Incompatibility of water-soluble contrast media and intravascular pharmacologic agents. An in vitro study.

In vitro incompatibilities between nine water-soluble contrast media and 21 intravascular pharmacologic agents were investigated using naked-eye observation and a centrifuge. Most of the previously reported incompatibilities were verified, and a few new incompatibilities were discovered: phentolamine mesylate with diatrizoate sodium, diatrizoate meglumine, ioxaglate, and iothalamate; diatrizoate meglumine with diazepam and meperidine hydrochloride; and diatrizoate sodium with meperidine hydrochloride. There were no incompatibilities when the pharmacologic agents investigated were mixed with ioxithalamate, iopromide, iopamidol, and iohexol.     

Effects of nonionic contrast media (CM) on the components of coagulation and complement systems

Several nonionic experimental contrast media (CM) were evaluated for their effects on coagulation cascade, platelet aggregation, and the activation of complement pathways. In an in vitro system, most of the contrast media tested showed a mild anticoagulant property by prolonging the clotting times, such as partial thromboplastin time and the thrombin time of pooled normal human plasma. However, aggregation of normal human platelets by adenosine-diphosphate (ADP), collagen, epinephrine, ristocetin, and thrombin was not blocked when the platelet-rich plasma was incubated with these agents. No quantitative or qualitative changes in the complement components C3 or C4 were detected when a mixture of CM and pooled normal human serum was analyzed by radial immunodiffusion, immuno- or crossed-immunoelectrophoresis techniques. These results indicate that nonionic contrast media produce certain transient hematologic changes and should be further tested for their immunologic properties in order to establish their absolute safety in diagnostic procedures.     

Diagnosis of cerebral lesions by Thallium 201

A new water-soluble myelographic contrast agent with more hydrophilic properties than metrizamide was developed and tested in the primate (Macaca mulatta) and the cat. A new animal model that allows study of the convulsive effects of intrathecally administered contrast agents in the awake monkey was designed. With this sensitive model the new contrast agent was shown to have a remarkable reduced convulsive effect when compared with metrizamide and other media. Intrathecal hypertonic solutions in the cat depress the evoked cortico-spinal responses whereas the neurotoxic effects of the iodinated water-soluble contrast media increase them. The net effect is a combination of the two actions.     

Red blood cell labeling with technetium-99m. Effect of radiopaque contrast agents

Radiographic contrast agents have been reported in the literature to interfere significantly with red blood cell (RBC) labeling in vivo by Tc-99m. Moreover, in the presence of contrast agents, red cells have been known to undergo significant morphologic changes. These observations led to the current RBC labeling study in patients (N = 25) undergoing procedures with the administration of contrast media. Before and after contrast administration, blood samples were drawn from each patient into vacutainer tubes containing heparin and RBC labeling was performed using 1-ml aliquots of these samples following the Brookhaven National Laboratory protocol. The differences in average percentage labeling yield with and without contrast media were not significant. In vivo labeling in hypertensive rats with administration of contrast media up to 600 mg likewise consistently gave high labeling yields at all concentrations. Purported alterations in cell labeling attributed to contrast agents are not reflected in these studies, and other pathophysiologic factors need to be identified to substantiate the previous reports. In vitro study offers a potentially useful and simple method to delineate effects of various agents on cell labeling.     

The release of histamine from human basophils by radiological contrast agents

The capacity of conventional and new low-osmolality contrast agents to stimulate histamine release from human basophils has been studied in vitro. When compared on an iodine concentration basis, the new agents release less histamine than the conventional agents at intermediate and higher concentration. However, the newer compounds exhibit a biphasic histamine release response to increasing iodine concentration with a low concentration peak, a phenomenon not previously described. Among the conventional ionic agents, meglumine salts were confirmed to be more potent histamine releasers than sodium salts. Possible mechanisms of this histamine release and the bearing of the findings on the safety of contrast media are discussed.     

Cutaneous ulceration due to contrast extravasation. Experimental assessment of injury and potential antidotes

Severe cutaneous ulceration may occur as a result of contrast media extravasation. We established a definitive animal model for assessing the cutaneous toxicity of commonly employed agents and used this model to evaluate possible antidotes to the effects of contrast media extravasation. The contrast agents studied were: meglumine/sodium diatrizoate 76%, meglumine iothalamate 60% and 43%, meglumine/sodium ioxaglate 60%, iohexol 350, and iopamidol 370, in varying volumes and osmolalities. Hypertonic saline (950 and 1900 mOsm/kg) also was injected. Agents were injected intradermally into BALB/c mice. The higher osmolality agents produced dose-dependent skin ulcerations. The lower osmolality agents failed to produce any skin lesions after the same volume doses. Hypertonic saline produced skin toxicity in a dose-dependent fashion similar to hyperosmolar contrast agents. Three antidotes were tested: hyaluronidase, topical heat, and topical cold. Hyaluronidase significantly reduced skin toxicity when injected immediately following contrast injection. Cold also significantly reduced skin toxicity, while heat caused no improvement.     

Effect of low osmolar, ionic and nonionic, contrast media on the cytologic features of exfoliated urothelial cells

The effect of low osmolar, ionic and nonionic, contrast media on the cytologic features of exfoliated urothelial cells were measured in vitro and compared to those induced by standard, high osmolar radiographic contrast media. The low osmolar agents were found to induce no significant adverse effects on the cytologic features of the urothelial cells, whereas the ionic agents clearly distorted certain cytoplasmic and nuclear features. These findings may support the use of low osmolar nonionic agents for retrograde urography if posturographic cytologic studies are contemplated.     

New and old contrast agents: Pharmacology,tissue opacification,and excretory urography

In equivalent doses for intravenous urograms conventional ionic contrast agents give iodine concentrations in the urine of approximately 30 mg iodine/ml, nonionic contrast media provide approximately 50 mg iodine/ml, and the ionic dimer Hexabrix approximately 70 mg iodine/mL. These new low osmolality, contrast media provide significantly higher urinary iodine concentrations than conventional ionic contrast media, provide better diagnostic quality excretory urograms, better patient tolerance, and fewer adverse side-effects and serious reactions. These new low osmolality, contrast media have significant advantages in intravenous urography in both safety and efficacy when compared to conventional higher osmolality contrast media.     

Effect of low osmolar,ionic and nonionic,contrast media on the cytologic features of exfoliated urothelial cells

The effect of low osmolar, ionic and nonionic, contrast media on the cytologic features of exfoliated urothelial cells were measured in vitro and compared to those induced by standard, high osmolar radiographic contrast media. The low osmolar agents were found to induce no significant adverse effects on the cytologic features of the urothelial cells, whereas the ionic agents clearly distorted certain cytoplasmic and nuclear features. These findings may support the use of low osmolar nonionic agents for retrograde urography if posturographic cytologic studies are contemplated.     

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.     

Anticoagulant effects of contrast materials: in vitro study of iohexol, ioxaglate, and diatrizoate

It has been reported that clot formation may occur when blood is mixed directly with nonionic contrast medium in a syringe during angiography. To investigate this possibility, we performed three in vitro experiments to determine the anticoagulant properties of a low-osmolar, nonionic contrast medium (iohexol); a low-osmolar, ionic medium (ioxaglate); and a high-osmolar, ionic medium (diatrizoate). In the first experiment, human arterial blood was incubated at room temperature in an angiographic syringe with each of the three media for 60 min, after which the mixture was filtered for clots. In the second experiment, the clotting times of venous blood in heparinized saline or serial dilutions of the three agents were determined. In the third experiment, the partial thromboplastin time of platelet-poor plasma in heparinized saline or serial dilutions of the three agents was measured. No clots were observed in any of the arterial blood samples. Iohexol prolonged the normal 15-min clotting time of venous blood to 160 min, compared with a clotting time of at least 330 min for ioxaglate and diatrizoate. Iohexol prolonged the normal 36-sec partial thromboplastin time of platelet-poor plasma to 40 sec, compared with 50 sec for diatrizoate and 54 sec for ioxaglate. Our data show that iohexol, like ioxaglate and diatrizoate, inhibits clot formation when mixed with blood in a syringe. It prolongs the clotting time to approximately the same degree as 600 U/l of heparinized saline, but to a lesser degree than the other two media. All three media have a minimal effect on the partial thromboplastin time. Our results do not show any risk of clot formation in the usual clinical setting in which there is inadvertent mixing of blood with iohexol, ioxaglate, or diatrizoate in an angiographic syringe.     

In vitro evaluation of vascular permeability to contrast media using cultured endothelial cell monolayers.

OBJECTIVE: The efficiency of contrast agents in medical imaging depends on their distribution into vascular and interstitial compartments. The aim of this study was to compare in vitro endothelial permeability to different classes of contrast agents with various vascular persistence properties: a triiodinated nonionic monomer (ioversol), an iodinated dextran polymer (P604), and an iron oxide nanoparticle (sinerem). METHODS: Permeability studies, through collagen-coated filters with or without porcine aortic endothelial cell monolayer, were carried out by placing each filter-ring (luminal chamber) into a beaker containing a culture medium (abluminal chamber). Contrast media, diluted in the culture medium, were added to the luminal chamber. Aliquots were sampled from the abluminal chamber for contrast agent determinations. The volume cleared of the compound was calculated from the luminal side to the abluminal side. Parallel permeability tests to [3H]-H2O and Evans blue albumin were performed as references. Finally, the modulatory effect of bradykinin on endothelial permeability to albumin or to contrast agents was studied. RESULTS: The volume cleared of ioversol, P604, and sinerem through membrane filters was decreased by 19.6%, 32.1%, and 52.0%, respectively, in the presence of a cell monolayer. Bradykinin (10(-6) M) significantly increased permeability to albumin, ioversol, and sinerem. Ioversol and sinerem induced a significant decrease in permeability to albumin. CONCLUSIONS: A relation between the molecular size of the contrast agents tested and their endothelial permeability can be established with this in vitro model.     

Effect of iomeprol on rat hippocampal slice synaptic transmission: comparison with other X-ray contrast agents

RATIONALE AND OBJECTIVES: All contrast agents should be neurologically safe because although some are not indicated for procedures, such as myelography, just the same they may come in contact with nervous tissue during contrast-enhanced imaging. This is because even when they are intravascularly injected, the presence of undiagnosed blood-brain barrier damage may allow them to penetrate the brain barrier. In the present study, we investigated the neurologic safety of iomeprol by studying in vitro its potential effects on the central nervous system (CNS) synaptic transmission. Other widely used x-ray contrast agents were also assessed for comparative purposes. METHODS: CNS synaptic transmission was evaluated in terms of evoked field potentials recorded from the pyramidal region of rat hippocampal slices. The field potentials were evoked by electrical stimulation of the Schaffer collateral pathway. The effects of the contrast agents were evaluated in terms of number and amplitude of population spikes (PS) and as the maximal slope of the excitatory postsynaptic potentials (EPSP). The contrast agents were tested at final concentrations of 3, 10, and 30 mg(iodine)/mL in iso-osmolal condition with respect to artificial cerebrospinal fluid (CSF). RESULTS: Iomeprol, like ioversol, principally exerted a mild inhibitory effect on CNS synaptic transmission, an effect that was preceded by a weak, transient excitation. Iopentol exerted a rapid and complete inhibition of synaptic transmission without showing any excitatory effects. Iobitridol, though belonging to the nonionic monomeric class, exerted, surprisingly, an epileptogenic action at the highest concentration, whereas its inhibitory action was slow and mild. Diatrizoate, as expected, exerted an epileptogenic activity even at the lowest concentration, followed by a marked inhibitory action. Ioxaglate, as expected because it is an ionic though dimeric contrast agent, exerted an epileptogenic action at the intermediate concentration, whereas it barely demonstrated an inhibitory effect at all. All the contrast agent effects observed in the study reversed or tended to reverse during washout. CONCLUSIONS: Even taking in account the limitation because of the use of an in vitro approach and high contrast agent concentrations, we can conclude that the positive neuro-tolerability of iomeprol is further confirmed by this model as it proved to be devoid of epileptogenic activity and, among the contrast agents exhibiting inhibitory action, it was the contrast agent with the least amount of activity. In addition, contrary to that generally reported in the literature, nonionic, low osmolal contrast agents are not all identical in their neuro-tolerability when assessed in the rat hippocampal slice model.     

Blood clot formation in angiographic catheters. In vitro tests with various contrast media

Human blood was injected into angiographic catheters filled with contrast media or flushing media. The catheters were allowed to stand at 37 degrees C for 10, 20 or 30 min. Physiologic saline was then injected through the catheters, the catheter contents were shaken and filtered, and any clots were identified. Diatrizoate, ioxaglate, iohexol, iopamidol and iopromide were tested. Physiologic and heparinized saline were used as controls. At 10 min, clots were found in 65 per cent of the catheters filled with physiologic saline, in 25 per cent with non-ionic media, in 19 per cent with heparinized saline, and in 4 per cent with ionic contrast media. At 30 min, all catheters with physiologic saline, 85 per cent with non-ionic contrast media, 46 per cent with heparinized saline and 23 per cent with ionic contrast media contained a clot. Although all the contrast media were anticoagulants, a more careful angiographic technique is needed for non-ionic media. All the non-ionic agents showed equal results. Physiologic saline without heparin is not suitable for flushing during angiography.     

Advantages of a low-osmolality ionic contrast medium in intra-arterial applications

Osmolality is recognized as a major contributing factor of contrast media related adverse reactions. The development of a new ionic contrast medium has made it possible to retain the ionic nature of contrast agents and have a lower osmolality than non-ionic and conventional ionic contrast media. Studies have indicated that low osmolality ionic contrast media is comparable to non-ionic agents and in some instances has proven to be superior to non-ionic contrast media.     

Iodinated radiographic contrast media: comparison of low-osmolar with conventional ionic agents [corrected

A large number of reports on radiographic contrast media have appeared over the past year. The majority of these compared various properties of the new, nonionic low-osmolar agents with those of conventional ionic contrast media, including types and rates of adverse reactions, nephrotoxicity, anticoagulant effects, degree of subcutaneous injury resulting from extravasation, and gastrointestinal tolerance. In this review, recent developments in each of these areas are discussed. Although, in general, the newer agents are safer and better tolerated than ionic contrast media, their greatly increased cost prevents them from completely replacing these media. In this time of increasingly cost-conscious health care, even expert opinion concerning indications for nonionic low-osmolar contrast media use (also summarized here) is widely divided.     

Contrast media

This article reviews the most recent papers on contrast media reported from October 1989 to September 1990. Areas of focus include water-soluble contrast agents and barium agents.     

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.     

Ultrasonic contrast agents: safety considerations reviewed

Ultrasonic contrast agents are usually comprised of a stabilised shell encapsulating a gas bubble. When these are introduced in the body they increase the acoustic scattering from the tissues through which they pass, and especially from the vasculature. Their primary uses lie in cardiological and oncological imaging. However, these microbubbles have the potential to act as centres for acoustic cavitation activity, and so it is important to consider the safety of their use from an acoustic standpoint. The addition of ultrasonic contrast agents to in vitro suspensions of red blood cells has been shown to lead to haemolysis when the sample is exposed to ultrasound at levels which leave the cells unharmed in their absence. In vivo the infusion of gas bubble contrast agents into experimental animals has been shown to enhance the incidence of petechiae and haemorrhage in the intestine. The Mechanical Index (MI) thresholds for the effects seen in vitro lie within the range of MIs available with diagnostic clinical scanners, but in vivo the thresholds lie at the top end of the exposure levels available clinically. No adverse effects in humans arising from the ultrasonic exposure of these contrast agents have been reported to date.