Fewer adverse drug reactions occur with nonionic than ionic contrast media [Classics Series]

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials

1. The prevalence of adverse drug reactions (ADRs) with the use of intravenous high-osmolar, ionic contrast media was over four-fold greater compared to low-osmolar, nonionic contrast.

2. Severe reactions, including dyspnea, hypotension, cardiac arrest and syncope occurred in over five times as many patients administered ionic media as compared to those administered nonionic media.

Original Date of Publication: June 1990

Study Rundown: Contrast agents, like any intravenously administered drug, pose a significant risk of immediate ADRs ranging from mild nausea, vomiting, pruritus or urticaria to severe and life-threatening reactions such as anaphylaxis or cardiac arrest. Prior to the widespread introduction of nonionic contrast agents in the 1980s, ionic agents were the only available contrast media for contrast-enhanced examinations or angiography, and the value of transitioning to the newer, unqualified agents was questioned on the basis of cost versus a potentially marginal safety benefit. The present study sought to determine if the use of nonionic over ionic agents would improve the safety of contrast-enhanced examinations through a large-scale prospective cohort during a transition period in Japan in which both agents would be in active use.

Including 330 000 cases over three years, the prevalence of any ADRs with the use of intravenous high-osmolar, ionic contrast media was 12.66% as opposed to 3.13% for low-osmolar, nonionic contrast media. Severe ADRs requiring immediate treatment occurred in 0.22% of patients administered ionic contrast media versus 0.04% of those administered nonionic agents. The most significant risk factors for the occurrence of ADRs included young age (less than 30), a history of atopy or other allergy, and a history of cardiac disease. These findings corroborated, on a large-scale, prior findings that the use of nonionic over ionic contrast agents posed a significant improvement in patient safety with regard to the occurrence of all ADRs, and even more importantly, the occurrence of severe and life-threatening ADRs at any level of baseline patient risk. Notably, this study did not examine the risk of contrast-induced nephropathy with these agents, instead focusing primarily on anaphylactic and anaphylactoid reactions.

Click to read the study in Radiology

In-Depth [prospective cohort]: This trial was conducted at 198 institutions across Japan over a period of three years and included 337 647 cases, during which both ionic (50.1% of cases) and nonionic (49.9% of cases) contrast agents were available and in current use in the country. The study was restricted to examinations utilizing intravenous contrast administration only. Cases were excluded if patients underwent examinations other than contrast-enhanced CT, intravenous urography or intravenous digital subtraction angiography, or if records of the ADR or contrast medium were incomplete. ADRs were recorded using a standardized event reporting form by the examining physician at each institution, and were reported at an average rate of 67.8% (range 59.1%-82.3%) independent of patient criteria. ADRs were defined as the acute onset of nausea, vomiting, sensation of heat, urticaria, flushing, vascular pain, hoarseness, coughing, sneezing, chest or abdominal pain, palpitations, rigors, or facial edema. Severe ADRs were defined by dyspnea, sudden hypotension, cardiac arrest or loss of consciousness.

The overall prevalence of all ADRs was significantly lower for ionic (12.66%) versus nonionic (3.13%) contrast agents (p <0.01). An even greater difference was appreciated for severe reactions, at 0.22% for ionic (n=367) versus 0.04% (n=70) for nonionic media (p <0.01). A single fatality occurred in each group, but they were not clearly causally associated with contrast administration. Over 70% of ADRs occurred within 5 minutes of contrast administration in either group. Subgroup analysis revealed that no significant differences in the prevalence of ADRs occurred according to sex or mode of injection. Groups with the greatest prevalence of severe ADRs included those with a history of prior reaction to contrast media (0.73% for ionic versus 0.18% for nonionic agents), a history of general allergy (0.53% for ionic versus 0.10% for nonionic agents) or atopy (0.49% for ionic versus 0.11% for nonionic agents), a history of cardiac disease (0.53% for ionic versus 0.10% for nonionic agents), and those aged 20-29 (0.24% for ionic versus 0.06% for nonionic agents.) Premedication with steroids, antihistamines or sedatives had a positive effect only on the prevalence of severe reactions for ionic agents, but not for nonionic agents. Lastly, subgroups receiving more than 80 mL of ionic contrast showed the lowest prevalence of ADRs (9.9-11.32%), while among those receiving nonionic contrast, the prevalence of ADRs was lowest for the subgroup receiving 81-100 mL (2.50%).

Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse Reactions to Ionic and Nonionic Contrast Media, A Report from the Japanese Committee on the Safety of Contrast Media. Radiology. 1990 Jun 175:621–28.

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