Lung tumor incidence after intrabronchial administration of the nonionic contrast agent metrizamide.

RATIONALE AND OBJECTIVES: Metrizamide has been used for examination of the gastrointestinal tract and tracheobronchial tree of infants. Contrast agents may enter the lungs during such examinations. The current study was undertaken to determine whether there would be any later pulmonary effects when metrizamide was administered to the lungs of weanling mice. METHODS: One hundred fifty mice (18-21 days old), divided into groups, received either 75 microL of metrizamide, using the manufacturer's diluent (190 mg iodine [I]/mL), or saline solution administered to the lungs by injection into the trachea. The mice were observed for the duration of their lives. Moribund animals were killed. At death, all animals underwent necropsy. The lungs were fixed in formalin, and histologic sections were examined for pathologic changes. RESULTS: The incidence of lung tumors was increased (P less than .05) in the lungs of mice receiving metrizamide compared with those receiving saline. Eighteen percent of the lung tumors in the metrizamide-treated mice were lymphomas, a histologic type not found in the saline-treated controls. CONCLUSIONS: A hypothesis proposing that metrizamide may be an initiator of carcinogenic transformation rather than a carcinogen was developed.

Effect of injections of contrast media on regional uptake of (14C)-2-deoxyglucose by the rat brain.

Mechanisms contributing to the rare but consistent neurotoxicity of contrast media currently in clinical use for the radiological examination of the subarachnoid space remain to be isolated. We assessed, by means of the (14C)-2-deoxy-D-glucose (2-DG) autoradiographic method, the effect of three non-ionic, low-osmolar contrast media, namely metrizamide, iopamidol and iohexol, on the local cerebral glucose utilization in the rat brain after intracisternal application. A significant (-30%) global reduction of the brain's metabolic activity occurred following intracisternal metrizamide injection. When compared with the mock-CSF control group the greater relative changes were observed in the supratentorial grey matter structures. In contrast, no significant changes were observed in metabolic brain activity in rats treated intracisternally with iopamidol and iohexol. These findings were consistent with the hypothesis that metrizamide is a competitive inhibitor of human brain hexokinase. The apparent lack of interference on neural tissue metabolism makes the second generation contrast media less neurotoxic and more suitable for neuroradiological subarachnoid investigations in clinical settings. The present experimental work establishes the 2-DG method as a viable laboratory approach to investigate aspects of neuronal dysfunction induced by contrast media.

Role of red blood cell deformation in toxicity of contrast media in cerebral angiography.

The authors investigated the effect on the brain of red blood cells that had been modified by contrast media. Rat blood was mixed with an equivolume of contrast media, and up to 200 microL of the mixture was infused to the internal carotid artery of the rat. Evans blue was administered intravenously to assess the integrity of the blood-brain barrier (BBB). Immediately after the death of the animal, or 2.5 hours after the infusion, the brain was removed for evaluation of the degree of BBB destruction and edema. Extensive destruction of the BBB, cerebral edema, and death of the animals were induced by infusion of blood mixed with an ionic contrast medium, such as diatrizoate and iothalamate, which deformed red blood cells. Microscopic observation showed atrophy and necrosis of nerve cells and decomposition of nerve fibers in the affected area of the brain. Cerebral damage was not observed in rats injected with blood mixed with a nonionic contrast medium such as iopamidol, iopromide, or metrizamide, which had less effect on red blood cells. Cerebral damage also was observed in the rats injected with blood mixed with a hyperosmotic solution of mannitol, as well as washed red blood cells mixed with an ionic contrast medium. This study's results indicate that hyperosmotic ionic contrast media affect red blood cells and cause disturbance in cerebral circulation.

A possible mechanism for the neural adverse reactions caused by metrizamide.

Causality of the metrizamide-induced neural adverse effects was explored among the effects on behavior, electroencephalogram (EEG), and brain glucose utilization in rats. Iotrolan, a new myelographic contrast agent, was used as a reference substance throughout the study. Supracortical subarachnoidal administration of metrizamide caused, within a few minutes, symptoms of sedation and anxiety, which were accompanied by appearance of slow wave or flattening in EEG not only of the cortex, but also of the regions of the hippocampus and thalamus. The rates of local cerebral glucose utilization (LCGU) in a wide range of the brain, measured by using 3H-2-deoxyglucose, were also altered significantly. Despite a limited distribution of metrizamide in the lateral region of the cortex, LCGU was suppressed significantly in the administered side of the parietal cortex, thalamus, subthalamic nucleus, medial geniculate body, and mammillary body and increased in the regions of hippocampus, caudate-putamen, and globus pallidus. It is concluded that, rather than inhibiting the hexokinase reaction in the brain cell, metrizamide appears to cause reduction of a net glucose transport into the cell and that this direct effect on the cortex is amplified and propagated, via neurotransmission, to the regions of the diencephalon and midbrain, causing secondarily various types of disturbance in the mental and motor functions. Iotrolan was proved to lack any biologic activity that may relate to the neural adverse effect observed with metrizamide.

Effect of contrast media on beta-endorphin secretion. An in vitro study.

The central nervous system may be highly susceptible to the toxic effects of contrast media (CM). Previous experiments demonstrated that vasopressin is released after the intravenous administration of CM. The present study examined the response of the opiocortin system to CM. Neurons of the rat basal hypothalamus, dispersed and attached to Cytodex-3 beads, were perfused with sodium diatrizoate, metrizamide or iohexol (3 mg iodine/ml). The effluent was collected, and the beta-endorphin (B-E) content was measured by a radioimmunoassay technique. Results, normalized to the internal positive control, were compared with release from normal saline (negative control) by analysis of variance. Diatrizoate and metrizamide caused significant release of B-E (p less than 0.03). Iohexol did not stimulate release of B-E. These results suggest that diatrizoate and metrizamide, but not iohexol, can stimulate the release of hormones from hypothalamic neurons. The phenomenon may play a role in some reactions to intravascular CM administration since these neurons are not protected by a blood-brain barrier.

In vitro models for testing the metabolic effects of myelographic contrast media.

Water-soluble nonionic x-ray contrast media have greatly improved the quality and safety of myelography. Toxic side effects are still observed however. The side effects are generally worse with the first nonionic agent, metrizamide, which has a glucoselike side group. Two in vitro models were developed to examine the effects of contrast media on glucose metabolism. Using rat hippocampus slices, the authors observed significant depression of carbon dioxide production by metrizamide and by deoxyglucose, a known metabolic inhibitor. Iohexol and iopamidol did not cause significant depressions. In rat brain synaptosomes the authors did not observe a depression of the uptake of deoxyglucose 14C by any media tested. These studies indicate that metrizamide can create metabolic depression but that it does not compete with glucose for the membrane glucose carrier.

A rat EEG model for evaluating contrast media neurotoxicity.

The electroencephalographic (EEG) effects of intracisternally administered x-ray contrast media were evaluated in rats as a means of assessing neurotoxicity. Rats were ventilated with a mixture of nitrous oxide and oxygen (70/30) sufficient to maintain light anesthesia/analgesia and neuromuscular blockade was induced to prevent movement artifacts. A femoral artery was catheterized for monitoring arterial blood pressure (BP), heart rate, blood gases, and pH. Four 22-gauge stainless steel needle electrodes were inserted underneath the scalp for recording EEG. Approximately 1 hour after the start of EEG recording, test agents were injected via the cisterna magna and rats were placed in a 20 degrees head-down position. EEG and BP were monitored continuously for up to 160 minutes postinjection. Blood gases and pH were monitored periodically. The effects of meglumine iothalamate (IOT), metrizamide (MET), iogulamide (IOG), and ioversol (IOV) were compared at dose levels from 30 to 240 mgI/kg. Normal saline was injected as a control substance and caused no changes in EEG, blood gases, pH, and BP for up to 160 minutes postinjection. IOT (30 mg I/kg) produced profound EEG effects consistent with epileptogenic activity, followed by slowing and subsequent death in 3 of 4 animals. Metrizamide had minimal EEG effects at 30 mg I/kg but at 60 mg I/kg, and 120 mg I/kg produced moderate to severe EEG changes including epileptiform patterns and death in 33% of animals. IOV caused mild EEG abnormalities in 4 of 12 animals at 120 mg I/kg, mild EEG abnormalities in 6 of 11 animals, and moderate EEG abnormalities in 1 of 11 animals at 240 mg I/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of seizures after myelography: comparison of iohexol and metrizamide.

A parallel, double-blind, randomized study comparing iohexol and metrizamide--both 180 mg l/ml--in lumbar myelography was carried out in 60 consecutive patients. Eight to 15 ml of contrast medium were administered with the upper level at the middle thoracic column. A detailed neurologic examination was performed before and 24 hr after myelography. EEG recordings--evaluated visually and with fast Fourier transformation analysis--and somatosensory evoked responses were registered before, 6 hr after, and 24 hr after myelography. All patients were observed for adverse reactions for 24-48 hr. Iohexol did not produce any epileptiform activity but epileptiform activity was detected in five patients receiving metrizamide. Iohexol produced significantly less frequent and less severe EEG changes than did metrizamide both at visual evaluation (p less than .0025) and at fast Fourier transformation analysis (p less than .04). No significant changes occurred in the early components of the somatosensory evoked potentials after either contrast medium. Iohexol caused significantly (p less than .002) less frequent and less severe adverse reactions than did metrizamide. The neurologic examination revealed no changes of clinical importance with either contrast agent.

Computed tomography, magnetic resonance imaging, and pathologic observations of the effects of intrathecal metrizamide and iohexol on the canine central nervous system.

A two-group crossover design experiment was used in eight dogs to compare the effects of intrathecally injected (0.25 mL/kg, 180 mg I/mL) metrizamide and iohexol. Additional acute observations were made in four of the dogs following a high dose (0.45 mL/kg of 300 mg I/mL) of each agent. In computed tomographic observations, there was progressive passage of each contrast medium across the interface between the cerebrospinal fluid and the brain, and statistically identical levels of each contrast medium were present in the cerebral gyri. There was a similar passage of contrast medium across the interface between the cerebrospinal fluid and the spinal cord. The rate of passage of each agent into the brain parenchyma suggested their active transport rather than a simple diffusion. In both T2-weighted magnetic resonance imaging and histopathologic studies, there was no evidence of cerebral edema following either high or low doses of each agent. In T1-weighted images made following the intravenous injection of gadolinium-DTPA (0.1 mmol/kg), the blood-brain barrier was intact.

Clearing media for the eye.

Non-ionic radiological contrast media have a high refractive index and are not toxic to living cells. They can be used as clearing media for unfixed ocular tissues. Corneal opacities in the rabbit could be made transparent, on a temporary basis, by soaking the stroma in contrast media, and no ill effects on the eye were noted.

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.

Complications of myelography after partial metrizamide withdrawal.

Lumbar metrizamide myelography (LMM) has been associated with a high incidence of side effects. A total of 94 patients underwent LMM for suspected disc disease or spinal stenosis. In Group 1 a 22-gauge spinal needle was used. Containing the same amount and concentration of metrizamide, an 18-gauge spinal needle was used in Group 2 after which there was partial withdrawal of the metrizamide (average withdrawal: 73%). In Group 1 a total of 38% of patients experienced one side effect whereas 8.5% had two side effects. In Group 2 a total of 8.5% of patients experienced one side effect and 4.25% had two side effects. This study demonstrates a statistically (P less than 0.003) lower incidence of side effects with metrizamide withdrawal after myelography.

The influence of non-ionic contrast media on the endothelium of small arteries. A comparison of metrizamide, iohexol and iopentol.

In 36 rabbits, small catheters were introduced into the central artery of one ear and into the saphenous arteries of both legs. Saline, metrizamide 170 mg I/ml, iohexol 137 mg I/ml and iopentol 137 mg I/ml, all solutions isotonic with blood, were tested. Perfusion with the test-solutions was performed with 2 ml x 3 at intervals of 5 min. In the case of iopentol, a dose-response study was performed, 1 ml x 3 and 4 ml x 3 being also tested. The solutions were administered under gentle pressure and at room temperature. Blood reflow was always observed between injections. All perfusates caused endothelial damage. Minor trauma led to endothelial cell contraction. More severe trauma increased the degree and numbers of contracted endothelial cells, frequently resulting in patches of denudation, sometimes the location for thrombus formation. In the control group only few effects on the endothelium were noted. Metrizamide caused more intimal damage at all times studied than either iohexol or iopentol. The immediate effects of saline and iopentol were quite identical, but at 2 h and 24 h iopentol caused much less intimal damage than saline.

Effects of radiographic contrast media on monolayer cell cultures.

The relationship between iodine concentration, osmolality, and toxicity for nine different contrast media was studied. High osmolal conventional ionic contrast media (Na-metrizoate, Na-iothalamate, meglumine/Na-diatrizoate, meglumine-calcium-metrizoate) and the new low osmolal nonionic (Metrizamide, iopamidol, iohexol) and ionic dimer (Meglumine/Na-ioxaglate) contrast media were tested. Monolayer cell cultures of human cervical carcinoma in situ cells were used as a test system. The toxicity of contrast media on cell cultures was strongly dependent on the osmolality, and different contrast media with the same osmolality had about similar effects on the cell cultures. However, contrast media seem to have some additional and more specific effects since equiosmolal saline and mannitol were better tolerated. When the toxicity was related solely to iodine concentration it emerged that the new low osmolal contrast media were much better tolerated than the high osmolal conventional contrast media.

In vitro testing for the risk of arachnoiditis from myelographic contrast media.

The risk of arachnoiditis from aqueous myelographic contrast media has been assayed reliably only in experimental animals. The effect of contrast media on protein and collagen production by fibroblasts in vitro was studied. Iocarmate, metrizamide, and iopamidol added to the culture medium caused cells to produce more protein and collagen. The degree to which the contrast medium stimulated collagen production correlated with the risk of arachnoiditis from the intrathecal use of the contrast medium. In vitro testing appears to be an effective assay for arachnoiditis.

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.

Chemotoxicity of contrast media and clinical adverse effects: a review.

The clinical effects of contrast agents not only result from high osmolality, but also from their own specific pharmacology, which mediates chemotoxic effects. In this review, the chemotoxic effects of the new nonionic agent, iohexol, are compared with those of standard ionic and other low osmolality contrast agents, ionic and nonionic. Iohexol has the lowest chemotoxicity of any agent yet synthesized. Its low systemic toxicity is the combined result of low chemotoxicity and low osmolality. Mechanisms of severe adverse reactions are reviewed, including the views of Lasser and Lalli, and the view that emphasizes the importance of cardiotoxic and hemodynamic effects. It is concluded that whichever view is taken of the mechanisms of severe adverse reactions, the new nonionic agents are likely to be safer than the ionic agents now in use.