The histologic effect of intraventricular injection of metrizamide.

A patient with sudden apoplexy and coma was found to have hydrocephalus on computed tomographic scan, and metrizamide was instilled into the ventricles. Subsequent autopsy disclosed a brainstem infarct secondary to a primary dissecting aneurysm of the basilar artery, and a histologic picture of encephalitis in the walls of the lateral and third ventricles. Metrizamide may cause pathologic changes that must be recognized for the correct interpretation by the pathologist of tissue sections previously exposed to metrizamide. In the present case, the changes were seen 11 days after exposure of the tissue to metrizamide, consonant with the time course of similar changes observed in animals. The localization of the cellular infiltrates to the Virchow-Robin spaces corroborates evidence from the literature that metrizamide enters brain parenchyma via these spaces.

Intrathecal toxicity of iohexol vs. metrizamide. Survey and current state.

Arachnoiditis, a common finding in patients who have had previous myelograms or spinal surgery, can cause pain, paresis, and can slow elimination of contrast medium from the subarachnoid space. The role of contrast media in producing arachnoiditis has not been well defined but can be studied in a primate model. This study compared incidence of arachnoiditis in monkeys after myelograms using two nonionic contrast media, iohexol and metrizamide. Conditions were chosen to produce the greatest possible effect of contrast medium on the arachnoid. Animals were sacrificed 12 weeks after the myelogram and the dural sac was removed for examination by light microscope. Under adverse conditions, high doses and high concentrations of iohexol produced little arachnoiditis, while metrizamide produced mild to moderate arachnoiditis. Iohexol was shown to have a greater margin of safety then metrizamide, which is considered an important clinical advantage.

Studies on the acute toxicity of ionic and non-ionic contrast media following rapid intravenous injection. An experimental study in mice.

The influence of the injection rate on the acute intravenous toxicity (LD50) on mice of the ionic high osmotic contrast medium Isopaque Coronar (370 mg I/ml) and the non-ionic low osmotic Amipaque (370 mg I/ml) was investigated. At slow injection (0.1 ml/sec). Amipaque had a significantly higher LD50 than Isopaque Coronar (17.3 respectively 9.8 gm I/kg). Also at rapid injection (2 ml/10 sec). Amipaque was significantly less toxic than Isopaque Coronar (13.4 respectively 6.1 g I/kg). Thus Isopaque Coronar increased approximately 60% in toxicity while Amipaque increased 28% when the rate of injection was increased. This difference was statistically significant (p less than 0.001). Several possible mechanisms that might explain this difference, with special interest in the disturbances on the pulmonary circulation following contrast media injection, are discussed.

Renal ablation with absolute ethanol. Mechanism of action.

The mechanism of renal ablation by intra-arterial ethanol was studied in 16 mongrel dogs. Ethanol injection rates were varied, and light and electron microscopic studies were performed to detect early parenchymal changes in the kidneys. Pure ischemic injury was also studied as a control. Findings showed extensive parenchymal injury plays a significant role in renal ablation with permanent thrombosis as a delayed event. Acute arterial occlusion occurred with slow ethanol injection rates due to embolization by damaged blood components.

Effect of oral metrizamide on hematocrit and serum osmolality in the neonate.

Sixteen newborns and young infants, weighing between 800 and 5200 grams, received orally administered metrizamide for evaluation of suspected gastrointestinal pathology. Images were judged good to excellent in 14 cases. No effect of metrizamide on hematocrit and serum osmolality was noted. Metrizamide appears to be a relatively safe and effective agent for examination of the neonatal gastrointestinal tract.

Comparative cranial CT enhancement in the normal primate.

The application of intravenous, intrathecal, and inhalation enhancement techniques to the CT evaluation of the nonhuman primate (Papio cynocephalus/anubis) is described. The falx cerebri cortical vasculature, vein of Galen, straight sinus and tentorium cerebelli were defined with intravenous enhancement. Intrathecal CT enhancement with air was limited by distortion in cerebrospinal fluid spaces. Intrathecal CT enhancement using a low dose of metrizamide accurately delineated the subarachnoid spaces and the brain substance they surrounded with minimal morbidity. Symmetrical brain enhancement (perfusion) was prominent following inhalation CT enhancement; the degree of enhancement correlated with the estimated xenon concentration in the bloodstream. In addition, by performing repeated CT scans during the clearance of xenon from the brain, an approximate analysis of regional cerebral blood flow was obtained.

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.

A comparison of the hemodynamic responses to metrizamide and meglumine/sodium diatrizoate in canine renal angiography.

Selective renal angiography causes a biphasic change in renal blood flow and vascular resistance. In this study, 5 ml of meglumine/sodium diatrizoate (288 mg I/ml, 1455 mosm/kg), metrizamide (290 mg I/ml, 593 mosm/kg), isontonic saline (287 mosm/kg) and hypertonic saline (1500 mosm/kg) were injected into the renal arteries of seven adult mongrel dogs to determine whether the minimum flow (or maximum resistance) was related to the osmolality of the injected agent. The maximum resistance response was significantly smaller for metrizamide (20 +/- 4%) and isotonic saline (19 +/- 2%) than for diatrizoate (36 +/- 6%) or hypertonic saline (50 +/- 7%). Hypertonic saline produced two distinct types of responses: the typical biphasic response or a severe immediate drop in flow. Thus the maximum resistance response was related to agent osmolality. The "injection artifact," or flow changes occurring during the injection, were different for the four agents, and these differences appeared correlated to agent viscosity. Although both contrast media caused relatively small changes in renal hemodynamics, metrizamide caused significantly smaller changes than meglumine/sodium diatrizoate.

Experimental study of the effectiveness of capillary embolization using contrast-enhanced Ethibloc.

In experimental and clinical use, Ethibloc in combination with 40% glucose preinjection has proven to be of major advantage in tumor embolization. However, its low radiographic contrast is a limiting factor in monitoring its vascular distribution and venous propagation. Various contrast media were tested in order to enhance this contrast in laboratory and animal experiments. Normal rat kidneys (N = 96) and renal tumors, induced by Dimethylnitrosamine (N = 66) were tested as in previous studies. Ethibloc-N was produced by substituting Lipiodol for poppy seed oil which is an ingredient of the original Ethibloc. This proved to be the only embolization medium that combined the excellent properties of the original Ethibloc with increased contrast. All other embolization media tested resulted in new complications such as under-or overembolization and pulmonary embolism.

Direct myocardial effects of intracoronary administration of new contrast materials with lost osmolality.

The effects of LV dynamics of the intracoronary administration of three new contrast materials with reduced osmolality were compared with those of a monomeric ionic material, sodium iothalamate, and the nonionic material, metrizamide. In eight anesthetized dogs, the monacid dimer, P286, caused increases in LV dimensions and decreases in LV systolic pressure and parameters of the contractile state. The changes were less than those caused by sodium iothalamte. The alterations in LV function tended to be greater, but not significantly so, during systemic hypoxemia compared to the normal state. The nonionic materials, P297 and iopamidol, like metrizamide, caused no deleterious effects on LV dynamics in either the normal or hypoxemic state. Nonionic materials actually caused a slight increase in parameters of the LV contractile state.

Cardiac function during left coronary arteriography in canines with ioxaglate, nonionic compounds, and diatrizoate.

The new contrast medium ioxaglate (P286) was compared with diatrizoate and the nonionic media metrizamide and C-29 regarding their effects on left ventricular pressure, the rate of rise in this pressure (dP/dt), stroke volume, peak aortic flow rate, and on the QT interval during left coronary arteriography in dogs. Ioxaglate and the nonionic compounds had significantly less effect on these parameters than diatrizoate. Contractility and QT time was least affected by the nonionic media, which have an osmolality similar to that of ioxaglate. This indicates that, in addition to osmolality, other properties of contrast solutions contribute to their toxic effects on the heart. Measuring contractility seems to be a more sensitive method in evaluating contrast media than measuring the performance of the heart as a pump.

Metrizamide, iothalamate, and metrizoate: effects of internal carotid arterial injections on the blood-brain barrier of the rabbit.

Experiments were conducted on anesthetized rabbits to determine the effect of internal carotid artery injection of various contrast media on permeability changes in the blood-brain barrier. Changes in respiratory pattern, neuromuscular effects, and trypan blue extravasation were recorded after 3-ml injections of ionic and nonionic contrast media. Metrizamide and iothalamate meglumine were compared at iodine doses of 300, 400, and 500 mg I/ml. Metrizoate at 280 and 440 mg I/ml and diatrizoate meglumine at 385 mg I/ml were also included for comparison. The results demonstrated that metrizamide at all three iodine concentrations used caused minimal disruption of the blood-brain barrier, the effect being no greater, statistically, than saline controls. Iothalamate was benign at the lowest iodine concentration, but caused significant barrier breakdown at the two higher concentrations. These results suggest that alterations in blood-brain barrier permeability following angiography are mediated by both hyperosmolality of the contrast medium and the chemotoxicity of the contrast molecule.

Direct and reflex myocardial effects of intracoronary administered contrast materials in the anesthetized and conscious dog: comparison of standard and newer contrast materials.

The direct and indirect actions on left ventricular dynamics of contrast material (sodium meglumine diatrizoate) currently used for coronary arteriography, modified ionic material (sodium meglumine calcium metrizoate) and non-ionic material (metrizamide) were assessed in conscious and anesthetized dogs. In both anesthetized and conscious animals, the diatrizoate compound caused an early (3--10 sec after injection) decrease in peak dp/dt and dp/dt/LVP40, followed by late (10--20 sec after injection) increases in these variables. The predominant early and later effects of the calcium metrizoate compound were increases in parameters of LV contractile state. Metrizamide produced no significant early alterations, but later induced a small increase in these variables. The positive inotropic actions of each of the contrast materials were attenuated by beta adrenergic blockade. The early effects of the contrast materials were similar in the presence of segmental ischemia. The late positive inotropic effects in response to the diatrizoate compound and metrizamide were not observed in the ischemic state, while the positive inotropic response induced by the calcium metrizoate compound was significantly reduced. Thus intracoronary administration of sodium meglumine diatrizoate produced direct myocardial depression, followed by adrenergically mediated myocardial stimulation. Calcium metrizoate caused prominent direct and adrenergically mediated augmentation in contractile state. Metrizamide induced the least alteration in LV contractile state.

Intrathecal tolerance of metrizamide in chloralose anesthetized cats.

The water soluble radiopaque medium, metrizamide (Amipaque) was introduced into the lumbar subarachnoid space in chloralose anesthetized cats at a standard volume of 0.35 cc/kg in concentrations of 300 mgI/cc to 500 mgI/cc during EMG recording. These animals did not differ from controls which received cerebrospinal fluid under otherwise identical conditions; both groups usually showed some mild and occasional muscle fasciculations or mild spasms. Treatment with metrizamide appeared to be a less deleterious procedure than that using hyperosmotic sucrose (1.32 M) as judged from EMG records. In contrast, equivalent amounts of neglumine iothalamate produced frank convulsions in 7 of 15 cases and a range of hyperirritability in the remaining 8.

A comparison of the cardiovascular responses to carotid injections of ionic and nonionic contrast media.

Selective injection of contrast media into the canine common carotid artery results in alterations in carotid flow, heart rate, and systemic arterial pressure. In this study the responses to injections of the nonionic agents metrizamide and iopamidol were compared to the responses to the ionic agents meglumine iothalamate, meglumine sodium diatrizoate, mannitol, and saline solution. Heart rate and pressure responses were smallest for metrizamide, greater for iopamidol, and greater still for the hypertonic ionic agents: responses were roughly correlated to agent osmolality. Carotid flow increased with all agents and was roughly proportional to the agent's osmolality. The exception was metrizamide which despite its lowest osmolality, produced a large increase in flow which was maintained much longer than for other agents. The total response to the nonionic agents was judged less severe than to the ionic agents; however, the responses to all agents were transient and not life threatening.

Effects of intracoronary administration of contrast materials on left ventricular dimensions and rate of relaxation.

The effects of intracoronary administration of ionic and nonionic contrast materials on (LV)left ventricular contractile state, relaxation rate (peak -dp/dt and [-dp/dt]50), and dimensions were determined in eight morphine-chloralose anesthetized dogs. Meglumine sodium diatrizoate caused decreases in peak dp/dt and -dp/dt and increases in left ventricular end systolic dimension (LVESD'), end diastolic dimension (LVEDD'), and end diastolic pressure(LVEDP). The decreases in peak -dp/dt and(-dp/dt)50 persisted after peak dp/dt returned to and exceeded control levels. Calcium meglumine sodium metrizoate caused increases in peak dp/dt but decreases in peak -dp/dt and(-dp/dt)50 and no significant changes in LVEDP, LVESD', or LVED'D. Metrizamide caused no significant changes. Ionic contrast materials induce important changes in LV dimensions and rate of relaxation in addition to producing a depression in contractile state. The decreases in relaxation rate are not reversed by addition of calcium ions.

Percutaneous injection of metrizamide into spinal cord cysts for preoperative diagnosis of syringomyelia.

Five cases of syringomyelia are reported in which the spinal cysts were percutaneously punctured and filled with metrizamide for preoperative diagnosis. There were no side effects from the puncture or the contrast medium. In all cases the cyst was larger than had been demonstrated by previous myelography. A communication to the fourth ventricle was seen in two cases. Four patients had surgical treatment; the neurologic deficits improved in two patients, while the condition of the others has remained unchanged.

Computed tomography in 75 clinical cases of syringomyelia.

Seventy-five patients with a clinical diagnosis of syringomyelia were examined by computed tomography after intrathecal injection of metrizamide. A central cavity was demonstrated in 67 patients. Tilting the patient head down did not increase the rate of cavity opacification. This evidence favors transneural migration of metrizamide into the cavity. The spinal cord was measurably enlarged in only a minority of the patients. In some, the cavity appeared to have clefts or wall defects. These results are discussed according to the etiopathogenic theories advanced by Gardner, Aboulker, and Williams.

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.

Brain parenchyma penetration by intrathecal ionic and nonionic contrast media.

Metrizamide, a nonionic water-soluble contrast medium, has been shown to penetrate normal brain when injected intrathecally. Recently it was suggested that the complications following intrathecal metrizamide are directly related to the cerebral concentration reached. Metrizamide, both in experimental animals and clinically, is regarded as less neurotoxic than equivalent iodine concentrations of ionic contrast media. In this study the degree and depth of brain penetration of intrathecal metrizamide and methylglucamine iothalamate (Conray 280), using a similar iodine concentration (280 mg l/ml), was compared at 1 hr in adult greyhound dogs. The depth of penetration and concentration reached in the cortical gray matter was determined by coronal computed tomographic scanning of the brain after removal. No significant difference was found between the two contrast media, suggesting that the rate of diffusion across the cerebrospinal fluid-brain interface is similar and that the difference in neurotoxicity is not explained by a reduced concentration of contrast medium in the case of nonionic metrizamide, when compared with ionic methylglucamine iothalamate. Using Evans blue as a qualitative marker, no evidence of gross blood-brain disruption was demonstrated in the area of maximum penetration with either contrast medium.