Dimeric Contrast Media Research Articles

Effects of non-ionic monomeric and dimeric iodinated contrast media on renal and systemic haemodynamics in rats.

Non-ionic dimeric contrast media (CM) are a new class of CM which are iso-osmolar with plasma. The aim of this study was to investigate their effects on systemic and renal haemodynamics. The non-ionic dimeric CM iodixanol and the non-ionic monomeric agent iobitridol (both at a dose of 1,600 mgI/kg) were compared in terms of their effects on systemic blood pressure (BP) and renal blood flow (RBF) in two strains of rats (Wistar and Sprague Dawley). Iodixanol significantly lowered BP in Wistar rats (-33 +/- 9% of baseline, 10 min post-injection, P < 0.001 vs. saline and iobitridol). Iobitridol had virtually no effect on BP. Iobitridol and iodixanol significantly decreased RBF. This effect was more marked following injection of the dimer rather than the monomer (iodixanol: -32 +/- 13% iobitridol: -20 +/- 4 of baseline at 16 min, P < 0.05). For both agents, RBF was still decreased 50 min following injection (iodixanol: -30 +/- 11%, and iobitridol: -20 +/- 5% of baseline). Iodixanol also decreased RBF in Sprague Dawley rats, while BP remained unchanged. This suggests that changes in BP/RBF autoregulation do not account for the renal haemodynamic effects of this agent. When measured 2 h following injection, the iodixanol-induced renal hypoperfusion was still detectable (-29% vs. saline-treated rats), although not significant (P = 0.06). This effect was no longer observed 4 h following injection. Increasing the saline infusion rate (18 mL/h vs. 2 mL/h) during the experiment did not significantly decrease the effects of iodixanol on BP and RBF in Wistar rats. In spite of its iso-osmolality, iodixanol, a non-ionic dimeric CM, depressed RBF and BP significantly more than iobitridol, a monomeric non-ionic agent, in Wistar rats. This effect was long-lasting and was not alleviated by increasing the hydration rate.

Nephrotoxicity related to contrast media.

The numbers of contrast media (CM)-enhanced examinations are increasing. The annual sale of iodine for CM now represents 60 million CM doses a year world-wide. In spite of improvements in chemical structure, CM are still the third leading cause of hospital-acquired acute renal failure. The definition of contrast nephropathy (CN) is discussed, as well as the mechanisms involved in the pathogenesis. Low osmolar contrast media (LOCM) are less nephrotoxic than high osomolar contrast media (HOCM) and cause fewer osmotoxic side-effects such as pain and heat sensations. The non-ionic dimeric contrast media which are iso-osmolar to plasma (IOCM) cause even fewer haemodynamic side-effects and result in better opacification of the urinary tract than LOCM. The nephrotoxicity of IOCM is low. The risk factors for CN and methods for prevention of CN are discussed.

Onset of late adverse drug reactions to dimeric non-ionic contrast media: iotrolan, iodixanol.

The problem of late adverse drug reactions to X-ray contrast media (CM) has increasingly been of concern due to several reports of such ADRs to the newer dimeric nonionic CM iotrolan (280 mg iodine/ml) and iodixanol (150/270/320 mg iodine/ml). Precise information about the time of onset of late reactions would be helpful for defining the necessary post-investigational observation period in normal usage as well as in future clinical studies with these CM. We surveyed a total of 1135 ADR reports associated with iotrolan 280 and 1354 reports associated with iodixanol 150/270/320, compiled from clinical experimental studies, observational post marketing studies (PMS) and from spontaneous reporting systems (SRS). Late ADRs (i.e. ADRs observed later than 1 h post injection (p.i.)) associated with iotrolan 280 have been observed in about 55% of cases from PMS and in 70% of cases from SRS. For iodixanol 150/270/320 late ADRs were observed in 48% of cases from clinical experimental studies, in 29% of cases from PMS and of 63% cases from SRS. The analysis of time patterns of ADR onset of both CM revealed that most of the late ADRs were observed in the first 24-h period which is the standard observation time in most clinical studies with CM. However, a few cases of late ADRs were observed between 24 and 72 h p.i. and single cases later than 72 h p.i. Therefore, in future clinical studies with dimeric CM patients should be observed for at least 72 h after the investigation.

Urine viscosity after injections of iotrolan or iomeprol.

Previous observations in rats caused us to speculate whether the injection of iotrolan, a nonionic dimeric contrast medium (CM), would increase urine viscosity enough to obstruct urine outflow in the collecting duct. The urine viscosity in dogs was measured directly with a viscosimeter after injections of iotrolan or of iomeprol, a nonionic monomeric CM. The injection of iotrolan increased urine viscosity considerably whereas iomeprol had little effect on this variable. The osmolality-dependent adverse reactions of CM have previously been emphasized but viscosity-dependent adverse reactions must also be considered when the CM is a polymer with a low osmolality.

High-volume nonionic dimeric contrast medium: first experiences during complex coronary interventions.

Interventional cardiology is a rapidly developing field of medicine with annually increasing numbers of coronary interventions. Especially through the development of alternative techniques for coronary angioplasty, new indications have been found and more difficult lesions are tackled. Inevitably, such complex interventions are time-consuming and require high amounts of contrast medium. Newer, mostly nonionic agents have been developed with improved tolerability as well as fewer cardiac and renal side effects due to their nonionic, hydrophilic structure, and their osmolality isotonic to plasma. This study sought to investigate the effects of high-volume nonionic, dimeric contrast medium during coronary interventions with special emphasis on renal and hemodynamic side effects during routine hospital stays. Retrospectively, 25 consecutive patients (age 56 +/- 10 yr) with normal renal and cardiac function receiving > 500 ml of the nonionic dimeric contrast medium iodixanol during complex coronary interventions were analyzed. The analysis was based on serum creatinine levels 1 day before and 2 days after contrast medium administration for the monitoring of renal function. Additionally, heart rate and left ventricular pressures were evaluated before and after left ventricular angiography. Mean serum creatinine rose from 0.9 +/- 0.2 mg/dl to 1.1 +/- 0.2 mg/dl (P < 0.05) after 2 days of coronary intervention. Heart rate, left ventricular systolic pressure, and left ventricular end-diastolic pressure did not change significantly. No major side effects were encountered in the short follow-up period of 2 days. Based on this retrospective analysis, high-volume nonionic, dimeric contrast medium administration in patients without preexisting renal insufficiency is associated with little impairment of renal function, and has only minor hemodynamic and general side effects. Iodixanol 320 mg I/ml is well-tolerated and effective for the use of cardioangiography. Given the limitations of this retrospective analysis, future prospective studies should systematically address the effects of high-volume contrast medium administration in otherwise healthy patients as well as in high-risk patients undergoing coronary interventions.

High‐volume nonionic dimeric contrast medium: First experiences during complex coronary interventions

Interventional cardiology is a rapidly developing field of medicine with annually increasing numbers of coronary interventions. Especially through the development of alternative techniques for coronary angioplasty, new indications have been found and more difficult lesions are tackled. Inevitably, such complex interventions are time-consuming and require high amounts of contrast medium. Newer, mostly nonionic agents have been developed with improved tolerability as well as fewer cardiac and renal side effects due to their nonionic, hydrophilic structure, and their osmolality isotonic to plasma. This study sought to investigate the effects of high-volume nonionic, dimeric contrast medium during coronary interventions with special emphasis on renal and hemodynamic side effects during routine hospital stays. Retrospectively, 25 consecutive patients (age 56 ± 10 yr) with normal renal and cardiac function receiving >500 ml of the nonionic dimeric contrast medium iodixanol during complex coronary interventions were analyzed. The analysis was based on serum creatinine levels 1 day before and 2 days after contrast medium administration for the monitoring of renal function. Additionally, heart rate and left ventricular pressures were evaluated before and after left ventricular angiography. Mean serum creatinine rose from 0.9 ± 0.2 mg/dl to 1.1 ± 0.2 mg/dl (P < 0.05) after 2 days of coronary intervention. Heart rate, left ventricular systolic pressure, and left ventricular end-diastolic pressure did not change significantly. No major side effects were encountered in the short follow-up period of 2 days. Based on this retrospective analysis, high-volume nonionic, dimeric contrast medium administration in patients without preexisting renal insufficiency is associated with little impairment of renal function, and has only minor hemodynamic and general side effects. Iodixanol 320 mg l/ml is well-tolerated and effective for the use of cardioangiography. Given the limitations of this retrospective analysis, future prospective studies should systematically address the effects of high-volume contrast medium administration in otherwise healthy patients as well as in high-risk patients undergoing coronary interventions. Cathet. Cardiovasc. Diagn. 40:241–246, 1997. © 1997 Wiley-Liss, Inc.

Elektronenstrahltomographische Darstellung der Koronararterien: Experimenteller Vergleich zwischen einem monomeren und einem dimeren Röntgenkontrastmittel

Comparison of a monomeric and a dimeric radiographic contrast medium in the visualisation of the coronary arteries via electron beam tomography (EBT). In a total of 6 Göttingen minipigs the heart was examined by EBT (40 sections, ECG-triggering, 1.5 mm section thickness, 100 ms acquisition time) after injection of both iopamidol (monomer, 370 mg l/ml) and iotrolan (dimer, 320 mg l/ml) at a dose of 740 mg l/kg. Injection rate and scan delay were adjusted to heart rate and circulation time. The intravascular increase in density after intravenous injection of iotrolan was significantly higher and longer than after injection of iopamidol (> 300 HE: 28 +/- 4 versus 17 +/- 5 cardiac cycles; p < 0.05). Iotrolan attained a higher score in the visualisation of the coronary arteries in three-dimensional surface reconstructions (p < 0.05). The dimeric contrast medium iotrolan proved superior to the monomeric agent iopamidol for visualisation of the coronary arteries via EBT.

Phase III clinical trial comparing iodixanol and iohexol in cerebral angiography

We report on our early clinical experience in the United States with the nonionic dimeric (6:1 ratio) contrast medium iodixanol in cerebral angiography. Iodixanol has an osmolality less than half that of monomeric, nonionic contrast media such as iohexol at equivalent iodine concentrations and is isosmotic to blood. Forty-nine adult patients undergoing elective cerebral angiography were studied in a phase III, double-blind, randomized, parallel-design clinical trial comparing the safety and diagnostic efficacy of iodixanol at 320 mg I/ml (IOD-320) and iohexol 300 mg I/ml (IOH-300). Diagnostically adequate cerebral angiograms were routinely obtained with both contrast agents. A total of 37% of the patients experienced adverse events (48% in the IOD-320 group and 25% in the IOH-300 group). No statistically significant differences were noted between the two groups studied in the proportion of patients with one or more adverse events or in the intensity of the adverse events. The most common adverse event was headache. There were no deaths or serious complications related to either contrast medium in this study. The results of this phase III trial support the conclusion that iodixanol at a concentration of 320 mg I/ml is comparable to iohexol at 300 mg I/ml in terms of efficacy (overall radiographic diagnostic visualization) and safety.

Effect of iodixanol on in vitro bleeding time

Both monomeric and dimeric ionic radio contrast media (CM) have been shown to be more anticoagulant than nonionic monomeric CM. Iodixanol is a relatively new nonionic dimeric contrast medium. We investigated whether the dimeric structure of iodixanol would produce the same level of anticoagulation that has been observed using nonionic monomeric CM. We used a global screening device that operates under physiologic flow conditions to monitor the effects of iodixanol on in vitro bleeding time (IVBT). This flow dynamic technique perfuses nonanticoagulated whole blood through a hollow fiber device. A leak in the fiber is created by a precision needle, and the resulting pressure fluctuations within the fiber are monitored to examine the ability of the hemostatic system to close the leak by forming a stable platelet plug. In 20 donors, iodixanol (25% CM/blood, v/v) was shown to lengthen the mean IVBT (18.74 min) compared with the normal blood mean IVBT (4.24 min). The addition of dimeric iodixanol to normal blood affects the IVBT in the same manner as nonionic monomeric CM (ioversol, iopamidol, and iohexol).

Clinical experience of the use of a non-ionic dimeric contrast medium

Clinical experience of the use of a non-ionic dimeric contrast medium

Clinical experience of the use of a non-ionic dimeric contrast medium

Clinical experience of the use of a non-ionic dimeric contrast medium

Safety and Pharmacokinetics of Iotrolan in Hysterosalpingography

The authors compared the safety and pharmacokinetics of Iotrolan (water-soluble) in hysterosalpingography (HSG) with those of Lipiodol (oil-soluble). Iotrolan and Lipiodol were administered intraperitoneally at doses of 100 mg iodine/kg to female rabbits. Retention in the body was investigated by x-ray imaging, plasma kinetics, and urinary and fecal excretion. Irritability in the abdomen was investigated by histologic examination. Iotrolan was entirely excreted into the urine within 2 days after administration. Conversely, Lipiodol was excreted into the urine, had a half-life of 50 days, and was retained for more than 21 days in the abdomen. Iotrolan induced no inflammatory reaction in the abdomen, whereas Lipiodol induced a marked abdominal inflammatory reaction, including granuloma formation. Iotrolan had no effect on iodine concentration in the thyroid; Lipiodol increased iodine concentration significantly. Iotrolan, which is a water-soluble and nonionic dimeric contrast medium, has potential greater safety for use in HSG than Lipiodol.

Iodixanol, a new non-ionic, dimeric contrast medium in cardioangiography: a double-masked, parallel comparison with iopromide

Iodixanol (320 mg I/ml) was compared with iopromide (370 mg I/ml) in a double-masked, parallel group, randomised trial of 120 patients undergoing cardioangiography in order to evaluate and compare safety, tolerability and radiographic efficacy. The overall diagnostic information and radiographic density were mainly optimal and no differences between the contrast media were detected. No serious adverse events were reported in either group, and there were no clinically relevant changes in blood chemistry. A statistically significant difference was found between the groups regarding discomfort during injection of contrast medium, the intensity of warmth being less for iodixanol (P = 0.003). Blood pressures and heart rate remained practically unchaged during coronary arteriography in both groups. During left ventriculography, the peak systolic pressure decreased after injection of iopromide (mean change ±SD: − 7.9 ± 11.1 mm Hg, P < 0.001), while there was no significant change after injection of iodixanol (mean change± SD: 0.9 ± 8.3 mm Hg). The results indicate that both contrast agents are effective, safe and well tolerated in cardioangiography, but administration of iodixanol results in a less intense sensation of warmth and a slightly better haemodynamic profile than does administration of iopromide.

CNS-Effects from Subarachnoid Injections of Iohexol and the Non-Ionic Dimers Iodixanol and Iotrolan in the Rabbit

The neural tolerance of the new non-ionic dimer iodixanol was compared with that of the clinically used monomer iohexol and the dimer iotrolan. Behaviour of non-anaesthetised rabbits was monitored for 3 hours after intracisternal injection, at a dose-volume of 1 ml/kg of iodixanol 150 mg I/ml, iodixanol 320 mg I/ml, iohexol 350 mg I/ml, or iotrolan 300 mg I/ml (10 rabbits in each group). Iotrolan induced generalized seizures in 5 rabbits, iodixanol 320 mg I/ml in 2 rabbits, and iodixanol 150 mg I/ml in one rabbit. No excitative changes were observed in rabbits, iodixanol 320 mg I/ml in 2 rabbits, and iodixanol 150 mg I/ml in one rabbit. No excitative changes were observed in rabbits injected with iohexol, but compared with the dimeric contrast media the difference was not significant. Iohexol produced significantly more severe depressive changes than iodixanol 150 mg I/ml (p < 0.01), iodixanol 320 mg I/ml (p < 0.05), and iotrolan 300 mg I/ml (p < 0.05). The results indicate that the excitative neurotoxic potential of the dimer iodixanol is likely to be lower than that of the clinically used dimer iotrolan, but slightly higher than that of iohexol. It may be expected that both dimers will produce a lower frequency of minor neurological adverse reactions than iohexol.

Biochemical and morphological effects of contrast media on the kidney.

The intravenous use of roentgen contrast media (CM) is associated with a low incidence of renal impairment. This paper considers the intravascular handling and retention of CM in relation to effects on renal function - specifically the ability of the kidney to reabsorb and catabolise low molecular weight proteins. Renal morphology following experimental administration of a high dose of an isotonic dimeric CM (iodixanol at 3 g I/kg) in rats showed numerous, large, protein-containing vacuoles or droplets in the cells of the proximal convoluted tubule. These were fully formed within 3.5 hours. The process of vacuole-formation involving the uptake of CM appears to be analogous to dextran uptake that occurs via fluid phase endocytosis. These vacuoles or CM droplets are abundant for 7 days but then slowly decline over several weeks. The quantitative recovery of (14)C iodixanol (3g I/kg) from the kidneys between 3.5 hours to 7 days after administration was about 1% of the dose, with some 0.2% of the original dose still present at 28 days. Subcellular analysis to determine the site of the radiolabel showed that the (14)C was associated with lysosomal marker enzymes. The CM-induced vacuoles/droplets are most probably giant lysosomes, which contain the intracellularly retained CM. Co-administration of tracer doses of (125)I-labelled cytochrome C with iodixanol showed some impairment of low molecular weight protein reabsorption, but remarkably this process was not effected when the vacuoles were fully formed. The conspicuous morphology of the vacuoles, the CM retention and the transient proteinuria and enzymuria cannot presently be associated with any functionally significant impairment of tubular or cellular processes.

Reducing Arrhythmogenic Effects in the Isolated Heart by Enriching Roentgen Contrast Media with Electrolytes: Survey and Present State

A review of the literature on the effects of adding electrolytes to ionic as well as nonionic contrast media (CM) in the isolated heart model reveals that both ionic and nonionic CM favor from such addtion, if the added electrolytes are balanced with respect to each other. By enriching nonionic monomeric as well as dimeric CM with such a balanced electrolyte solution, the risk of ventricular fibrillation is reduced and myocardial contractibility is improved compared to nonionic CM without such enrichment. The new nonionic dimer iodixanol is slightly hypotonic to plasma in concentrations suitable for coronary arteriography. The water solution of iodixanol therefore contains an osmotic space in which electrolytes can be added, therby making it isotonic with plasma.

A comparison of a conventional non-ionic contrast medium (iohexol) alone and with adrenaline and an iso-osmolar non-ionic contrast medium (iotrolan) in computed tomographic arthrography of the shoulder

The physico-chemical properties of the iso-osmolar dimeric contrast medium iotrolan offers potential advantages in computed tomographic arthrography (CTA). A trial was undertaken comparing iotrolan with iohexol to assess if these theoretical benefits produced an increase in the measured densities in a series of shoulder CTAs. The results showed that iotrolan did produce clinically useful increases in density when compared to a monomeric non-ionic contrast medium. The addition of adrenaline to the monomeric contrast medium produced a significant improvement in the computed tomography density which surpassed that offered by the dimeric contrast medium alone.

Contrast media-induced ventricular fibrillation: An experimental study of the effects of dimeric contrast media during wedged catheter injection in dogs

We investigated the cardiac effects of an ionic dimer, ioxaglate and two nonionic dimers, iotrolan, and iodixanol. During a simulated wedged catheter situation, 22 ml of each contrast medium was injected into the left anterior descending branch of the left coronary artery in seven open-chested, anesthetized dogs. Of 13 injections with each contrast medium, ioxaglate induced ventricular fibrillation in 11 after 34 +/- 5 sec, iotrolan in 6 after 42 +/- 4 sec, and iodixanol in 3 after 61 +/- 1 sec. Ioxaglate markedly lengthened monophasic action potential duration in contrast medium-perfused myocardium. Iotrolan, and iodixanol induced biphasic changes, first lengthening and then shortening action potential duration. The electrophysiological changes occurred later when using iodixanol. The risk of ventricular fibrillation during long-lasting contrast media exposure to the myocardium, as in a wedged catheter situation, appears to be much lower with iodixanol compared with ioxaglate and also lower than when using iotrolan.

Systemic and Pulmonary Haemodynamic Effects of Intravenous Infusion of Non-Ionic Isoosmolar Dimeric Contrast Media

The systemic and pulmonary haemodynamic effects of i.v. infusion (1 ml/s) of high doses (4 ml/kg) of 2 non-ionic, isoosmolar dimeric contrast media (CM) were investigated in 17 female pigs. The 2 CM were iodixanol and iotrolan. Both CM induced a significant increase of the following parameters: mean arterial, mean right atrial, mean pulmonary arterial, mean pulmonary arterial occlusion pressure, cardiac output, stroke volume, and diuresis. The plasma concentration of atrial natriuretic peptide was significantly increased following infusion of the 2 CM. A significant decrease was seen in the systemic and pulmonary vascular resistance.

Systemic and Pulmonary Haemodynamic Effects of Intravenous Infusion of Non-Ionic Isoosmolar Dimeric Contrast Media

The systemic and pulmonary haemodynamic effects of i.v. infusion (1 ml/s) of high doses (4 ml/kg) of 2 non-ionic, isoosmolar dimeric contrast media (CM) were investigated in 17 female pigs. The 2 CM were iodixanol and iotrolan. Both CM induced a significant increase of the following parameters: mean arterial, mean right atrial, mean pulmonary arterial, mean pulmonary arterial occlusion pressure, cardiac output, stroke volume, and diuresis. The plasma concentration of atrial natriuretic peptide was significantly increased following infusion of the 2 CM. A significant decrease was seen in the systemic and pulmonary vascular resistance.