Nonionic Contrast Agent Research Articles

Thrombin generation in nonclottable mixtures of blood and nonionic contrast agents.

The four newly introduced contrast agents--iopamidol, iohexol, ioversol, and ioxaglate--are of much lower osmolality than conventional agents, and claims have been made that they are substantially safer. A chromogenic assay for thrombin was applied to 1:1 (50%), 2:1 (67%), and 4:1 (80%) contrast agent-whole blood mixtures, each containing enough contrast agent to render them unclottable. Thrombin generation occurred in the nonionic-whole blood mixtures and increased with time. No thrombin could be detected in any ioxaglate-whole blood mixtures. The authors conclude that this difference presents a novel hazard in that iopamidol, iohexol, and ioversol permit thrombin generation to occur while inhibiting the fibrin polymerization step of blood coagulation, thus posing a significant, albeit theoretical, threat to patient well-being.

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.

Comparison of soft tissue effects of conventional ionic, low osmolar ionic and nonionic iodine containing contrast material in experimental animals

Conventional, low osmolar, and non-ionic iodine containing contrast media and saline controls were placed in the paws, muscles, and subcutaneous tissues of Sprague-Dawley rat thighs. The paw injections were observed and photographed, while the thighs were examined histologically. Results showed that although the low osmolar and non-ionic agents did produce inflammatory reactions and focal necrosis in the soft tissues, they were much better tolerated than were the conventional ionic agents. A non-ionic or low osmolar ionic contrast agent should be strongly considered when a possibility for extravasation exists.

Southwestern Internal Medicine Conference: Renal Failure Following Radiologic Procedures

Radiologic procedures that employ intravascular contrast material with or without angiography may lead to renal failure. In procedures that use intravenous contrast alone, the mechanism of renal injury is not precisely known, but direct toxicity to renal tubular cells is likely to be a major factor. Ionic and nonionic contrast agents are both capable of causing this adverse reaction. Renal failure occurring during angiography may also be secondary to the effects of radiocontrast, but the additional possibility that micro cholesterol emboli have been dislodged from atheroma located on the intima of large vessels must be considered. The acute or subacute development of renal failure in the presence of skin changes (livido reticularis), hypertension, multiple organ failure or dysfunction, and a fatal outcome favors the later diagnosis.

Age dependence of renal function: clearance of iohexol and P-amino hippurate in healthy males

Iohexol, a newly developed non-ionic contrast agent, has been recently documented as a reliable glomerular filtration marker. This study describes the age dependence of the single injection clearance of iohexol in a sample of healthy male volunteers ranging from 21 to 77 years of age. In parallel, renal plasma flow was studied by measuring the total clearance of p-amino hippuric acid administered as a continuous infusion. In subjects older than 50 years a negative correlation to age was found for both p-amino hippuric acid and iohexol clearance, with a reduction of 52 ml/min and 12 ml/min per decade, respectively, whereas no age dependence was found for younger subjects. Correlation between p-amino hippuric acid and iohexol clearances was 0.81. However, the filtration fraction, defined as the ratio of iohexol to p-amino hippuric acid clearance, was higher in the elderly subjects. A consistent discrepancy was found between total and renal clearances of p-amino hippuric acid, indicating significant renal metabolism. Renal clearance of creatinine was poorly correlated to iohexol clearance and did not show any relationship to age.

Heparin in angiography: current patterns of use.

All members and fellows of the Society of Cardiovascular and Interventional Radiology were surveyed to determine current patterns of heparin use in angiography. Five hundred responses (68%) were received. In general, significant differences exist across the United States in the mean heparin dose for angiography, mean dose for angioplasty, heparin concentration in flush solutions, and, especially, frequency with which heparin is mixed with nonionic contrast media. Few respondents routinely use systemic (bolus) heparinization for angiography. Heparin concentration in flush solutions varies from 0 IU/L to 12,000 IU/L. Eleven percent of respondents mix heparin with nonionic contrast agents, at a median dose of 5 IU/mL. Results of this survey reveal patterns of practice but do not represent a standard of practice. Protocols for heparin use should be based on experimental evidence, and heparin dosage must be individualized for each procedure and each patient. Large-scale, prospective studies of the merits of systemic heparinization and of mixing heparin with nonionic contrast agents are needed.

Iohexol myelography in the horse.

Iohexol, a water soluble non-ionic contrast agent, was evaluated for myelography in the horse. Both 300 and 350 mg iodine/ml iohexol gave diagnostic cervical myelograms. Pathological changes were limited to extradural oedema and an increase in the number of white blood cells and specific gravity in the cerebrospinal fluid two days after myelography. This increase in white blood cells in the cerebrospinal fluid was, however, much less than that recorded by other authors using metrizamide and iopamidol contrast media. These findings indicate that iohexol is a less irritant myelographic contrast agent than those previously evaluated in the horse.

Ultrafast computed tomography in the diagnosis of cardiac disease

Ultrafast computer tomography (CT) is one of the major new imaging modalities that has become available for the evaluation of patients with heart disease. With cine CT it is possible to obtain high resolution images of the heart at 58-ms intervals. The inplane resolution is 0.7 to 1.5 mm, and the slice thickness is 3 to 9 mm. Images require the intravenous injection of nonionic contrast agents to obtain quantitative information about cardiac function. Cine CT has thus far been used in 3 general areas that relate to the evaluation of patients with heart disease: evaluation of cardiac structure and function, evaluation of vein bypass graft patency and flow reserve, and measurements of regional myocardial perfusion. Because of the outstanding spatial resolution of the images, it is possible to obtain very precise information about cardiac structure and function. The weight of the left ventricle and right ventricular walls can be measured to ± 5%, and the stroke volumes and end-diastolic volumes of all 4 cardiac chambers can also be measured with an accuracy of ± 5%. With this technology it is possible to determine the magnitude of aortic regurgitation within ± 5 to 8%. This modality has also proved useful in the diagnosis of surgically resectable left ventricular aneurysm and a multitude of other cardiac disorders that involve abnormalities in cardiac structure, including congenital heart defects, aortic aneurysms and constrictive pericarditis. These diagnostic procedures use the peripheral injection of usually about 100 ml of contrast media and can ordinarily be completed in less than 15 minutes. Ultrafast CT is also useful in the determination of vein bypass graft patency. A recent multicenter study indicated that the patency of bypass grafts could be determined with an accuracy of about 92%. Accuracy was not different in internal mammary artery conduits or saphenous vein grafts. Recent experimental studies with cine CT indicate that if one uses aortic route injection of contrast it will be possible to measure regional myocardial perfusion with outstanding accuracy. Studies in animals suggest that myocardial perfusion rates that vary from as low as 10 to as high as 600 ml/min × 100 g can be measured with an accuracy of about ± 15% with ultrafast CT.

Nephrotoxicity of a nonionic (iopamidol) versus an ionic (diatrizoate) contrast agent in the patient after cardiac transplant with moderate cyclosporine-induced renal insufficiency

It has been speculated that nonionic contrast agents may be less harmful to the kidney than ionic contrast agents. 1,2 Preexisting renal insufficiency has been shown to be a major risk factor for contrast-induced renal failure. 3 We therefore conducted a prospective study to evaluate the effects on renal function of an ionic and a nonionic contrast agent in cardiac transplant patients with impaired renal function secondary to cyclosporine therapy.

Renal papillary blushes and nonionic contrast agents.

Renal papillary blushes and nonionic contrast agents.

Differing mechanisms of clotting inhibition by ionic and nonionic contrast agents.

The anticoagulant potency of ioxaglate has been shown to be approximately twice that of iopamidol and iohexol. Those findings were obtained with use of the thrombin time as a test and platelet-poor plasma as a thrombin substrate. The authors confirmed these findings with use of a whole-blood version of the same test. However, the thrombin time measures only the final stages of the clotting process. A measure of the entire intrinsic pathway would more nearly simulate the situation in the angiographic suite. When measured with such an assay, the anticoagulant potency of ioxaglate was equivalent to that of diatrizoate and was approximately four times that of iopamidol and iohexol. Because of this difference in potency, it seemed likely that the ionic agents were inhibiting the clotting cascade at a late stage as well as at an earlier stage. To investigate this possibility, whole blood-contrast agent mixtures were activated, incubated for several minutes, and then diluted with either citrated or heparinized whole blood. There was rapid clot formation when the unclotted iopamidol and iohexol mixtures were diluted with citrated whole blood but not when they were diluted with heparinized whole blood. The ionic mixtures did not clot in the presence of either anticoagulant. Thus, in unclottable mixtures nonionic agents still permitted the generation of procoagulants. These procoagulants are theoretically capable of causing clotting on reinjection.

Contrast Nephrotoxicity

Experimental studies have suggested that nonionic contrast agents are less nephrotoxic than ionic contrast agents. To examine the relative nephrotoxicity of the two types of agents, we randomly assigned 443 patients to receive either iopamidol (nonionic) or diatrizoate (ionic) for cardiac catheterization. The patients were stratified into low-risk (n = 283) or high-risk (n = 160) groups, on the basis of the presence of diabetes mellitus, heart failure, or preexisting renal insufficiency (base-line serum creatinine level, greater than 133 mumol per liter). Serum and urine analyses were performed at base line and 24 and 48 hours after the infusion of contrast material. Nephrotoxicity was defined as an increase in the serum creatinine level within 48 hours of at least 44 mumol per liter. The median maximal rise in the serum creatinine level was 18 mumol per liter in both the diatrizoate group (n = 235) and the iopamidol group (n = 208) (P not significant; power to detect a difference greater than 9 mumol per liter, greater than 90 percent). Creatinine levels increased by at least 44 mumol per liter (0.5 mg per deciliter) in 10.2 percent of the patients receiving diatrizoate and 8.2 percent of the patients receiving iopamidol (P not significant). Among the high-risk patients, creatinine levels increased by at least 44 mumol per liter in 17 percent of the patients in the diatrizoate group, as compared with 15 percent of the patients in the iopamidol group (P not significant). We were unable to demonstrate a difference in the incidence of nephrotoxicity between patients receiving a non-ionic contrast agent and those receiving an ionic contrast agent.

Induction of ventricular arrhythmia by high and low osmolarity ionic and nonionic contrast media

Studies that used prolonged contrast media infusion in canine arteries have generated controversy regarding the arrhythmogenic potential of low osmolarity, nonionic contrast agents. In order to establish the relative safety of these agents in the more typical setting of bolus injections, 4 ml intracoronary bolus injections of Hypaque-76 (n = 54), lohexol-350 (n = 51), and lohexol-140 (n = 51) were given in random order to 10 anesthetized, open-chest dogs undergoing programmed cardiac stimulation. Hemodynamics and electrocardiogram were monitored during stimulation, both during and for 2 minutes after the end of contrast infusion. Occurrence of tachycardia did not differ statistically among agents. Sustained ventricular tachycardia (five episodes) and ventricular fibrillation (seven episodes) occurred only after Hypaque-76 injections ( p < 0.002). These results differ from those in studies that use continuous contrast infusion and suggest that low osmolarity nonionic contrast agents are as safe as high osmolarity nonionic contrast media. Both appear safer than ionic contrast material.

Hemodynamic Effects of Ioversol in the Dog and Rat

The hemodynamic effects of selectively administered ioversol were examined in the dog and rat. At concentrations ranging from 32% to 37% I, wt/vol, ioversol was compared with nonionic (iohexol, iopamidol) and ionic (diatrizoate) contrast media for cardiovascular responses following injections into the femoral vein, right and left coronary arteries, left ventricle, and the pulmonary and femoral arteries of the dog, and into the carotid artery of the rat. Regardless of the intravascular route of injection, ioversol generally caused minimal effects on the heart rate, minimal to moderate decreases in myocardial contractility, left ventricular pressure, mean arterial pressure, pulmonary vascular resistance, and systemic vascular resistance. These effects of ioversol were comparable to those of iohexol and iopamidol, and were relatively less profound than those of diatrizoate. Under experimental conditions injections of ioversol exerted hemodynamic effects comparable to those of other nonionic agents, yet relatively diminished as compared with a representative high-osmolality ionic contrast agent. These results suggest that the nonionic contrast agent, ioversol, should be well tolerated in patients following injections via similar intravascular routes.

A prospective trial of ionic vs nonionic contrast agents in routine clinical practice: comparison of adverse effects

A multicenter study of adverse effects of ionic and nonionic contrast agents was conducted in three similar time periods. In 1985, before approval of the nonionic contrast agents by the Food and Drug Administration, 6006 consecutive patients received iv ionic agents for urography or CT. After approval of the nonionic agents, 7170 consecutive patients referred for the same examinations were studied. The two groups of patients were significantly different, but the differences were small and did not uniformly favor either group. The incidence of adverse effects in the patients given ionic contrast material was significantly higher than that of the nonionic group (4.17% vs 0.69%, p less than .001). The reactions were also more severe in the ionic group than in the nonionic group (p less than .005). A patient questionnaire disclosed that many patients did not feel well for hours to days after the procedure and also did not immediately resume normal activities of daily living. The nonionic agent was significantly less distressful than the ionic agent. We conclude that nonionic agents cause fewer and less severe adverse effects. Reducing adverse effects can save the patient or the examining site either time or money. However, this study does not show that nonionic agents are more cost-effective than ionic agents.

Interstitial lymphangiography: initial clinical experience with a dimeric nonionic contrast agent.

Interstitial lymphangiography performed with intradermal injection of a new nonionic dimeric contrast agent was used to examine 34 normal lower extremities and 35 lower extremities with proved lymphedema. An infusion pump was used to inject 2 mL of the contrast agent into the intradermal interdigital space at a rate of 0.1 mL/min. In all normal extremities, the injection deposit appeared homogeneous, and one to five lymph vessels could be identified. Diffusion of contrast agent into perilymphatic tissue occurred 30-40 cm proximal to the injection site; inguinal lymph nodes were, therefore, not routinely visualized. The findings at interstitial lymphangiography were abnormal in all extremities with advanced lymphedema. The results indicate that interstitial lymphangiography with the use of a nonionic dimeric contrast agent allows morphologic assessment of lymphatic vessels and facilitates the diagnosis of lymphatic obstructive disease.

Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization. A prospective trial.

To determine the incidence of cardiovascular and renal toxicity of a nonionic contrast agent when used for cardiac catheterization, and to assess the value of electrolytes and urinalysis results as predictors of nephropathy induced by a contrast agent. Nonrandomized trial using a criterion standard and a cohort analytic study with a 48-hour follow-up. Referral-based university hospital. Convenience sample of patients having diagnostic cardiac catheterization. Renal function and clinical status were evaluated at baseline in 1,144 patients; at 24 hours in 1,077 (94%); and at 48 hours in 663 (57%). After patients received saline for hydration, coronary angiography and left ventriculography were done with iopamidol (average dose, 203 +/- 56 cc). The definite and possible incidence of major acute cardiovascular complications from nonionic contrast media was 0.2% and 0.7%, respectively. The mean serum creatinine level increased 11.5 mumol/L from baseline at 24 hours (P less than 0.0001) and 16.8 mumol/L from baseline at 48 hours (P less than 0.0001). Results in a randomly selected training sample were studied to determine predictors of a rise in serum creatinine of 44.2 mumol/L or more. The baseline serum creatinine level and age were significant predictors of renal injury, but hypertension, diabetes mellitus, congestive heart failure, vascular disease, the volume of contrast agent injected or baseline values of urinary variables did not predict nephrotoxicity. In an independent validation sample, only the baseline serum creatinine level was confirmed as a predictor of nephrotoxicity, whereas age was not. A model that predicted contrast-induced nephropathy by the serum creatinine level showed an exponential increase in the risk for nephrotoxicity if the baseline level was 106.1 mumol/L or higher. Patients have a small but significant rise in serum creatinine after cardiac catheterization with a nonionic contrast agent. Baseline renal insufficiency is the only confirmed predictor of nonionic contrast-induced nephrotoxicity.

Experimental trials with Gd(DO3A)—a nonionic magnetic resonance contrast agent

Gd(DO3A), a member of a new family of nonionic MRI contrast agents, was evaluated in vivo in a rat model. In 10 animals, enhancement of an intracerebral glioma was studied following Gd(DO3A) injection. Correlation with tissue pathology was obtained in all cases. Comparative studies of renal enhancement were performed in 15 animals, utilizing disodium-Gd(DTPA) 2−, sodium-Gd(DOTA) −, and Gd(DO3A). With the glioma model, Gd(DO3A) administration provided enhancement of tissue with an altered blood-brain barrier, thus permitting identification of the bulk of the neoplastic lesion. Comparative studies revealed that enhancement of normal renal medulla was equal or superior with Gd(DO3A).

Age dependence of renal function: clearance of iohexol and p-amino hippurate in healthy males.

Iohexol, a newly developed non-ionic contrast agent, has been recently documented as a reliable glomerular filtration marker. This study describes the age dependence of the single injection clearance of iohexol in a sample of healthy male volunteers ranging from 21 to 77 years of age. In parallel, renal plasma flow was studied by measuring the total clearance of p-amino hippuric acid administered as a continuous infusion. In subjects older than 50 years a negative correlation to age was found for both p-amino hippuric acid and iohexol clearance, with a reduction of 52 ml/min and 12 ml/min per decade, respectively, whereas no age dependence was found for younger subjects. Correlation between p-amino hippuric acid and iohexol clearances was 0.81. However, the filtration fraction, defined as the ratio of iohexol to p-amino hippuric acid clearance, was higher in the elderly subjects. A consistent discrepancy was found between total and renal clearances of p-amino hippuric acid, indicating significant renal metabolism. Renal clearance of creatinine was poorly correlated to iohexol clearance and did not show any relationship to age.

Lumbar myelography with iopamidol: a methodological approach to the investigation of side effects.

Pathophysiology of adverse reactions occurring during myelography with non-ionic contrast agents, such as iopamidol, seem related to their direct action on the nervous system. The authors try a multivariate approach, involving neurophysiological, neuropsychological and neurochemical parameters on a pilot group of twelve subjects. Any possible change in the above examinations is thoroughly analyzed and correlated to the postulated neurotoxic properties of contrast media.