The toxicity of the non-ionic water-soluble contrast media iohexol and metrizamide (Amipaque) in selective vertebral angiography

Summary Selective left vertebral angiography was carried out in 25 rabbits comparing the toxic effects of iohexol and metrizamide (Amipaque). The iodine concentration for iohexol was 280 and 350 mg/ml and for metrizamide 350 mg/ml. Short general convulsions were seen in many of the animals with iohexol in the concentration of 350 mg iodine/ml. Cardiovascular reactions were seen with both contrast media, but were more marked with iohexol than with metrizamide in the concentration of 350 mg iodine/ml. Both iohexol and metrizamide are far less toxic than the ionic contrast medium metrizoate, but metrizamide seems to be less toxic than iohexol in vertebral angiography.     

Renal function following nephroangiography with metrizamide and iohexol. Effects on renal blood flow, glomerular permeability and filtration rate and diuresis in dogs

The non-ionic ratio 3.0 contrast media metrizamide and iohexol used in high-dose unilateral nephroangiography in dogs produce homogeneous nephrograms and no marked effects on renal blood flow, glomerular filtration rate, and osmotic diuresis, in contrast to previously reported results using the same technique with iodine-equivalent doses of the ionic ratio 1.5 contrast medium diatrizoate (25). Iohexol affected glomerular permeability significantly less than metrizamide and diatrizoate.     

Intravascular studies with iohexol (Omnipaque). Results from the first 49 clinical trials

In order to assess the vascular clinical trial program of iohexol (Omnipaque) in Europe, the results from the first 49 vascular trials are collectively reported. The included iohexol material comprises 1742 patients. In 40 comparative trials, other contrast media like metrizamide (Amipaque), ioxaglate (Hexabrix) and various monomeric ionic media were administered in 1292 patients included in this analysis. No severe or unexpected adverse reactions related to iohexol were encountered. No clinically significant differences in radiographic image quality between the media were documented. The overall tolerability of iohexol was superior to that of monomeric ionic media and seemed to be as good as that of metrizamide.     

The effect of iohexol on glucose metabolism compared with metrizamide

In a previous in vitro study we demonstrated reduced CO2 production in rat hippocampal tissue when metrizamide was added. This metabolic depression is believed to be a result of the 2-deoxy-D-glucose (2-DG) portion of the metrizamide molecule since 2-DG is a known competitive inhibitor of glucose metabolism. This competitive inhibition probably occurs at the cell membrane since it has never been shown that metrizamide penetrates neural cells. Further the inhibition is most likely related to competition for the membrane glucose carrier. A new nonionic contrast medium, iohexol, does not contain a 2-DG component and if the hypothesis for the metabolic inhibition is valid we should not expect metabolic inhibition with iohexol. This hypothesis was tested using the rat hippocampus model previously used for metrizamide. We compared iohexol with metrizamide in isotonic concentrations and also examined the effect of hypertonicity. These experiments did not demonstrate inhibition of CO2 production with iohexol at near physiologic osmolalities, however, there was a marked depressive effect with increasing osmolality. This effect from hypertonicity is, however, probably of less importance in vivo where water will rapidly diffuse toward the hypertonic areas. The apparent lack of interference of the iohexol molecule on glucose metabolism should therefore make iohexol a more suitable contrast medium, for subarachnoid investigations than metrizamide.     

Experimental study of arachnoiditis from iohexol, an investigational nonionic aqueous contrast medium

Myelography was performed in 16 monkeys using either metrizamide or iohexol, a new nonionic aqueous contrast medium. Eight of the animals received almost five times the recommended clinical dose of contrast medium per unit of body weight; the other eight received the equivalent of a high clinical dose. The severity of resultant arachnoiditis 12 weeks later was evaluated by repeat myelography and by histologic study of the arachnoid. No animals had severe arachnoiditis. Two of the four animals examined with the higher dose of metrizamide had moderate arachnoiditis and one had mild arachnoiditis; with the lower dose of metrizamide, two of four animals had mild arachnoiditis. No significant evidence of arachnoiditis was seen in any of the eight animals examined with iohexol.     

Quality of urograms in infants: a comparison of sodium diatrizoate, metrizamide and iohexol

A consecutive series of 314 intravenous urograms performed in infants were reviewed and assessed for quality. The first 106 examinations were performed using sodium diatrizoate (Hypaque 270) as the contrast medium, the next 98 patients received metrizamide (Amipaque 280) and the final 110 received iohexol (Omnipaque 300). Thirty-five patients had to be excluded from the study for a variety of reasons, after which there were totals of 98 in the diatrizoate, 90 in the metrizamide and 91 in the iohexol groups. Assessing quality in terms of nephrographic and pyelographic density, sodium diatrizoate was found to be better than the non-ionic agents. Although the differences reached statistical significance they are small and unlikely to affect the information obtained in clinical practice. There was no difference in overall quality between metrizamide and iohexol. Comparing the degree of pyelographic distension and ureteric visualization using the three agents, no difference was found between the groups.     

Iohexol vs. metrizamide: study of efficacy and morbidity in cervical myelography

A double-blind study was conducted in 60 patients undergoing either cervical or more complete myelography via C1-C2 puncture. Patients received either iohexol or metrizamide at a 300 mg l/ml concentration. The contrast media were equally efficacious in the production of high-quality radiographs and CT scans. However, the incidence of adverse reactions differed markedly. Of patients receiving metrizamide, 68% had some type of adverse reaction, whereas only 26% receiving iohexol had symptoms. The incidence of headache (metrizamide, 34%; iohexol, 26%) was not statistically different, but the quality of the headache differed: half of the metrizamide headaches were moderate or severe, whereas all iohexol headaches were mild. Nausea (31%) and vomiting (28%) were common with metrizamide but unusual (3% nausea) with iohexol. Of the metrizamide patients, 21% had overt psychologic changes that did not occur in the iohexol group.     

Iohexol compared to metrizamide in cervical and thoracic myelography

Summary A randomized double blind study with iohexol (Omnipaque) and metrizamide (Amipaque) in cervical myelography was performed in 50 patients, 29 with iohexol and 21 with metrizamide. The myelographies were performed either with lumbar or with C₁–C₂ puncture in about equal groups, using 300 mg I/ml and 240 mg I/ml of the contrast media respectively. The image quality was equal with both contrast media, excellent in about 4/5 and good in 1/5 of the examinations. Subjective side effects were twice as frequent with metrizamide as with iohexol. The most frequent side effect was headache, occurring in 34% with iohexol and in 67% with metrizamide. Altogether 24% or the patients had EEG changes after iohexol as compared to 47% after metrizamide. All EEG changes were slight dysrythmia-except in three patients with spike activity after metrizamide. These were the only ones with mental reactions as well. It can be concluded that in this trial iohexol was better suited for cervical myelography than metrizamide.     

Lumbar myelography with iohexol and metrizamide: a comparative multicenter prospective study

Diagnostic quality of radiographs and adverse reactions associated with the use of metrizamide and iohexol as contrast agents in lumbar myelography were compared in a prospective randomized double blind study in 350 patients at seven centers. The contrast media were administered in comparable volumes at a concentration of 180 mg I per ml. Overall quality of radiographic visualization was graded good or excellent in 95% of 175 metrizamide studies and in 98% of 175 iohexol studies. Ninety-three patients examined using metrizamide (53%) and 130 patients examined using iohexol (74%) experienced no discomfort during or after myelography. Postmyelographic headache was associated with 38% of metrizamide examinations and 21% of iohexol examinations. Nausea and vomiting were also more common with metrizamide. Five patients examined using metrizamide (3%) experienced transient confusion and disorientation following lumbar myelography. No such reactions were observed following iohexol myelography.     

Metrizamide compared with iohexol for cervical myelography: a double-blind study

A double-blind comparative study of iohexol and metrizamide for use in cervical myelography through lumbar puncture was carried out in a group of 30 patients. No difference was found in the quality of radiographic examinations of the cervical or lumbar regions nor in the postmyelographic computed tomographic examinations of the cervical spine. The overall incidence of side effects was significantly higher in the metrizamide group (93.4%) than in the iohexol group (40%) (p = 0.002). The differences in incidence of nausea (53% in the metrizamide group compared with 13% in the iohexol group) and vomiting (46.6% with metrizamide, 6.6% with iohexol) were also significant (p = 0.02). Pyramidal signs and seizures occurred only after metrizamide myelography.     

Cognitive and affective changes after myelography: a comparison of metrizamide and iohexol

A battery of brief cognitive tests and a mood scale were administered to 42 patients before and after cervical myelography with either metrizamide (20 patients) or iohexol (22 patients). The patients receiving metrizamide experienced a deterioration in mood after myelography and a relatively greater decline in cognitive test performance than did those receiving iohexol. These two side effects tended to occur together in the metrizamide group, suggesting a common underlying cause; but there was no correlation between changes in mood and cognitive function after myelography with iohexol. These results suggest that metrizamide has a greater neurotoxic effect than iohexol.     

Iohexol and metrizamide in lumbar myelography. Comparison of side effects

In routine lumbar myelography carried out in 100 patients iohexol (n = 50) produced side effects in fewer patients (p less than 0.03), especially meningeal and cerebral (p less than 0.03), and among these a lower rate of headache (p less than 0.07), than did metrizamide. The overall frequency of afflicted patients (50% after iohexol and 72% after metrizamide) was high, mainly because of deliberate inclusion of patients with a high risk of side effects in the investigation. The side effects recorded up to six hours after the administration of the contrast medium were less frequent when using iohexol. If severe side effects are present at 24 hours or appear thereafter, as occurred in a few of the present patients after iohexol, surgical treatment or discharge of the patient is in some cases unnecessarily delayed.     

Iopamidol and neural tissue metabolism. A comparative in vitro study

Metrizamide was the first water-soluble contrast medium with a neurotoxicity low enough to allow it to be used routinely in the entire subarachnoid space. However, neurologic complications are still observed in some patients following the use of metrizamide. The cause of this toxicity has not been established, but existing evidence suggests an interference with glucose metabolism. In previous studies, a depression in CO2 production in neural tissue slices was demonstrated when isotonic metrizamide was added but not isotonic iohexol. In addition to iohexol, there is another new, nonionic, monomeric, water-soluble CM, iopamidol, soon to be released for clinical use in the United States. Iopamidol, like iohexol, has shown fewer adverse reactions and seems to be safer for myelography than metrizamide. Direct comparative studies of iopamidol and iohexol are sparse and the cause of their toxicity is not yet understood. This study was performed to determine the effect of iopamidol on neural tissue glucose metabolism as compared with the effects of iohexol and metrizamide. Metrizamide decreased CO2 production in neural tissue slices by 23%. Iopamidol and iohexol did not produce significant depression. Moreover, this model could not demonstrate any significant difference between iopamidol and iohexol in direct comparisons. The new monomeric contrast media, iopamidol and iohexol, thus do not appear to interfere with glucose metabolism. Adverse reactions to these new media are most likely caused by other mechanisms.     

The effect of intrathecal iohexol on visual evoked response latency: a comparison including incidence of headache with iopamidol and metrizamide in myeloradiculography

Fifty consecutive unselected patients referred for myeloradiculography and examined by the same radiologist, when facilities for measuring the visual evoked response were available, are considered. The effect on the visual evoked response of the examination and the incidence of headache following the use of iohexol as the contrast medium are compared with those after the use of iopamidol and metrizamide reported in a previous study. A total of 400 cases examined with iopamidol and 200 cases examined with iohexol are reviewed with regard to the incidence of headache. Whereas iopamidol and, to a greater extent metrizamide, were found to cause significant lengthening of the visual evoked response latency 20 hours after the radiological examination, iohexol did not. Furthermore there was no significant difference in the 20 hour reading following the use of iohexol compared with the original control group of patients who underwent lumbar puncture alone. There was a lower incidence and severity of headache following the use of iohexol than with iopamidol and a markedly reduced incidence compared with metrizamide. Iohexol is considered less neurotoxic than iopamidol which had previously superceded metrizamide as the contrast medium used for myeloradiculography in the Royal Surrey County Hospital. Volumes of up to 14 ml of iohexol 300 mg I/ml have been used for lumbar radiculography and for total myelography and up to 10 ml for direct lateral cervical puncture. In 350 cases examined to date with iohexol the only serious sequel was a case of chemical meningitis following the lumbar injection of 10 ml of the 300 mg I/ml solution for a cervical examination. The patient made an uneventful recovery.     

Iohexol versus metrizamide for lumbar myelography: double-blind trial

Lumbar myelography was performed in 50 patients; 25 received iohexol (an investigational aqueous contrast agent) and 25 received metrizamide. The two media produced radiographs of equal quality. However, iohexol is stable in solution, while metrizamide is not. Further, markedly less morbidity resulted from iohexol. These features indicate that iohexol may be superior to metrizamide as a contrast agent for lumbar myelography.     

A comparison between iohexol and metrizamide, two nonionic contrast media, in aorto-femoral angiography

Iohexol, a recently developed non-ionic contrast medium, is shown to be well tolerated on aorto-femoral angiography. The aortic injection of 40 ml of iohexol (350 mg I/ml) was usually associated with a moderate sensation of heat and an absence of pain. A transient fall in blood pressure, no different from that resulting from metrizamide, was associated with some increase in heart rate.     

Local glucose utilization changes caused by subarachnoid contrast media in the rabbit

The glucose metabolism effects of six hour exposures to subarachnoid injections of metrizamide, iohexol, iodixanol and control solutions were studied in vivo in 18 rabbits. The brain tissue uptake of intravenously injected 14C labelled deoxyglucose was measured using autoradiographic techniques. Metrizamide and iodixanol caused significant (p less than 0.05) decreases in deoxyglucose uptake in the outer cortical areas where the contrast medium concentrations were highest. Iohexol and the control CSF solution did not cause significant effects. The results appear to indicate that iohexol has less effect on brain tissue glucose metabolism than either metrizamide or the new non-ionic dimer iodixanol.     

Penetration of subarachnoid contrast medium into rabbit spinal cord. Comparison between metrizamide and iohexol

The penetration into rabbit spinal cord of two nonionic contrast media, iohexol and metrizamide, and a reference tracer, technetium DTPA, were compared. The spinal subarachnoid space was perfused for 4 hours with a CSF solution to which technetium DTPA and either iohexol or metrizamide had been added. The contrast media and technetium DTPA concentrations reached a plateau level in CSF outflow within 80 minutes. The contrast media concentrations in CSF were higher than the technetium DTPA (P less than .001). In the cord tissue, technetium DTPA reached higher concentrations than the contrast media (P less than .001), and iohexol reached higher concentrations relative to technetium DTPA than metrizamide (P less than .001). The mean contrast media distribution volumes in the thoracic cord were 13% (iohexol) and 12% (metrizamide). The smaller distribution volume observed for metrizamide could be related to the larger effective size of "associated" metrizamide molecules or an interference with diffusion perhaps related to binding to glucose carriers.     

Iohexol versus metrizamide for cervical myelography: double-blind trial

Cervical myelography was performed by lateral C1-C2 puncture in 60 patients. Thirty patients received iohexol (an investigational aqueous contrast agent) and 30 received metrizamide in order to provide a prospective, randomized, double-blind trial comparing these contrast media. The two media produced radiographs of equal quality. Contrast-related morbidity was suffered by four patients (13%) in the iohexol group and by 11 patients (37%) in the metrizamide group. These features indicate that iohexol is superior to metrizamide as a contrast agent for cervical myelography.     

Iohexol lumbar myelography: clinical study

Forty-three patients underwent lumbar myelography with the new, nonionic contrast medium iohexol. Multiple laboratory examinations, neurologic examinations, and electrocardiograms showed no significant alterations after intrathecal injection of the contrast agent. Mild electroencephalographic changes were seen in one patient. Nineteen adverse reactions occurred in 13 patients; only one of them was considered severe. No patient experienced a seizure, auditory or visual hallucination, or similar neuropsychologic reaction. This is a distinct improvement over the side effects described for previous water-soluble contrast agents. The adverse reactions occurring with iohexol myelography are fewer in number and less severe than with metrizamide myelography, and radiographic visualization obtained with iohexol is equal to that obtained with metrizamide. With iohexol, it appears that the most disturbing and disabling neuropsychologic reactions have been reduced to an acceptable minimum.