Comparison of intravenous contrast agents for CT studies in children.

One hundred and eighty children undergoing CT examination were randomly allocated to receive meglumine diatrizoate, iohexol, or iopamidol as their i.v. contrast agent. Minor side effects were detected in 85% of children receiving meglumine diatrizoate, in 18% of those receiving iohexol, and in 36% of those receiving iopamidol. Because many of these minor side effects cause patient motion or delay scanning after contrast medium injection, they potentially degrade image quality. These findings are an indication for the use of low osmolarity contrast agents for i.v. use in pediatric CT imaging.     

Extravascular extravasation of radiographic contrast media. Effects of conventional and low-osmolar agents in the rat thigh

We compared the damage resulting from intradermal injection of four commonly used radiographic contrast media in laboratory rats. Sixty percent meglumine diatrizoate (Reno M 60) and ioxaglate (Hexabrix) produced significantly more ulceration and crusting on gross inspection and more necrosis, edema, and hemorrhage on histologic evaluation than iopamidol 300 (Isovue) or 0.9% (normal) saline. Thirty percent meglumine diatrizoate (Reno M Dip) had an intermediate toxicity, resulting in significantly more visible swelling and more microscopically detected hemorrhage than iopamidol or saline, but less ulceration/crusting and necrosis than Reno M 60 and ioxaglate. Since the three contrast agents of similar osmolality produced different degrees of tissue damage, our results suggest that factors other than high osmolality are partially responsible for determining the severity of injuries from extravasated contrast media.     

Effects of contrast agents on the fallopian tube in a rabbit model

The authors evaluated the effect of different iodinated contrast agents on the fallopian tube and adnexal tissue in 15 rabbits. Ethiodized oil, an oil-soluble agent, was used in five rabbits. The following water-soluble agents were used: iothalamate meglumine 30% (n = 3), iothalamate meglumine 60% (n = 3), and ioxilan (n = 4). The agents were injected through catheters placed in the fallopian tubes. Fallopian tubes and peritoneal cavities were histologically evaluated. The contralateral tube served as a control. Ioxilan and iothalamate meglumine 30% produced no pathologic response in the tube or peritoneal cavity. Iothalamate meglumine 60% was associated with mild inflammatory infiltrate, mucosal edema, giant cell reaction, and periovarian adhesions that were bilateral but more pronounced on the injected side. Use of ethiodized oil resulted in papillary fibrous adhesions on the ovarian surface, and fat granulomas were seen in the periovarian tissues. The safety of oil-based contrast agents for use in hysterosalpingography is therefore questioned. No significant differences were found among the water-soluble contrast agents.     

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.     

Experimental evaluation of iotrolan as an arthrographic contrast medium--knee arthrography with iotrolan in rabbits

Authors evaluated the efficacy and tolerability of iotrolan, a nonionic dimeric contrast medium used for myelography, as an arthrographic contrast medium in comparison with meglumine/sodium diatrizoate and iopamidol in rabbit. Iotrolan (Isovist, 300 mgI/ml) was injected in one knee joint and diatrizoate (Urografin, 292 mgI/ml) or iopamidol (Iopamiron, 300 mgI/ml) in the other at a dose of 1.5 ml/knee. Knee arthrograms were taken 2, 5, 10, 20, 30, 45 and 60 min after injection. Contrast density was determined by measuring the transmission density in the supra-patellar bursa with an image analysis system. The anterior displacement of the patellar from the femur was measured as an indicator of hydrarthrosis. Contrast duration in the supra-patellar bursa was longer with iotrolan than with diatrizoate and iopamidol. Hydrarthrosis was less pronounced with iotrolan than with diatrizoate and iopamidol. These results suggest that iotrolan has the advantage over existing contrast media for arthrography with respect to the efficacy and tolerability.     

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.     

Hemodynamic and electrocardiographic effects of ioversol during cardiac angiography. Comparison with iopamidol and diatrizoate

We studied the hemodynamic and electrocardiographic responses to left ventriculography and coronary arteriography with three angiographic contrast agents. Two were nonionic agents (ioversol 32% iodine, 60 patients, and iopamidol 37% iodine, 30 patients). The third was a conventional ionic agent (diatrizoate 37% iodine, 30 patients). Cardiovascular hemodynamics and the electrocardiogram were recorded for 5 minutes after left ventricular injection and for 2 minutes after coronary injections. Following left ventriculography, diatrizoate caused a greater increase in cardiac output, left ventricular end diastolic pressure, and corrected QT interval while causing a greater decrease in arterial pressure than did either ioversol or iopamidol, which were indistinguishable from each other. Following left coronary arteriography, diatrizoate caused a significant decrease in heart rate, prolongation of the corrected QT interval, and increase in T wave amplitude. In contrast, neither ioversol nor iopamidol caused significant changes in any electrocardiographic parameters. Adverse reactions were more common with diatrizoate than with either ioversol or iopamidol. There were no recognizable differences in angiographic image quality among the three agents. We conclude that the angiographic performance of ioversol is equivalent to that of iopamidol and that both cause less hemodynamic and electrocardiographic disturbance than diatrizoate.     

The effect on the blood-brain barrier of intracarotid contrast media--iopamidol and diatrizoate

The effect on the blood-brain barrier (BBB) was assessed following intracarotid injection of iopamidol (300 mgI/ml.), meglumine diatrizoate (305 mgI/ml.) and isotonic saline. Four ml/kg of 2% Evans blue solution and 0.1 mCi 99m Technetium-DTPA (Tc-DTPA) were used as tracers. No blue staining was observed in the saline group. Three out of 10 animals showed blue staining in the iopamidol group. All ten animals showed blue staining in the diatrizoate group. There were statistical differences between the diatrizoate and the other two groups. Tc-DTPA extravasation was 0.37 +/- 0.13 (mean +/- SD) in the saline group, 1.29 +/- 0.77 in the iopamidol group and 3.88 +/- 1.67 in the diatrizoate group. Statistical differences were observed among three groups. These observations suggest that Tc-DTPA is very sensitive in detecting a subtle BBB injury and that iopamidol had a significantly smaller effect on the BBB than did meglumine diatrizoate.     

Comparison of iohexol 300 and diatrizoate meglumine 60 for body CT: image quality, adverse reactions, and aborted/repeated examinations.

Six hundred patients were prospectively randomized and given either diatrizoate meglumine 60 or iohexol 300 during dynamic contrast-enhanced body CT in order to compare image quality, contrast reactions, and the number of aborted studies or studies in which images had to be repeated. Three hundred two patients received iohexol 300, and 298 patients received diatrizoate meglumine 60. Thirty-nine percent (119/302) of the patients given iohexol 300 and 63% (188/298) of the patients given diatrizoate meglumine 60 had at least one adverse reaction thought to be related to contrast material during, or within 24 hr of, the body CT scan. When reactions of discomfort (heat or warmth, flushing, bad taste) were excluded, 16% (48/302) of the patients who received iohexol and 33% (99/298) of the patients who were given diatrizoate meglumine 60 had at least one adverse reaction. The differences in both types of reactions between the two agents were significant (p less than .001). Among scans evaluated for study quality, 71% (214/302) of the iohexol 300 group and 62% (184/298) of the diatrizoate meglumine 60 group had optimal enhancement (p = .02). However, when the optimal and adequate categories were combined, 301 of 302 patients given iohexol 300 and 292 of 298 patients given diatrizoate meglumine 60 had diagnostic-quality studies (no statistical difference). Studies were not terminated nor were images repeated in 97% (292/302) of the patients given iohexol 300 and in 94% (280/298) of those given diatrizoate meglumine 60. The CT study was repeated because of movement during the contrast injection or aborted because of contrast-related reactions in 0.7% of the patients given iohexol 300 and in 3.0% of the patients given diatrizoate meglumine 60. This difference was statistically significant (p = .04). Our results suggest that the difference in image quality, number of adverse reactions, and number of aborted/repeated CT scans performed with iohexol 300 or diatrizoate meglumine 60 are not sufficiently different to warrant conversion to nonionic agents for body CT scans.     

Pulmonary angiography with iopamidol: patient comfort, image quality, and hemodynamics

The choice of a contrast agent for pulmonary angiography has important implications for patient comfort, image quality, and perhaps the safety of the procedure, particularly for "high-risk" patients. In a prospective study the nonionic, low-osmolality agent iopamidol eliminated the problem of image degradation due to coughing, and patients showed excellent tolerance for it. However, pressure measurements obtained within 3-5 minutes of injection of iopamidol and diatrizoate sodium meglumine 76% showed no significant difference in the hemodynamic effects of the two contrast agents, either for normotensive or for pulmonary hypertensive patients. Contrary to a common presumption, pulmonary hypertension by itself did not appear to increase the risk of pulmonary angiography. The theoretic presumption of greater hemodynamic stability with low-osmolality contrast agents was not clinically evident in this trial with iopamidol. At present, enhanced patient comfort and improved image quality remain the only confirmed bases for choosing this contrast agent for pulmonary angiography.     

Hemodynamic effects of high versus low-osmolar contrast media for ventriculography in severe aortic stenosis

The hemodynamic effects of high-(diatrizoate meglumine/sodium) and low-(iopamidol) osmolar constrast administration for left ventriculography were compared in 15 patients with severe aortic valve stenosis. Patients were similar with respect to aortic valve gradient, aortic valve area, age, body surface area, and baseline hemodynamics as well as associated coronary disease and valvular insufficiency. Administration of diatrizoate meglumine/sodium was associated, with a 22% increase in heart rate, and marked (27%) decrease in left ventricular systolic pressure, with a small (15%) increase in left ventricular end diastolic pressure. In contrast, administration of larger volumes of iopamidol was associated with only a slight (9%) increase in heart rate, a small (6%) decrease in left ventricular systolic pressure, and a smaller (6%) increase in left ventricular end diastolic pressure. In patients with severe aortic valve stenosis iopamidol may offer a safer hemodynamic profile than diatrizoate meglumine/sodium.     

Comparison of diatrizoate, iopamidol, and ioxaglate for the contrast enhancement of experimental hepatic tumors in CT

The accumulation of diatrizoate and two new low osmolality contrast agents, iopamidol and ioxaglate, was investigated in three experimental tumors (a well differentiated mammary adenocarcinoma, a poorly differentiated colon carcinoma, and a hepatoma) in the rat. All three tumors were implanted into the liver 12 to 14 days prior to intravenous injection of the contrast agents in a dose of 300 mg iodine per kg. Iodine concentrations were determined in blood, liver, and tumors at 1, 5, 10, and 30 minutes using x-ray energy spectrometry. Ratios between tumor iodine and blood iodine concentrations increased more with time with diatrizoate than either iopamidol or ioxaglate and were at 30 minutes significantly greater for diatrizoate than the other two agents. This suggests that the contrast medium efflux from the vascular compartment into the extravascular compartment of all tumors is greater for diatrizoate than either iopamidol or ioxaglate. Although it is known from clinical experience that the differential enhancement between hypodense hepatic tumors and liver parenchyma decreases rapidly with time after contrast administration, this investigation suggests that the substitution of diatrizoate by either iopamidol or ioxaglate should not affect appreciably the contrast enhancement in this condition in dynamic CT completed within the first minutes after contrast administration. In a later phase, after contrast administration, however, both iopamidol and ioxaglate should conceal hypodense hepatic tumors less than diatrizoate.     

Contrast absorption and pancreatic inflammation following experimental ERCP

The effect of saline and contrast agents intraductally injected into the pancreatic duct in sufficient volume to cause acinarization was studied in normal rats and in rats with acute pancreatitis. The effect of pancreatic inflammation on the disappearance of injected contrast material was investigated by injecting meglumine diatrizoate and 125I into the pancreatic duct. The activity appeared quickly in the venous blood of normal rats (peak activity at 5 minutes after injection). In rats with sodium taurocholate-induced pancreatitis, the appearance of activity in the blood was retarded. Ninety-two percent of the rats demonstrated pancreatic atrophy or pancreatitis histologically four days following acinarization of intraductally injected saline or metrizamide, meglumine diatrizoate, or meglumine sodium diatrizoate.     

Comparative effects of nonionic (iopamidol) and ionic (sodium and meglumine diatrizoate) contrast media for urography on urinary excretion of water and solutes

Urinary water and solute excretion before and for 40 minutes after intravenous bolus injection of a nonionic (iopamidol) or an ionic medium (sodium meglumine diatrizoate) have been studied in subjects with normal renal function. Iopamidol produced less urinary losses of water, potassium, sodium, and chloride than did diatrizoate; uric acid excretion was also less enhanced. Surprisingly, both contrast agents produced a comparable increase in urinary pH and bicarbonate excretion. These data show that nonionic agents produce fewer changes in urinary excretion of water and solutes; the less enhanced excretion of uric acid after a nonionic medium may be an important reason to choose the latter agents for urography in patients at risk for urate neophropathy.     

Ionized calcium levels in coronary sinus blood during coronary angiography: effects of four contrast media.

The changes in ionized calcium level in the coronary sinus during coronary angiography were compared for four contrast media (meglumine sodium diatrizoate, iohexol, iopamidol, and meglumine sodium ioxaglate) in 44 subjects. Blood samples were collected before and 5, 15, and 30 seconds after injection of contrast medium into the left coronary artery. The hematocrit and ionized calcium level of each specimen were measured. Meglumine sodium diatrizoate produced the largest changes in hematocrit and ionized calcium level. The time-concentration curve of the hematocrit was similar for all four contrast media, but diatrizoate and ioxaglate produced a prolonged decrease of ionized calcium. The cause of this is not clear, but the phenomenon may be related to differences of ionic status among the contrast media. With respect to maintenance of the ionized calcium level, nonionic low-osmolality contrast medium with added calcium may be preferable for coronary angiography.     

Comparative effects of nonionic (iopamidol) and ionic (sodium and meglumine diatrizoate) contrast media for urography on urinary excretion of water and solutes

Urinary water and solute excretion before and for 40 minutes after intravenous bolus injection of a nonionic (iopamidol) or an ionic medium (sodium meglumine diatrizoate) have been studied in subjects with normal renal function. Iopamidol produced less urinary losses of water, potassium, sodium, and chloride than did diatrizoate; uric acid excretion was also less enhanced. Surprisingly, both contrast agents produced a comparable increase in urinary pH and bicarbonate excretion. These data show that nonionic agents produce fewer changes in urinary excretion of water and solutes; the less enhanced excretion of uric acid after a nonionic medium may be an important reason to choose the latter agents for urography in patients at risk for urate neophropathy.     

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.     

Alteration of the ionized calcium level in coronary sinus blood during coronary arteriography]

Injection of contrast medium into the coronary circulation produces a decrease in the concentration of ionized calcium in blood and thus causes a deterioration of myocardial contractility. In this study, changes in the ionized calcium level in the coronary sinus during coronary arteriography were compared for four different contrast media in human subjects. The contrast media used were meglumine sodium diatrizoate, iohexol, iopamidol and meglumine sodium ioxaglate. Blood samples were collected from the coronary sinus before and 5, 15 and 30 seconds after the first injection of contrast medium into the left coronary artery. The ionized calcium level of each specimen was measured using an ion specific electrode, and hematocrit was measured using the centrifuge method. Diatrizoate produced the greatest changes in both hematocrit and ionized calcium. The time concentration curve of hematocrit was similar for all four contrast media, but diatrizoate and ioxaglate produced a prolonged decrease in ionized calcium. The cause of this phenomenon is not clear, but it may be related to differences in the ionic status of the contrast media. Nonionic low-osmolality contrast media with added calcium may be preferable for coronary arteriography with respect to maintenance of the ionized calcium level.     

Pulmonary arteriography: comparison of cough stimulation effects of diatrizoate and ioxaglate

Twenty-five patients were observed in a prospective crossover study to determine whether the new low-osmolality contrast agents would be less prone than conventional agents to produce coughing during pulmonary arteriography. Selective left and right pulmonary arteriography (two views of each side) was performed with alternating administrations of diatrizoate sodium meglumine and ioxaglate sodium meglumine. Twenty-one patients had all four injections while four patients received injections on only one side. Sixteen of 25 patients coughed on at least one injection of diatrizoate, with three of these experiencing explosive coughing. One of 25 patients coughed with ioxaglate, and that was only minimally. This difference is statistically significant (P less than .001, on the basis of McNemar chi 2 test for paired data). When no coughing occurred, the quality of the diatrizoate and ioxaglate radiographs was indistinguishable. We conclude that ioxaglate is useful in pulmonary arteriography because of its lack of cough stimulation.     

Further support for the glucose hypothesis of metrizamide toxicity. The effect of metrizamide and glucose analogue-free contrast media on hexokinase

Metrizamide neurotoxicity has been hypothesized to be caused by an inhibitory effect of the drug on glucose metabolism. Metrizamide contains a glucose side chain, and glucose analogues including metrizamide have been shown to be inhibitors of hexokinase, an enzyme that is central to cerebral glucose metabolism. We studied the effect of the nonionic contrast agents iohexol, iotrol, and iopamidol, and the ionic contrast meglumine diatrizoate, on hexokinase in vitro. Although metrizamide reproducibly caused competitive inhibition of the reaction, the nonglucose contrast agents had no significant effect on the enzyme. These results add further support for the glucose hypothesis of metrizamide neurotoxicity.