histamine and trypsin and the occurrence of positive skin tests, the IgE mediated allergic mechanism is also one of the evidences for the occurrence of acute adverse reactions of iodine contrast agents [5] [6].Studies have shown that patients with IgE-mediated allergy-like reactions have a history of exposure to relevant allergens [7]. The data of this retrospective analysis showed that only 11 patients who had been exposed to iodine contrast agents should not be excluded from the IgE mediated acute adverse reactions of iodine contrast agents. There were no correlations between dose and severe allergies, and 1 ml dose for skin test may produce a fatal anaphylactic shock. Unless the pharmacopoeia states the need for skin testing prior to examination, Otherwise, our patients would not have skin test. However, studies have shown that the incidence of ADR in subjects with positive skin test is as high as 64.7%, and the incidence of anaphylactic shock is as high as 81.8%, indicating that positive skin test is an important early warning indicator of anaphylactic shock [7]. The cause of ADR to iodine contrast is not the iodine in the contrast itself, because iodine is necessary for the synthesis of thyroid hormones and is one of the elements that everyone needs to take. The mechanism of allergy-like reactions to iodine contrast has nothing to do with iodine itself. Fish and shell sh are rich in iodine. Some people who are allergic to shell sh can eat scaly sh, but some people who are allergic to scaly sh can eat shell sh, because what causes allergies is not iodine in seafood, but tropomyosin in shell sh or actin in scaly sh [8] [9].

Relationship between categories of iodine contrast agents and adverse reactions
Studies have shown that the cause of ADR is related to high osmotic pressure and the high content of related ions in the blood [10].In the development history of iodine contrast agents, there were three historical leaps, namely, the development of ionic contrast agents in the 1950s, the rst and second generation of non-ionic monomer contrast agents in the early 1970s, and the development of non-ionic dimer contrast agents in the late 1970s.At present, there are four types of iodine contrast agents: ionic monomers, non-ionic monomers, ionic dimers and non-ionic dimers. These categories differ in three important respects: iodine-particle ratio, osmotic pressure, and viscosity [1] [12].Large sample studies by Shehadi, Valls and Kopp showed that the total incidence of ADR and severe allergic reactions of high-osmolar agents were signi cantly higher than that of low-tonic iodine contrast agents [13][14] [15].Compared with ionic agents, non-ionic agents have the advantages of low-osmolarity, good stability, high temperature sterilization which were more stable and safe.
ESUR has reached a consensus that there is no signi cant difference in the incidence of ADR between low-osmolar and isoosmolar contrast agents.In Suh's meta-analysis and Bertrand's multicentre double-blind study, there was no signi cant difference in the incidence of adverse reactions between low-osmolar and iso-osmolar contrast agents [1] [16].However, in this study, the incidence of ADR of isot-osmolar contrast agents iodixanol was signi cantly higher than that of low-osmolar contrast agents ioversol, iohexol and iopromide. The high rate of ADR of iodixanol may not be related to its iso-osmolar properties, but to its high viscosity. Compared with other non-ionic monomer iodine contrast agents, iodixanol with iodineparticle ratios of 6:1 has higher viscosity. However, studies on the original drug of iodixanol, Visipaque, found that the incidence of adverse reactions of iodixanol was not signi cantly different from that of other low-osmolar contrast agents, so is the reason for the high adverse reactions of generics iodixanol (Aidixian) related to its produce? We need further studies with multi-center large samples of different batches of its products for more in-depth analysis.

Risk factors related to adverse reactions of iodine contrast agents
There are literature studies that reports that the history of allergy, asthma, allergic diseases, gender, age, dose, ow rate and route of administration of iodine contrast agents are statistically signi cant in the occurrence of adverse reactions of iodine contrast agents [17][18] [19]. According to a prospective, observational study in coronary angiography, the history of iodine contrast agent by artery is immediate hypersensitivity is an important risk factor in arteriography, so for the patients who have undergo with iodinated agents may replace the other types of iodine contrast agent in arteriography for reducing the occurrence of ADR [20].
One of the main purpose of this study was to compare between iodixanol (Adixian) and several other iodine contrast agent differences in incidence of ADR. We apply the protocols with same doses and ow rates, results show that there were no signi cantly statistical difference of gender and age.
There was signi cant difference between the arterial administration group and the intravenous administration group (P = 0.036).At the same ow rate, high viscosity contrast agent may produce more adverse reactions. Kopp`s study found that the incidence of ADR in patients by intravenous injection was signi cantly higher than that in patients by intravascular injection [15], which may be due to higher arterial pressure than venous pressure and less in uence by the viscosity of contrast agent. In this study, the incidence of ADR of iodine contrast agent in arteriography was signi cantly lower than that of intravenous administration, which also indicated from another perspective that high viscosity contrast agents may produce more adverse reactions during intravenous administration. 4. Whether fasting, hydration, heating and corticosteroid prophylaxis can reduce the incidence of adverse reactions?
It is generally believed in the literature that premedication corticosteroid for at-risk patients cannot reduce the incidence of adverse reactions [21]. Fasting can reduce the incidence of nausea [22], and heating contrast agent in advance can make patients feel more comfortable, thus reducing the incidence of adverse reactions [19]. Hydration may have no obvious effect on reducing the occurrence of acute adverse reactions, but it can reduce the incidence of contrast-induced nephropathy [23] [24]. In our study, pre-heating with contrast agent, adequate hydration before and after the examination, and fasting for at least 4-6 hours before the examination was regularly used. Since this was a retrospective study, we did not set up the corresponding control group for the study analysis.
All patients in this study did not adopt pre-medication and they will be observed for at least 30-60 minutes by venous indwelling needle, because 90% of the adverse reactions happen during this period.
In conclusion, the overall incidence of ADR of the 4 types iodine contrast agents was low. In our study, the incidence of ADR of iodixanol(Aidixian) was the highest, and most of them were moderate acute adverse reactions, which may be related to the high viscosity of iodixanol. As a generic agent, we need to observe the acute and delayed adverse reactions of iodixanol, including CIN and other adverse reactions by a multicenter, prospective and observational study, and further analyze the risk factors of adverse reactions.