Plasma histamine levels following administration of radiographic contrast media

The effect of two conventional high-osmolality and two new low-osmolality contrast media on plasma histamine levels has been examined. The study population included 25 patients undergoing intravenous urography with Urovison 58% (sodium and meglumine diatrizoate), 24 patients receiving intravenous Hexabrix 320 (sodium and meglumine ioxaglate) for urography, 16 patients receiving intravenous Iopamiro 370 (iopamidol) for urography and 12 patients receiving Urografin 76% (sodium and meglumine diatrizoate) for coronary angiography. Seventy-four percent of the 77 patients studied suffered adverse reactions ranging from a feeling of warmth and nausea to laryngeal oedema and bronchospasm. Hexabrix 320 and Iopamiro 370 were associated with the least patient discomfort. All contrast agents usually produced a rise in plasma histamine following injection (Iopamiro 370 causing the least change) and the histamine levels then fell towards preinjection values over a space of about 10 minutes. No relationship was observed between the magnitude of the increase in histamine and the severity of the reaction that occurred. However, a relationship was suggested between the mean peak plasma histamine level achieved and the occurrence of a Grade II reaction (i.e., dry retching/vomiting, mild urticaria or rash). These findings raise the probability that histamine contributes to the more severe grades of reaction to radiographic contrast media.     

Immunologic basis for adverse reactions to radiographic contrast media

The lymphocyte transformation test (LTT) was used to elucidate whether certain side effects induced by radiographic contrast media have an immunologic etiology. Groups studied were: 8 patients who had previously experienced adverse reactions in association with urography, 6 patients who underwent urography without notable side reactions, 17 occupationally exposed nurses, and 9 unexposed controls. The lymphocytes from 2 hypersensitive patients and from 11 nurses exhibited a positive proliferative response to amidotrizoate. Five nurses who had shown a positive response, had a previous history of hypersensitivity reactions when handling contrast media, whereas the remaining 6 were free of symptoms. Amidotrizoate-specific memory cells were absent in patients who underwent urography without signs of hypersensitivity and in 7/9 of unexposed control subjects. Lymphocytes from patients sensitive to amidotrizoate cross-reacted to structurally related ionic contrast media while non-ionic contrast agents did not induce proliferation of the lymphocytes. Thus, ionic radiographic contrast agents have antigenic properties in man. Irradiated mixtures of radiographic contrast media and serum proteins were, in general, not effective in inducing an LTT response.     

Eosinophilia caused by iodinated radiographic contrast media

Statistically significant eosinophilia was noted in the peripheral blood of a group of 108 patients 48 h after the administration of iodinated radiographic contrast medium (RCM). The duration of eosinophilia was approximately 6 days. Eosinophilia had no accompanying clinical symptoms except for two cases where urticaria appeared. The incidence of eosinophilia was irrespective of dosage or type of RCM. Possible mechanisms responsible for eosinophilia have been considered. Since eosinophilias of other aetiologies are common, it is of practical importance to distinguish these from RCM-induced eosinophilias.     

Ventilatory effects of radiographic contrast media.

Respiratory adverse reactions have been reported with the use of contrast media. This study investigates the effects of different radiographic contrast media (RCM) on ventilation and blood gases. Tidal volume and respiratory rate of male Wistar rats anaesthetised with Inactin (100 mg kg-1 intraperitoneally), were measured continuously by integration of tracheal airflow. Contrast media (diatrizoate 370, ioxaglate 320 and iopromide 300) or mannitol controls matched for volume, pH and osmolarity (4 ml kg-1) were administered via a jugular cannula (n > or = 6 per group). Carotid artery blood was sampled at 2, 7, 12, 17, 25 and 30 min post-injection for PaO2, PaCO2 and pH. Systemic blood pressure was monitored from the same cannula. No significant reduction was observed in minute ventilation (tidal volume x respiratory rate per minute) with any of the contrast media. All contrast media and control solutions produced a fall in PaO2 within 4 min; returning to basal levels at 10 min (diatrizoate 35.6% (p < 0.05), ioxaglate 15.2% (p < 0.02), iopromide 16.2% (p < 0.01); controls: 17.3% (p < 0.01), 13.5% (p < 0.02) and 12.0% (NS), respectively). The fall in PaO2 induced by diatrizoate was significantly (p < 0.05) larger in comparison to the other groups. Ioxaglate, iopromide and their mannitol controls induced a comparable fall in PaO2. There was a concurrent rise in PaCO2 and fall in pH that reached significance for diatrizoate (p < 0.01). The changes in blood gases with RCM administration cannot be explained by changes in ventilation and may be due to an effect on pulmonary perfusion.     

Influence of radiographic contrast media on phagocytosis

To evaluate the influence of radiographic contrast media (CM) on human polymorphonuclear leucocytes (PML), the ability of these cells to ingest latex particles after in vitro exposure to five different radiographic contrast media was investigated. All CM inhibited the phagocytic properties of PML. The inhibition was dose dependent. The inhibitory effect was partly due to hyperosmolality but CM specific inhibition was also evident.     

Effects on the ATP content of cultured cells after radiographic contrast media exposure. Evidence for accumulation of contrast media in cultured cells

The ATP content of cultured cells after exposure to meglumine-calcium metrizoate, sodium metrizoate, iohexol, iopamidol and saline was studied. Initially, the ATP content diminished rapidly for a short period and thereafter slowly during the incubation. After incubation with contrast media or saline, the ATP content slowly increased to normal when the cells were reincubated with fresh nutrient medium. Different contrast media and saline with the same final osmolality produced a similar effect on the ATP content of the cultured cells. Cellular association of meglumine-sodium diatrizoate, sodium metrizoate, sodium-iothalamate, iohexol and iopamidol was also examined. The established cell line NHIK 3025 as well as primary cultures of human umbilical endothelium were found to accumulate contrast media in a time- and concentration-dependent manner. When the incubation was carried out at 4 degrees C, the cellular accumulation of contrast medium was less than 35 per cent of that seen at 37 degrees C. It therefore seems that energy-dependent processes are involved to some degree.     

Interaction of ligandin with radiographic contrast media.

Ligandin (Y protein) is an abundant cytoplasmic glutathione transferase present in liver, kidney and gut in various animals and man. Its interaction with four radiologic contrast media (Telepaque, 3-(3 amino-2,4,6, triiodophenyl -2 ethylpropanoic acid, sodium salt; Hypaque, sodium -3, 5-diacetamido-2,4,6,-triiodobenzoate; Cholografin, N,N'adipyl-bis-(3-amino-2,4,6-triiodobenzoic acid) N-methyl-glucosamine; Diodrast, 3,5-Diiodo-4-pyridone-N-acetic acid, Diethanolamine Salt was investigated by observing inhibitory effects on the enzyme-catalyzed conjugation of glutathione with 1-chloro-2, 4-dinitrobenzene. Lineweaver-Burk plots of reciprocal initial velocity versus reciprocal inhibitor concentrations at fixed glutathione and chlorodinitrobenzene concentrations demonstrate non-competitive inhibition by all contrast media except Diodrast. No conjugates of contrast media with glutathione were formed. It is postulated that intracellular accumulation of contrast media is aided by intracellular binding with ligandin. Inhibition of the GSH transferase activity of ligandin can disrupt the mercapturate formation, an important detoxification process.     

Formation of potential antigens from radiographic contrast media

The use of radiographic contrast media is occasionally accompanied by more or less serious adverse effects, evidently of complex etiology, following intravascular administration. Some of these reactions are suspected of having an allergic basis. The in vitro and in vivo formation of iodinated serum proteins following gamma irradiation in the presence of two commonly used radiographic contrast media is demonstrated. Non-toxic concentrations of ascorbate present during the irradiation is shown to prevent the formation of such iodo-proteins in vitro as well as in vivo. The amounts of potentially antigenic iodoprotein formed during radiographic procedures will certainly be very small, but this quantity may be sufficient to elicit a hypersensitivity reaction in cases when an individual has been previously sensitized to immunologically similar iodo-proteins, a mechanism that could account for certain rare and unpredictable reactions. The radiation induced formation of iodo-proteins may also serve as a model for the formation of iodine containing antigens mediated by a free radical mechanism, i.e. in the metabolism of iodinated compounds like erythrosine, a widely used colouring agent for certain foods.     

Effects of radiographic contrast media on monolayer cell cultures

The relationship between iodine concentration, osmolality, and toxicity for nine different contrast media was studied. High osmolal conventional ionic contrast media (Na-metrizoate, Na-iothalamate, meglumine/Na-diatrizoate, meglumine-calcium-metrizoate) and the new low osmolal nonionic (Metrizamide, iopamidol, iohexol) and ionic dimer (Meglumine/Na-ioxaglate) contrast media were tested. Monolayer cell cultures of human cervical carcinoma in situ cells were used as a test system. The toxicity of contrast media on cell cultures was strongly dependent on the osmolality, and different contrast media with the same osmolality had about similar effects on the cell cultures. However, contrast media seem to have some additional and more specific effects since equiosmolal saline and mannitol were better tolerated. When the toxicity was related solely to iodine concentration it emerged that the new low osmolal contrast media were much better tolerated than the high osmolal conventional contrast media.     

Iodinated radiographic contrast media possess antioxidant properties in vitro

PURPOSE: To study potential properties of iodinated radiographic contrast media (IRCM) for intravascular use in in vitro free radical generating reactions. MATERIAL AND METHODS: Superoxide (*O2-) and hydroxyl (*OH) radicals were generated in xanthine oxidase and Fenton reactions. *O2- was assayed by the nitroblue tetrazolium (NBT) method, whereas *OH was assayed by an aromatic hydroxylation (2-hydroxybenzoic acid) method. Total antioxidant status (TAS) of test substances was determined by a colorimetric assay. Finally, acetyl-cholinesterase (AChE) activity was measured in the absence and presence of IRCM. RESULTS: High concentrations (>50 mM) of IRCM inhibited *O2- production, ionic more than non-ionic IRCM. Medium concentrations (25-50 mM) of IRCM reduced *OH production, and both types of IRCM were equally potent. Low concentrations (<25 mM) of non-ionic IRCM displayed higher antioxidant capacity than their ionic counterparts when tested in the TAS assay. Visipaque 320 (iodixanol) was found to have the highest TAS value, followed by Omnipaque 350 (iohexol), Hexabrix 320 (ioxaglate), and Urografin 370 (diatrizoate). CONCLUSION: IRCM have in vitro antioxidant properties in concentrations relevant for their clinical application. These properties may therefore be of potential importance when evaluating IRCM effects in vivo, particularly those concerning cardiovascular and renal function.     

Cytostatic effects of radiographic contrast media in synchronized cell cultures

The cytostatic effects of conventional high osmolal ionic contrast media (meglumine-calcium metrizoate and Na-metrizoate) and new low osmolal nonionic contrast media (iohexol and iopamidol) in synchronized cell cultures were tested. The cell-cycle prolongation was most pronounced when the contrast media were added in the G1 phase, but there was also a marked effect when the contrast media were added in the S phase or late in the G2 phase. The cytostatic effect even persisted into the first cell cycle following the termination of the exposure. All four contrast media exerted effects stronger than that of equiosmolal saline. Iohexol and iopamidol produced a more severe effect than meglumine-calcium metrizoate and Nametrizoate at equal osmolality. Thus, the cytostatic effect of contrast media cannot be explained only by hypertonicity; the contrast media must have an additional specific cytostatic effect. When the cytostatic effect was related to iodine concentration, the new low osmolal nonionic contrast media influenced the cell cycle less than the conventional high osmolal ionic contrast media.     

Production and characterization of improved liposomes containing radiographic contrast media

The authors have investigated liposomes prepared by the reverse-phase evaporation method (REVs) and a modification of this technique that employs a microemulsifier (MREVs), for the delivery of radiographic contrast media (RCM) to the liver and spleen. The modification entailed substituting a Microfluidizer (Microfluidics Inc., Newton, MA) for the sonication step of the REV technique. The MREV procedure is amenable to large-scale production and continuous-flow operation and yields products with high RCM encapsulation. Efficiently entrapped are ionic, high-osmolar diatrizoate (24.38 +/- 2.62% versus 8.35 +/- 0.55%; MREV versus REV), and nonionic, low osmolar Iotrolan (Schering AG, Berlin, FRG) (24.84 +/- 2.13% versus 7.25 +/- 1.19%) RCM with iodine-to-lipid ratio of 1.5:1. The MREV procedure, therefore, has practical advantages over the REV method. High liver and spleen uptakes of Iotrolan-containing vesicles were noted in normal rats. The diatrizoate MREVs lost their contents on contact with serum, resulting in urinary excretion of this agent. Computed tomography values of splenic and hepatic sections, 1 hour after intravenous injection of Iotrolan MREV (500 mgI/kg), are 0.78, and 0.08 Hounsfield Units (HU)/mgI/kg, respectively (versus 0.01, and 0.006 HU/mgI/kg for free Iotrolan).     

Gadolinium-containing contrast media for radiographic examinations: a position paper

Recently, it has been suggested that gadolinium-based contrast media could be used for radiological examinations in patients with significant renal impairment, previous severe generalized reaction to iodinated contrast media or thyroid disease about to undergo radioactive iodine treatment; however, the indications for and risks of using gadolinium agents in this way are not well known; hence, the Contrast Media Safety Committee of The European Society of Urogenital Radiology reviewed the literature to issue a position paper on this subject. A comprehensive literature review was performed and the resulting report was discussed at the Ninth European Symposium on Urogenital Radiology in Genoa, Italy, June 2002. Review of the literature indicates that according to experimental data on animals gadolinium-based contrast media have more nephrotoxic potential than iodinated contrast media in equivalent X-ray attenuating doses; therefore, gadolinium-based contrast media should not replace iodinated contrast media in patients with renal insufficiency for radiographic examinations. For patients with previous severe generalized reactions to iodinated contrast media, and in patients about to undergo thyroid treatment with radioactive iodine gadolinium-based contrast media in approved intravenous doses, up to 0.3 mmol/kg body weight will not give diagnostic radiographic information in most cases. Gadolinium-based contrast media are not approved for radiographic examinations.     

Death following intravascular administration of contrast media

Adverse reactions to intravascularly administered contrast media preceding death and the autopsy findings in 44 patients are presented. There is a wide scatter of the age distribution of fatal reactions. The highest incidence is in the 50-70 year age group. Similar observations were obtained from the 405 deaths due to contrast media reported to the Food and Drug Administration of the United States. In the same age group the number of reactions is highest, likewise the autopsy findings. The predominant autopsy findings are pulmonary edema, congestion and hemorrhage; arteriosclerosis, both general and coronary. In the younger age group the autopsy findings are limited mostly to the respiratory tract. Fatal reactions to contrast media occur often without warning and most deaths occur within 15 min to 6 hours. Reactions to contrast media occur without relation to sex or age.