Radiopaque Agent Research Articles

Nature of adverse reactions to radiopaque agents; preliminary report.

The nature of the adverse reactions to the intravascular administration of radiopaque agents is not known. 1 Such reactions or complications vary from mild, with nausea and vomiting and urticaria, to severe, with syncope, shock, convulsions, respiratory distress, and focal hemorrhage, to fatal. They occur with intravenous urography, angiocardiography, regional aortography, and arteriography. It is difficult to arrive at an over-all estimation of rates, due to different criteria of what constitutes a reaction as well as variables in observing and reporting. From our observations, as well as those in the literature, it would appear that reactions increase with increasing dose, concentration, and speed of injection of these substances. Although the rate, in the main, has decreased with the introduction of newer agents, their increased use in a wide variety of diagnostic situations has resulted in an increased incidence of reactions. For reasons to be detailed elsewhere, 2 we

The nature of the toxic action of radiopaque diagnostic agents.

The question has been asked, “What is toxicity?” A reply comes from the answer to another question: What is the dose of a drug? The answer is: “Enough$” Enough to lead either to the desired result or to an undesired result. In the latter instance we have toxicity. We wish to know the nature of the toxicity of radiopaque diagnostic agents, but so little information is available that discussion must be largely speculative. The first approach is the statistical one, as shown in Figure 1. This is the characteristic curve of the acute lethal toxicity of iodopyracet in the rat, taken from the data of Hoppe, Larsen, and Coulston (1). I t is plotted on “logarithmic probability” paper, on which the abscissa represents the dose on a logarithmic scale and the ordinate is the percentage mortality on a scale that is multiples of the standard deviation from the average lethal dose, the LD 50, which is seen to be 6 gm. per kilogram of body weight. The point at the lower left is the approximate observed mortality in man of iodopyracet, about 1 in 100,000 at the usual dose of 20 c.c. of a 35 per cent solution, which is approximately 0.12 gm. per kilogram. This is taken from the report of Pendergrass, et al (2). The dose expected to give this mortality in the rat is about 4 gm. per kilogram. There are three explanations (at least) for these observations which must be considered. The first is that all people are more sensitive than all rats, but show the same frequency distribution of sensitivity. This would move the characteristic curve over to give an LD 50 of about 0.2 gm. per kilogram, or about 33 c.c, of the 35 per cent solution. This is probably not the LD 50 in man. Further evidence against this is that the LD 50 of these radiopaque diagnostic agents is about the same in rat, rabbit, cat, and dog (1). The second possibility is that the characteristic curve for toxicity in man is less steep than for the rat. That is, there is a wider individual variation among the members of the population, so that there are some individuals with a quantitative idiosyncrasy in that they respond in a manner in which all individuals would respond if given enough, but do so at a small dose. It seems likely that this is true. The third possibility is that the individuals who die have a qualitative idiosyncrasy; that is, they respond in a manner that is different from the reaction that would be produced in all individuals if given enough, and that the production of this atypical response bears little relation to the dose. These are the characteristics of so-called “drug allergy,” and there are reasons to believe that undesired reactions to these agents are of this nature.

Intravenous urography using mixtures of radiopaque agents.

In recent years increasing efforts have been made to produce intravenous urograms that rival retrograde films. Since some of the organic iodides differ in their mode of excretion, it seemed reasonable that combinations of two radiopaque agents might produce a higher concentration of iodide in the urine without an increase in the total amount of medium injected. Diodrast and Neo-Iopax were selected, since their mechanisms of excretion are entirely different. Most of the Neo-Iopax reaches the urine by glomerular filtration, as Smith (16, 18) demonstrated in 2 patients. In the usual dosage, most of the Diodrast (about 70 per cent) is secreted by the convoluted tubules and only 30 per cent by filtration, although for a few minutes after injection filtration is higher, depending directly on the plasma levels. At first the Diodrast and Neo-Iopax were injected at different times in separate syringes, but after suitable tests it was found that the contrast substances could be safely combined in the same syringe. Thirty consecutive adult pyelograms were obtained with 15 c.c. of 35 per cent Dio-drast mixed with 15 c.c. of 50 per cent Neo-Iopax, injected slowly over a five- to six-minute period. The films were compared with numerous others obtained by exactly the same technic with 30 c.c. of 35 per cent Diodrast or 30 c.c. of 50 per cent Neo-Iopax. A slight but definite increase in density of the roentgen shadow was noted when the mixture of the two iodides was used. Another advantage of the mixture, besides the increase in x-ray density, has also become apparent. It has proved to be safe and to cause very few minimal side-reactions, less than are observed with the unmixed individual drugs. Mild arm pain (vein cramps) still resulted, undoubtedly due to the Neo-Iopax. Nausea and a sensation of warmth occurred in a mild degree. No severe reactions such as vomiting, syncope, or urticaria were produced. At present, higher concentrations and larger amounts of one or both drugs are being used to determine which produces the greatest increase in density with the minimum of side-reactions. Even these large quantities can be given slowly without producing severe arm cramps. If 50 per cent Neo-Iopax is used alone, it is usually injected rapidly to avoid vein irritation. With the mixtures, this is no longer necessary. It is felt that a slow injection will reduce the incidence of severe shock-like complications, although there is no definite proof for this statement. Routine rapid injections are not necessary, even though some workers have claimed an increase in urine concentration by this method (14). Fairly severe reactions have occurred with rapid injections of 50 c.c. of 70 per cent Urokon (3). Barry and Rose (2) observed two extremely severe shock reactions in a series of 1,160 rapid injections of 25 c.c. of 70 per cent Urokon and still another was recorded by Porporis et al. (11), while Zink (20) had one among 350 cases.

Contrast substances for angiocardiography; study of side effects.

During the fifteen years since Robb and Steinberg boiled commercially available 35 per cent Diodrast to achieve a concentrated contrast solution for angiocardiography (1) many radiopaque agents have been employed for this purpose. In the United States, there has been widespread clinical use of Diodrast 70 per cent (2) and Neo-Iopax 75 per cent (3). The authors have had considerable angiocardiographic experience with these substances (the synonyms of which are given in Table I) and also with Urokon Sodium 70 per cent (4). It is the purpose of this communication to discuss these contrast agents with reference to the side effects related to their angiocardiographic use. Regardless of the contrast substance employed, angiocardiography results in a profound physical and, therefore, emotional experience for the patient. An attempt was made to assess the nature of the immediate reaction in patients undergoing angiocardiography. Shortly following each injection, co-operative adult patients answered a questionnaire given by a physician (who was unaware of the medium employed). Diodrast, Neo-Iopax and Urokon in concentrated solutions were each used in 25 examinations, consisting of two injections of the usual 40 to 50 c.c. dose of the agent about fifteen to twenty minutes apart. For purposes of estimating the incidence of vascular thrombosis, only patients in whom a “clean” percutaneous insertion of the needle had been made and in whom a one week follow-up inspection was possible were accepted for the study. Details of the immediate reactions to the three drugs are presented in Table II; certain general response patterns became apparent and are discussed individually. Immediate Reaction to Angiocardiographic Use of Diodrast (2, 4) Starting at eight to twelve seconds after the beginning of the injection, there occurs an intense sensation of heat in the thorax, face, and head which sweeps downward over the entire body, usually including the rectum and genitalia. The feeling of heat over the body apparently indicates the arrival of the contrast agent in the capillary bed. That it involves peripheral vasodilatation is evidenced by the accompanying flush. In the words of a physician who underwent angiocardiography, “One feels like a balloon and the entire body seems to be on fire” (5). A metallic or bitter taste is often noted in the mouth. The sensation of heat reaches a maximum in about fifteen to thirty seconds and diminishes during the next few minutes. Weakness is the next most prominent symptom and usually outlasts the feeling of heat. Manometric blood pressure studies made on a patient who received one injection of each of the three agents suggest that the weakness associated with Diodrast is at least temporarily associated with a fall in blood pressure (Fig. 1A). This is in accord with published clinical and experimental investigations (2, 4, 6, 7).

Late effects of thorium dioxide in man.

THE USE of thorium dioxide in man has been controversial since its introduction in 1930. 1 In the form of a colloidal suspension, thorium dioxide is a radiopaque diagnostic agent of greatest usefulness in visualizing the liver and spleen. Numerous observers have shown that this particulate material is taken up by the reticuloendothelial system after intravenous injection. 2 The bulk of it is thus concentrated in the liver and spleen, which are then readily visible roentgenographically. In many patients it has been possible to demonstrate such lesions as liver abscesses and tumors without recourse to surgical measures. 3 In this technique of hepatosplenography thorium dioxide is a unique agent. Some observers have recognized potential dangers in the use of thorium dioxide, in view of its prolonged radioactivity and apparently permanent domicile in the body. 4 In experimental animals it has been possible to produce malignant tumors with the use of