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.     

Iotrolan in urography: efficacy and tolerance in comparison with iohexol and iopamidol

Iotrolan was compared with iohexol and iopamidol for efficacy and general tolerance in excretory urography in three controlled, randomized, inte-individual, double-blind studies. Two hundred and eighty-four patients received fixed doses of 100 ml, 120 ml or 150 ml iotrolan 280 or iohexol 300/iopamidol 300 by rapid or bolus injection. Contrast quality in films taken 3–40 min after injection was rated by experienced radiologists both on an overall basis and with regard to distinct anatomical regions (parenchyma, pelvicalyceal system, ureter, bladder). In all studies, contrast quality was assessed as better in the iotrolan group. In two studies (dosages 100 and 120 ml), significant differences in contrast quality were found in lavour of iotrolan (P < 0.05), and in the third study (dosage 150 ml) there was a trend towards better contrast quality in the iotrolan group (P = 0.06). General tolerance of iotrolan was good with only minor side effects (iotrolan 6.3%, iohexol/iopamidol 9.9%), but the difference was not significant. No severe adverse reactions were observed with iotrolan. In comparison with non-ionic monomers, iotrolan shows very good efficacy and general tolerance for excretory urography.     

Iotrolan in urography: efficacy and tolerance in comparison with iohexol and iopamidol

Iotrolan was compared with iohexol and iopamidol for efficacy and general tolerance in excretory urography in three controlled, randomized, inte-individual, double-blind studies. Two hundred and eighty-four patients received fixed doses of 100 ml, 120 ml or 150 ml iotrolan 280 or iohexol 300/iopamidol 300 by rapid or bolus injection. Contrast quality in films taken 3–40 min after injection was rated by experienced radiologists both on an overall basis and with regard to distinct anatomical regions (parenchyma, pelvicalyceal system, ureter, bladder). In all studies, contrast quality was assessed as better in the iotrolan group. In two studies (dosages 100 and 120 ml), significant differences in contrast quality were found in lavour of iotrolan (P < 0.05), and in the third study (dosage 150 ml) there was a trend towards better contrast quality in the iotrolan group (P = 0.06). General tolerance of iotrolan was good with only minor side effects (iotrolan 6.3%, iohexol/iopamidol 9.9%), but the difference was not significant. No severe adverse reactions were observed with iotrolan. In comparison with non-ionic monomers, iotrolan shows very good efficacy and general tolerance for excretory urography.     

Peripheral and penile angiography with iotrolan 280 versus non-ionic monomers: results of the European clinical phase II and III trials

To evaluate diagnostic quality, safety and local tolerance in peripheral arteriography, isotrolan (280 mg iodine/ml) was compared to the non-ionic monimers iopamidol (300 mg iodine/ml), iohexol (300 mg iodine/ml) and iopromide (300 mg iodine/ml) in nine randomized, double-blind, the suitability of iotrolan 280 was evaluated in an interindividual, non-randomized, single-blind study. Pelvic-leg arteriography was performed in 298 patients, selctive femoral arteriography in 201, intra-arterial digital subtraction angiography in 20. Despite the 7% lower iodine content of iotrolan, its contrast density was rated as good as that of the non-ionic monomers. Due to the few motion artifact, caused by motor pain reactions, the overall diagnostic quality of iotrolan was good. The slightly higher viscosity of iotrolan did not impair injectability. General tolerance was excellent with iotrolan and with non-ionic monomers (2.3% minor adverse events versus 4.6%). With respect to local tolerance, iotrolan demonstrated clear advantages. The frequency of completely painless injections was 91% in non-selective femoral angiography and 70% in penile arteiorgraphy (62, 25 and 10%, respectively, with comparator agents). in intra-arterial DSA of the hand, the injectio of iotrlan 280 was tolerated with minimal or no pain in 100% of patients (58% with iohexol 300). Iotrolan proved to be highly suitable for peripheral arteriography and for arteriography of the penis. Its major advantage is excellent local tolerance in examinations in which even low-osmolar non-ionic monomers may cause significant pain and unpleasant sensations of heat. Better local tolerance results in an improvement of diagnostic quality due to fewer motion artifacts.     

Hemodynamic and electrophysiologic effects of low osmolar contrast agents during coronary angiography in the dog and the rabbit

The electrophysiological tolerability of ioxaglate (160 mgI/ml) and iohexol (140 mgI/ml) was assessed in rabbits (n = 12 per group). There was a significant induction of ventricular fibrillation in the group given iohexol. An explanation for this phenomenon could be the lack of sodium in this preparation. Ioxaglate, iopamidol and iohexol (all at 320 mgI/ml) were also compared during coronary angiography in the dog (n = 10) after bolus administration, using the carotid approach (5 and 8 ml-0.5 ml/sec). Each dog received all the compounds in the left coronary artery and selectively in the left anterior descending artery, at random. Four dogs had lethal ventricular fibrillations after iohexol. Iopamidol and iohexol induced significant bradycardia in comparison with saline. A biphasic effect on myocardial contractility was observed with all contrast media: a short-lasting, typical decrease in dP/dt was seen with ioxaglate by the end of injection, while iohexol and iopamidol caused a similar negative inotropic effect in some cases (25%) after increasing dP/dt. The positive inotropic effect was greater with iopamidol and iohexol than with ioxaglate (p less than 0.05). The possible clinical consequences of the lack of sodium in contrast media preparations and of the changes in myocardial function are discussed in the light of the present results.     

Electrolyte disturbances caused by intravenous contrast media.

The changes in serum electrolytes (sodium, potassium, ionized calcium, and total calcium) produced by high-dose (3 ml/kg) intravenous contrast media were investigated in Japanese white rabbits. The test solutions included sodium/meglumine diatrizoate (370 mgI/ml), sodium/meglumine ioxaglate (320 mgI/ml), iohexol (350 mgI/ml), iopamidol (370 mgI/ml), 20% mannitol, and isotonic saline. The alterations in serum ionized calcium were relatively small and transient, and correlated with changes in the hematocrit. Diatrizoate caused a significant decrease in ionized calcium in comparison with other contrast media and mannitol. The ratio of ionized calcium to total calcium showed no significant decrease in any group. The changes in potassium did not correlate with those in hematocrit. Diatrizoate caused a smaller decrease in potassium than low-osmolality contrast media, which may suggest that diatrizoate caused a shift in potassium from extravascular space to intravascular space. In conclusion, intravenous infusion of high doses of low-osmolality contrast media did not cause clinically significant alterations in serum electrolytes.     

A comparison of the systemic responses to rapid intravenous injections of ioxilan, iohexol, and diatrizoate in rabbits

Rapid intravenous injections of contrast media are used for angiocardiography, intravenous digital subtraction angiography (DSA), and rapid scan computed tomography procedures. These rapid intravenous injections have been shown to produce significant hemodynamic changes that appear related to contrast media osmolality. In this study the systemic responses to 2-second injections at a dose of 1.5 mL/kg were compared for a new nonionic agent, ioxilan (350 mgI/mL), and for iohexol (350 mgI/mL), meglumine/sodium diatrizoate (370 mgI/mL), and saline. Ioxilan has a lower osmolality and viscosity than iohexol and is formulated with a 3 mM sodium citrate as a buffer and anticoagulant. All of the test solutions produced statistically significant changes in arterial pressure and respiratory rate (P less than .05, Student's t-test). The decrease in arterial pressure seen with diatrizoate (20.1%) was significantly greater than the decrease seen with either ioxilan (10.2%) or iohexol (10.2%). All of the responses observed were transient and would not be of clinical concern in a healthy patient. Ioxilan, which contains the calcium binding agent, sodium citrate, and iohexol appear to cause less systemic effects then diatrizoate.     

Clinical safety of iotrolan 280: the Japanese experience

Iortrolan is a new non ionic, dimeric, iodinated X-ray contrast agent that is isotonic with body fluids. In Japan iotrolan (280 mg iodin/ml) was evaluated in well controlled multi-center trials to compare its efficacy, safety and utility with that of iopamidol (300 mg iodine/ml), considered to be the standard non-ionic monomeric X-ray contrast agent in this country. Safety data from four phase III studies are presented. Two studies involved intra-arterial injection (cerebral and peripheral arteriography) and two were intravenous (computed tomography and urography). Iotrolan 280 was administered to 333 patients and 337 patients received iopamidol 300. The safety evaluation of iotrolan 280 was by assessment of adverse events, pain and heat sensation following intra-arterial injection, as well as clinical laboratory tests and an overall safety rating by the investigator. The results showed that there was a significant reduction in pain and heat sensation with iotrolan 280. Fewer adverse events were seen with iotrolan 280 compared with iopamidol 300, but this difference was not signicant in this limited patient population. Clinical laboratory tests showed no clinically relevant change attributed to contrast agent injection not any significant difference between the two agents. The overall safety rating, based on all of the above results, was “safe” in 94.6% of patients receiving iotrolan 280 and 92.0% of patients receiving iopamidol 300, suggesting that iotrolan 280 was at least as safe for intra-arterial and intravenous use as iopamidol 300.     

Renal tolerance of iotrolan 280 —a meta-analysis of 14 double-blind studies

Clinical data from 14 randomized double-blind studies were reviewed to compare the renatl tolerance of non-ionic monomeric contrast agents (iopamidol 300, iopromide 300, iohexol 300) with the non-ionic dimer iotrolan 280. A prospective study of iotrolan 280 versus iohexol 300 in renally impaired patients was also evaluated. Differences between the contrast agents were investigated using sub-group analysis of patients with an increased risk of contrast-induced nephropathy. Both the prospective study and meta-analysis of previous studies indicate that iotrolan 280 has less influence on renal function than the non-ionic monomeric comparator agents.     

Viscosity of some contemporary contrast media before and after mixing with whole blood.

The viscosity of 7 contrast media was measured using a rotational viscometer. When solutions with similar iodine concentrations were compared, the highest viscosities were found for the nonionic dimers iodixanol and iotrolan, the lowest for diatrizoate, iopamidol, and iopromide, and intermediate values for iohexol and ioxaglate. The viscosity of iohexol and ioxaglate was found to vary linearly with temperature and quadratically with concentration. Whole-blood viscosity was measured for 5 subjects at high and low shear rates before and after mixing with contrast media in various proportions. Low-shear viscosity was found to decrease and high-shear viscosity to increase with contrast medium concentration. It is concluded that the contrast media currently used may affect blood rheology less than previous agents, despite their higher viscosity.     

Iotrolan,a non-ionic dimeric contrast agent in cerebral angiography

We report the European experience with iotrolan 280, a new, non-ionic, isotonic, dimeric, iodinated contrast agent in cerebral angiography. Six randomized, double-blind, controlled, interindividual studies took place at four study centers in Germany. All the studies used intra-arterial contrast administration: iotrolan 280 was administered to 186 patients, iopamidol 300 to 127 patients, iohexol 300 tp 30 patients and iopromide 300 to 30 patients. Iotrolan 280 gave impoved contrast quality with improved opacification of small cerebral vessels. LOcal pain and heat sensations were fewer following iotrolan administration. There was a trend towards better neural tolerance of iotrolan 280 as shown by electroencephaplogram.     

Iotrolan, a non-ionic dimeric contrast agent in cerebral angiography

We report the European experience with iotrolan 280, a new, non-ionic, isotonic, dimeric, iodinated contrast agent in cerebral angiography. Six randomized, double-blind, controlled, interindividual studies took place at four study centers in Germany. All the studies used intra-arterial contrast administration: iotrolan 280 was administered to 186 patients, iopamidol 300 to 127 patients, iohexol 300 tp 30 patients and iopromide 300 to 30 patients. Iotrolan 280 gave impoved contrast quality with improved opacification of small cerebral vessels. LOcal pain and heat sensations were fewer following iotrolan administration. There was a trend towards better neural tolerance of iotrolan 280 as shown by electroencephaplogram.     

Excretory urography with iohexol: evaluation in children

A multicenter clinical study was conducted using iohexol, a second-generation nonionic contrast medium, for excretory urography performed in 130 children. Doses of iohexol (300 mg iodine/ml) ranged between 150 and 660 mgI/kg (0.5 and 2.2 ml/kg). Iohexol was tolerated well, and no significant adverse reactions occurred. Sixty-five iohexol urograms were evaluated to determine the minimum dose for adequate visualization of the kidneys and collecting systems. A dose greater than 300 mgI/kg (1.0 ml/kg) always resulted in a urogram of diagnostic quality, while visualization was insufficient for diagnosis in 10% of studies done with doses of 150-300 mgI/kg (0.5-1.0 ml/kg). Another 65 iohexol urograms were compared in a blinded manner with a similar number of studies performed using iothalamate meglumine at comparable iodine concentration and dose. Visualization of calyces and pelvoinfundibular structures achieved with iohexol was rated better with statistical significance, but there was no difference in visualization of the renal parenchyma or ureters. Use of iohexol in excretory urography may be advantageous in children who are at greatest risk for an adverse reaction to contrast media or in those most likely to benefit from use of a low osmolality contrast agent.     

Effects of nonionic contrast media on the blood-brain barrier. Osmolality versus chemotoxicity.

This study was performed to assess the relative contributions of contrast medium osmolality and chemotoxicity to contrast-induced blood-brain barrier (BBB) damage. Experimental carotid angiography was carried out in rabbits with mannitol at an osmolality of 714 mOsm/kg, with the nonionic, monomeric contrast media iohexol and ioversol at similar osmolalities, and with the nonionic, dimeric contrast media iodixanol and iotrolan at osmolalities less than half that of the mannitol. The amount of damage caused by the procedure was assessed by determining the amount of intracerebral extravasation of intravascularly injected technetium-99m-pertechnetate. Mannitol caused no detectable BBB damage, but all four contrast media caused BBB damage that was significantly more severe than that caused by mannitol. The BBB damage caused by carotid angiography with iohexol, ioversol, iodixanol, and iotrolan was not attributable to their osmolalities, but due to some other physical and/or chemical effects of these media on the BBB.     

Iotrolan in pediatric examinations

Iotrolan, a new non-ionic, dimeric, iodinated contrast agent, was compared with iohexol, a non-ionic, monomeric contrast agent, for suitability in pediatric patients. Two studies were performed. The gastrointestinal medication was studied in 20 infants using iotrolan 300 versus iohexol 300. Contrast quality with iotrolan 300 appears to be superior to iohexol 300. The renal indication was studied in a large, multicenter, double-blind trial, 167 children received intravenous doses of either iotrolan 280 or iohexol 300 for urography, and contrast quality and safety were assessed. Iotrolan 280 appears to give better contrast quality in all areas of the kidney and the ureters. On the results of our experience, we recommend iotrolan 300 for gastrointestinal imaging in pediatries, where barium sulfate is contraindicated, and iotrolan 280 in pediatric urography. We suggest that iotrolan 280 may also be suitable for all intravascular administrations.     

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.     

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.     

Diffusion of contrast media in cerebrospinal fluid: comparison of iohexol,iopamidol and iotrolan in vitro

Summary Diffusion of iohexol (300 and 240 mgI/ml), iopamidol (300 and 200 mgI/ml), and iotrolan (300 and 240 mgI/ml) in the cerebrospinal fluid (CSF) of 16 patients was studied in vitro. Test tubes containing CSF were kept in a waterbath at 37°C. Contrast medium was injected along the wall into the tubes, and diffusion of contrast media in the tubes was followed with repeated computed tomography for 5 h. The contents of the tubes were then mixed by shaking, and the tubes were scanned immediately and 8 h later. The contrast media first settled in the bottom of the tubes and then diffused upwards. Iotrolan diffused more slowly than the other media, but the difference was only significant at a concentration of 300 mgI/ml. The difference between iohexol and iopamidol was minimal. In general, diffusion was slower in CSF samples with an elevated protein content, but the difference in the diffusion of contrast medium in normal and pathological CSF was seldom statistically significant, perhaps owing to the small number of samples (5) with an elevated protein content. All contrast medium-CSF mixtures remained homogeneous after mixing. These experiments showed measurable differences in the diffusion of contrast media in CSF, but it does not seem very likely that these would be significant in clinical practice.     

Effect of iodinated contrast media on blood clotting

Recently, blood clot formation in catheters used for the injection of nonionic contrast media (CM) during angiography has been reported as being due to activation of hemostasis in the catheter. However, CM exhibit inhibitory properties regarding coagulation and platelet functions. The effect on blood clotting of iohexol, iopamidol, ioxaglate, diatrizoate, and ioxitalamate at a ratio of 10% v/v with nonanticoagulated human whole blood was evaluated using the kinetics of fibrinopeptide A (FpA) generation. Blood aliquots were taken every 2 minutes until blood clot occurred. Two groups of contrast media were identified: (1) iohexol and iopamidol, which increased the clotting time, and (2) ioxaglate, diatrizoate, and ioxitalamate, for which all clotting times were over 30 minutes and no FpA generation occurred.     

Clinical safety assessment of iotrolan 280 in European clinical studies

Iotrolan (280 mg iodine/ml) a new non ionic, isotonic dimeric, contrast agent, was evaluated in multicenter clinical stidues conducted in Europe between March 1987 and September 1992. The studies compared the efficacy and safety of the agent with the non-ionic monomeric contrast agents available at the time. Iotrolan was given intravenously to patients undergoing urography, head and body computed tomography phlebography and digital subtraction angiography. The agent was also studied after intra-arterial injections in cerebral, visceral and peripheral angiographic procedures as well as digital subtraction angiography. Data from 32 prospective double blind, randomized, controlled clinical studies, were evaluated. A total of 1203 patients received either iopromide, iohexol or iopamidol (all in concentration of 300 mg iodine/ml), and a further 1207 patients received iortrolan. As there were no sognificant differences (P = 0.0853) in adverse events between the comparative agents, their adverse event data were pooled for evaluation with data from patients receiving iotrolan. Adverse experiences were recorded in two categories — local tolerance (heat and pain) and general tolerance (generalized heat and adverse clinical events). After intra-arterial injection iotrolan had a significantly lower incidence of local heat sensation (P = 0.0001) and a significantly lower incidence of local pain (P = 0.0001) compared with comparator agents. Also, after intravenous injection iotrolan had a significantly lower incidence of local heat (P = 0.0038). In the overall evaluation of general tolerance for all indications, iotrolan was shown to produce significantly less generalized heat (P = 0.0012) and a lower incidence of adverse events (P = 0.061) compared with the reference agents.