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, fibrinolytic system, and kinin system, as well as the release of histamine, prostaglandin, bradykinin, and other mediators .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 .Studies have shown that patients with IgE-mediated allergy-like reactions have a history of exposure to relevant allergens . 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 . 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 shellfish are rich in iodine. Some people who are allergic to shellfish can eat scaly fish, but some people who are allergic to scaly fish can eat shellfish, because what causes allergies is not iodine in seafood, but tropomyosin in shellfish or actin in scaly fish .
2. 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 .In the development history of iodine contrast agents, there were three historical leaps, namely, the development of ionic contrast agents in the 1950s, the first 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 .Large sample studies by Shehadi, Valls and Kopp showed that the total incidence of ADR and severe allergic reactions of high-osmolar agents were significantly higher than that of low-tonic iodine contrast agents .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 significant difference in the incidence of ADR between low-osmolar and iso-osmolar contrast agents.In Suh's meta-analysis and Bertrand's multicentre double-blind study, there was no significant difference in the incidence of adverse reactions between low-osmolar and iso-osmolar contrast agents .However, in this study, the incidence of ADR of isot-osmolar contrast agents iodixanol was significantly 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 iodine- particle 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 significantly 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.
3. 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, flow rate and route of administration of iodine contrast agents are statistically significant in the occurrence of adverse reactions of iodine contrast agents . 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 .
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 flow rates, results show that there were no significantly statistical difference of gender and age.
There was significant difference between the arterial administration group and the intravenous administration group (P = 0.036).At the same flow 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 significantly higher than that in patients by intravascular injection , which may be due to higher arterial pressure than venous pressure and less influence by the viscosity of contrast agent. In this study, the incidence of ADR of iodine contrast agent in arteriography was significantly 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 . Fasting can reduce the incidence of nausea , and heating contrast agent in advance can make patients feel more comfortable, thus reducing the incidence of adverse reactions . Hydration may have no obvious effect on reducing the occurrence of acute adverse reactions, but it can reduce the incidence of contrast-induced nephropathy . 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.