Effect of ionic and non-ionic contrast media on aggregation of red blood cells in vitro. A preliminary report

Fresh human blood without additives, and contrast medium were mixed and examined immediately by light microscopy in a non-flowing state. Sodium meglumine diatrizoate, meglumine diatrizoate, meglumine iodamide, sodium meglumine ioxaglate, iopromide, iopamidol, iohexol, and metrizamide were tested in concentrations of 300 mg I/ml. Physiologic saline and 5% glucose were used as controls. All media were tested in a randomized order with blood samples from 23 volunteers. No aggregation was detected in physiologic saline, and few rouleaux were found in ionic contrast media. Irregular red cell aggregates were found in all low-osmolal contrast media: in 17 per cent of the specimens in ioxaglate, in 52 per cent in metrizamide, and in 78 to 100 per cent in other non-ionic media. Irregular aggregates were seen in all specimens with glucose. It remains to be demonstrated whether or not the irregular aggregation of human red cells in non-ionic contrast media has clinical significance. Iohexol was also tested with blood samples from several laboratory animals, but in nearly every case no aggregates were found. Results of animal experiments or tests with animal blood seem to be poorly applicable to man.     

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.     

Passive blood/contrast agent exchange in angiographic catheters and its effects on platelets.

A static column of contrast agent or saline in an angiographic catheter will passively exchange with blood during angiography. The authors investigated the time course of this exchange in 5.5- and 7-F polyethylene catheters inclined at various angles. Passive blood exchange occurred 2 cm into the catheters within 7-15 seconds at most catheter tip angles, except for those catheters oriented so that their tips were nearly horizontal. In a separate series of experiments, the effect of contrast agent on platelet function and blood clotting was analyzed. The agent was sufficiently diluted in blood so as to simulate an angiographic procedure. The studies were performed in 60 cylindrical polyethylene containers with both unheparinized and heparinized blood. Use of an ionic contrast agent, more than a nonionic agent, lengthened the time for platelet aggregation (mean increases for ionic vs nonionic agents were 46.4 and 37.1 seconds, for unheparinized and heparinized blood, respectively), platelet adhesion to polyethylene surfaces (mean increases, 46.0 and 64.2 seconds), and platelet-stimulated coagulation (mean increases, 38.5 and 43.9 seconds). Conventional, intermittent flushing with saline or filling the catheter with contrast agent may be insufficient to prevent blood from rapidly back-filling the catheter tips. Contrast agents (ionic more than nonionic) distributed in the patient's blood volume inhibit platelet coating of catheter lumens and/or blood clotting under such circumstances.     

Prevention and dispersion of contrast media induced red cell aggregates. An in vitro study

Red cell aggregation was observed microscopically when human blood and contrast media were mixed on glass slides. Aggregation was more frequent in low-osmolal media: mainly rouleaux were formed in ioxaglate but irregular aggregates in non-ionic media. Aggregation was similar at concentrations of 150 and 300 mg I/ml. Pre-treatment of glass slides with heparinized saline reduced red cell aggregation but saline alone was almost as effective. Most of the irregular aggregates dispersed when saline or heparinized saline was applied to them. Saline and heparinized saline had an identical dispersing effect. After incubation of the aggregates in iopamidol in plastic tubes for one or five minutes, saline was injected into the tubes, and after mixing the solution was poured onto glass slides and examined under the microscope. Only a few small irregular aggregates were detected in 6/60 specimens. It is concluded that ionicity of a flushing medium and shear of the injection are able to disperse red cell aggregates during angiography.     

Risk of thromboembolism during diagnostic and interventional cardiac procedures with nonionic contrast media

To investigate the relationship between clot formation and thromboembolism, canine blood was withdrawn into catheter-syringe or catheter-steerable wire systems containing either contrast medium or normal saline as used in debubbling techniques. The contrast media used were iohexol, iopamidol, ioxaglate, and diatrizoate. Without the use of heparin, after a 30-minute incubation, blood clots were harvested from all catheter-syringe systems except those with diatrizoate and from all catheter-steerable wire systems. Significantly more blood clot was harvested from the catheter-steerable wire system. With use of heparinized blood, no clot was found in any system. Twelve dogs that underwent coronary angiography were divided into two groups; one received heparin (5,000 IU) and the other did not. Thromboembolism occurred in all nonheparinized dogs that underwent angiography with iohexol or iopamidol but not in any other group. The authors found that in a dog model nonionic contrast media are more thrombogenic than ionic contrast media, especially in the catheter-steerable wire system. The blood clot in the catheters is associated with thromboembolism during angiography. The authors maintain that in this setting, blood clotting and thromboembolism with nonionic agents can be eliminated with heparin.     

Prevention of postvenographic thrombosis by heparin flush: fibrinogen uptake measurements

The incidence of postphlebographic venous thrombosis was investigated by 125I-labeled fibrinogen uptake tests in 60 patients whose veins were flushed with saline solution containing 10,000 IU of heparin after leg phlebography. Ionic methylglucamine iodamide was used as the contrast medium. In six patients superficial thrombophlebitis extending from the contrast-medium injection site was observed after phlebography. The incidence of deep venous thrombosis was 3.3%, significantly less than that reported for studies using triiodinated ionic contrast media without flushing the veins with a heparin solution. It is comparable to the incidence of venous thrombosis reported after using nonionic contrast media. The authors conclude that flushing the veins with heparinized saline solution can improve the safety of phlebography considerably.     

Effects of uro-angiographic contrast media on blood coagulation--a scanning electron microscopic study on time dependent changes of blood clot and a clinical study]

Anticoagulant activity of ionic and nonionic contrast media (CM) was investigated in vitro and in vivo. Based on the time course of FPA and TAT generations and gross examinations of the blood clots on the catheters placed in CM-blood mixtures [an 2 to 8 ratio (20% v/v)]. It was demonstrated that blood coagulation was activated during the period of 20 to 30 minutes when nonionic CM (iopamidol, iohexol) was employed, but no activation of blood coagulation was noted with ionic CM (diatrizoate, ioxaglate). Scanning electron microscopic examinations of the clots on the catheters revealed that fine fibrin meshwork fibers, in which many red blood cells were trapped in bound, were observed with nonionic CM. In contrast, no fibrin mesh was formed with ionic CM after 30 minutes. In vivo, antithrombin III and fibrinogen significantly decreased in the patients who underwent infusion of nonionic CM. Our studies confirmed that nonionic CM show weaker anticoagulant activity than do ionic CM. And these findings account for previous reported thromboembolic complications with the use of nonionic CM. Extreme caution should be therefore exercised when nonionic CM are employed during prolonged angiographic and interventional procedures.     

Central and renal haemodynamic effects of intravenous infusion of non-ionic and ionic contrast media. An experimental investigation in the pig

The central and renal haemodynamic effects after intravenous infusion (1 ml/s) of a non-ionic (iohexol) and an ionic (metrizoate) contrast medium were investigated in 16 pigs. The injected contrast media induced marked haemodynamic changes compared with normal saline. However, there were no significant differences between the ionic and the non-ionic media. It was concluded that the effects were only partially caused by an increase in the blood volume due to the injected volume. In addition, the effects related to the viscosity, the osmolality and other not specified pharmacodynamic properties of the media are proposed to be of importance.     

Advantages of non-ionic contrast media in vascular applications

The use of non-ionic contrast media for vascular applications is currently under investigation. Initial studies in the United States have demonstrated non-ionic contrast media have several advantages when compared to conventional ionic contrast media. A comparison of the ionic and non-ionic contrast media, including their physiologic effects, is presented to familiarize the radiologic technologist with this new product.     

Effect of various contrast media on platelet aggregation--an in vivo study

Recently, some radiologists using non-ionic contrast media for angiography have noted the increased tendency of thrombus formation in the injection syringe or angiographic catheter contaminated with blood. In vitro studies by some authors have shown that non-ionic contrast media had only a slight anticoagulative effect as compared with ionic contrast media. But the in vivo studies comparing the anticoagulative effect of both ionic and non-ionic contrast media have not been performed previously. We investigated the effect of non-ionic and ionic contrast media on platelet aggregation in 40 patients undergoing angiography. The in vivo study revealed a negligible influence of both non-ionic and ionic contrast media on systemic platelet aggregation. The dose of contrast media also showed no significant correlation with platelet aggregation. Our study suggests that the data from in vitro experiments cannot be extended to in vivo study as for the relationship between contrast media and their anticoagulant effect.     

The effects of angiographic contrast media on the aggregation and morphology of red cells in vitro

The effects of four angiographic contrast media on the aggregation and morphology of human red cells in vitro, using microscopic observations were studied. The media included an ionic contrast medium, sodium meglumine amidotrizoate (amidotrizoate); non-ionic low-osmolal contrast media, iopamidol and iohexol; and an ionic low-osmolal contrast medium, sodium meglumine ioxaglate (ioxaglate). Strong, large aggregates formed in the control blood, without media, where aggregation of red cells was inhibited by contrast media mixed with the blood in a ratio of 2:1. Almost no aggregates were observed for amidotrizoate, an ionic contrast medium, while there were a few rouleaux formed in the presence of ioxaglate. Nearly all of the red cells aggregated in the presence of iopamidol and iohexol; iohexol produced the greater aggregation of the two. Besides rouleaux, irregular aggregates were formed with iohexol. When the contrast media were mixed with blood in a ratio of 1:2, their inhibitory effects on aggregation declined. These results clearly indicate that contrast media inhibit the in vitro aggregation of red cells, and ionic-contrast media produced more potent inhibitory effects than non-ionic media. With added NaCl and meglumine, iohexol did not induce red cell aggregation. This suggests that ionic-contrast media have greater inhibitory effects on aggregation than non-ionic media, a result of their ionic properties. Red cells were morphologically quite normal in the presence of ioxaglate, where most red cells were crenated in the presence of iopamidol and iohexol, and shrank in the presence of amidotrizoate. In the presence of iopamidol and iohexol with the osmolality adjusted to that of a saline solution, both normal red cells and crenation were observed. This suggests that non-ionic contrast media may directly effect morphological changes in red blood cells. These results revealed that ioxaglate, an ionic contrast medium, was the best in vitro medium, to prevent aggregation of red cells and crenation deformity of erythrocytes.     

Effects of two low osmolality contrast media on red blood cell filterability and aggregation in vitro.

The in vitro effects of ionic ioxaglate and non-ionic iopamidol were compared. Filtration measurements were carried out on an hemorheometer; erythrocyte aggregation was evaluated by means of an erythrocyte aggregometer, and red blood cell morphology was observed with an optical microscope. Ioxaglate and iopamidol reduced erythrocyte filterability to the same extent; by contrast neither ionic nor non-ionic contrast media significantly modified aggregation or shape of red blood cells. The decrease of erythrocyte deformability observed in this study may cause clotting in catheters or syringes during angiographies investigations.     

Inflammatory markers increase following exposure to radiographic contrast media

PURPOSE: Increased levels of markers of systemic inflammation have been noted in patients following coronary angiographic procedures. The purpose of the present study was to examine the influence of the type of the angiographic procedure as well as the type of radiographic contrast media (RCM) on markers of inflammation. MATERIAL AND METHODS: Thirty-seven patients undergoing diagnostic or interventional coronary angiographic procedures were randomly assigned to receive one of three RCM - an ionic low osmolar agent; a non-ionic, iso-osmotic agent; or a non-ionic, low osmolar agent. Sera were analyzed at baseline (prior to receiving RCM), and at 2, 6 and 24 h thereafter for interleukin (IL)-6 and soluble receptors for tumor necrosis factor alpha (TNFalpha)-1 and TNFalpha- 2. RESULTS: Statistically significant increases over time in each RCM group were noted for IL-6 and both TNFalpha receptors. Comparable increases in inflammatory markers were observed in patients undergoing diagnostic angiography and in patients undergoing an associated coronary intervention. While these markers increased following exposure to both ionic and non-ionic RCM, there was a consistent trend towards lessened marker release with non-ionic RCM. CONCLUSION: Both diagnostic and interventional coronary angiographic procedures are associated with an increase in serum inflammatory markers. While both ionic and non-ionic RCM are associated with increases in serum inflammatory markers, this increase may be attenuated with non-ionic RCM.     

Heating contrast media: role in contemporary angiography

While constant injection pressure was maintained, in vitro flow rates of contemporary contrast media through selected, typical, contemporary angiographic catheters were measured at room and body temperatures. Heating the contrast media increased the flow rate by greater than 8% only when high-viscosity (ionic monomeric 76% and ionic dimeric 58.9%) contrast material was used in small (4- and 5-F) catheters. Although flow rates with other combinations of catheter length, contrast material, and injection pressure cannot be predicted from these results, heating of contrast material is probably most useful when a high-viscosity contrast medium is used in a small catheter.     

Pure and diluted contrast media in the visualization of the portal venous system using digital angiography

We report the results of intra-arterial digital subtraction angiography (DSA) in 100 patients with portal hypertension. The portal venous system was evaluated; all patients underwent angiography of the celiac and superior mesenteric arteries before surgery. Forty-four of them were also examined after Warren splenorenal shunts. Therefore, a total of 144 exams was evaluated. The authors always employed low-osmolality ionic and non-ionic contrast media (iodine concentration: 300-350 mg/ml). In 70 cases pure contrast medium was injected (20-25 ml); in the extant 74 cases it was diluted with an equal volume of saline solution (osmolality and iodine concentration reduced by 50%). Intra-arterial DSA always visualized portal venous system, collateral circulation, shunt location and postoperative changes. The major advantage of intra-arterial DSA is the smaller amount of contrast medium injected, so that local and systemic side effects are rare. According to our experience, it is best to dilute the contrast medium and inject the same amount as in conventional angiography, at the same rate. Other well-known advantages of intra-arterial DSA are quicker execution, less injury to arteries using smaller-caliber catheters, and low cost. The major disadvantage of intra-arterial DSA, as it appeared also in our study, is the field size of the intensifier, which in our case was limited to 6-9 inches. This is an insufficient coverage for the whole portal system to be studied, and some contrast medium injections become therefore necessary. An average of 3 injections were given to each patient. This problem reduces the advantage of less contrast medium per injection. At any rate, even though intra-arterial DSA exhibits this limitation, it can nevertheless yield important information in the pre- and postoperative evaluation of patients with portal hypertension.     

Effects of intravenous injection of diatrizoate, iohexol or ioxilan on renal size, urine profiles and blood profiles in the rabbit

Diatrizoate, iohexol or ioxilan were injected intravenously in 18 rabbits. The contrast medium passage through the kidneys was recorded on digital subtraction images for the first 50 s followed by 100 mm exposures up to 15 min after injection. The renal area was measured planimetrically. Urine profiles (glucose, phosphate, LDH, GGT, NAG), blood profiles (potassium, urea) and the relative clearance of albumin and sodium were followed for 5 days and compared with a control group injected with saline. All kidneys were examined by light and immunofluorescence microscopy. All three contrast media produced excellent arteriograms and urograms. The three different contrast media caused a rapid increase of the kidney area within the first minute, reaching an average maximum of 10 to 12 per cent after 5 min, followed by a gradual decline. Contrary to expectations the increase in renal area was similar for all three contrast media, so hyperosmolality is no likely explanation of this phenomenon. None of the contrast agents caused significant changes in any of the profile components with one exception: the GGT excretion was significantly elevated during the first 24 h after diatrizoate administration as compared with the effect of saline. Light and immunofluorescence microscopy revealed no differences.     

The immediate effects of retrograde pancreatography on the pancreas

Endoscopic retrograde pancreatography (ERP) may be followed by elevated serum amylase or occasionally by pancreatitis. This is said to be due to the irritating effect of contrast media (CM) or to the cation content of CM. We investigated the effect of intraductally injected CM (ionic CM with and without sodium, non-ionic CM) on the porcine pancreas. All types of CM as well as control media (saline, 7% sodium bicarbonate solution) produced small foci of histological pancreatitis, although without any clinical signs of pancreatitis.     

Demonstration of the renal venous system at routine nephroangiography. A comparison between metrizoate, metrizamide and ioxaglate

The demonstration of renal veins during routine nephroangiography was retrospectively investigated and blindly scored in 60 patients. Three different types of contrast media were used: one high-osmolar ionic monomeric (metrizoate) and two low-osmolar, the non-ionic monomeric (metrizamide) and the ionic monoacidic dimeric (ioxalate). The renal veins and the inferior vena cava were significantly better and more often demonstrated when ioxaglate was used compared with metrizoate and metrizmide. There was no significant difference between metrizoate and metrizamide. Following semiselective renal artery injection, the main renal veins were demonstrated with a diagnostically acceptable quality with ioxaglate in 76 per cent, with metrizamide in 40 per cent and with metrizoate in 29 per cent. On selective renal artery injection the demonstration of renal veins increased to 85 per cent with ioxaglate and remained unchanged with metrizmide (38%) and metrizoate (26%). Semiselective or selective nephroangiography with ioxaglate at an ordinary dose was in most patients sufficient to allow evaluation of renal vein involvement in disease, rendering high dose selective nephroangiography or selective nephrophlebography unnecessary. A slower diffusion rate of ioxaglate compared with metrizoate and metrizamide is considered to be the major explanation for the better demonstration of the renal veins.     

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.     

Iohexol and metrizoate in urography of insulin dependent patients

A double blind urographic study with the ionic contrast medium metrizoate or the non-ionic medium iohexol was performed on 69 insulin dependent diabetic patients. Metrizoate caused 24 per cent and iohexol 11 per cent mild adverse reactions and metrizoate a significant decrease in creatinine clearance values. Thus iohexol turned out to be better tolerated by these diabetic patients than metrizoate.