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Dynamic computed tomography time--density study of normal human tissue after intravenous contrast administration.

Dynamic sequential 3-second CT scans of human abdominal organs were obtained after an intravenous bolus injection of diatrizoate. Time--density curves obtained from the renal cortex and medulla were compared with similar curves obtained from the aorta, inferior vena cava, muscle, and normal liver. CT scans revealed the changes in density produced by the contrast agent reflecting the differential phases of blood flow in the aorta and inferior vena cava. Changes in density in the liver, muscle, and the cortex and medulla of the kidney undoubtedly were related to vascular and extravascular contrast agent. Renal cortical density increased rapidly after bolus administration and peaked approximately 6 seconds after the peak in aortic contrast and slowly declined over the observation period. Renal medullary density increased slowly and at first remained significantly below the cortex but was slightly above cortical values after 30 seconds. These studies indicate that dynamic CT scanning is an effective way of monitoring the contrast media pharmacokinetics within tissue and that human renal function can be monitored and evaluated by using this technique.

Aortography↗

New angiographic agents with less fibrillatory propensity.

Coronary angiography with Renografin-76 (meglumine sodium diatrizoate, Squibb) lowers the ventricular fibrillation threshold (VFT) significantly and in a dose-dependent manner. Recently new contrast materials have been synthesized for possible angiographic use. We compared the fibrillatory propensities of Hexabrix (meglumine sodium ioxaglate, Guerbet), a monacid dimer; Exypaque (Nyegaard; U.S. iohexol, Winthrop), a new nonionic agent; and Amipaque (metrizamide, Winthrop), an older nonionic agent, to Renografin-76 in anesthetized dogs. The VFT following subselective left circumflex artery injections of 370-mg I and 740-mg I doses of each agent was compared to the control (no injection) threshold in 115 paired experiments in 25 dogs. At the low dose, the VFT for Renografin was significantly lower (61.8 +/- 2.3% of control threshold) than that of Hexabrix or Exypaque (69.3 +/- 2.1%, respectively; P less than 0.05). At the higher dose, the differences were more pronounced among Renografin, Hexabrix, and Exypaque (32.4 +/- 1.4%, 65.7 +/- 2.6%, and 59.2 +/- 2.4%, respectively; P less than 0.001). No statistical difference was detected between the latter two agents at these doses in nonischemic dogs. Amipaque was also less fibrillatory than Renografin and equivalent to the other two agents. These newer agents appear to offer enhanced safety for use in angiographic studies in the heart.

Angiography↗

Contrast enhancement pharmacokinetics of six ionic and nonionic contrast media.

The contrast enhancement of six contrast media (CM) was compared in 13 tissues of the rat after rapid intravenous bolus injection. The rats were sacrificed at 0 and 40 seconds and 2, 5, and 15 minutes after contrast injection. 125I labeled diatrizoate, metrizamide, ioxaglate, iohexol, iopamidol, and a nonionic dimer, iodecol, were each injected at a dose of 612 mg iodine per kg body weight, and iodine concentration (IC) and contrast enhancement were calculated from radioactivity measurements. Higher blood IC values were obtained with the nonionic CM; similar enhancement patterns were seen in the spleen, heart, lungs, and brain. Renal IC was directly related to the number of iodine atoms per ion or molecule of CM. In consequence, renal IC was inversely related to the CM osmolality, but no such correlation was seen with the blood IC. Metrizamide produced the greatest IC in the organs of the gastrointestinal tract. There was no apparent correlation of IC with molecular structure of physicochemical parameters of the CM in any of the other tissues studied.

Animals↗

In vitro complement consumption by contrast materials and analogues: reactors vs. nonreactors.

Blood samples from previous contrast reactors and nonreactor controls were incubated with diatrizoate and several contrast analogues. Total complement levels were assayed. All the agents caused complement activation generally proportional to their concentration. Reactors' sera responded to lower concentrations of contrast or analogues than did control sera. Such studies might be of value in predicting contrast reactors.

Acetamides↗

The influence of contrast medium dose on filtration fraction in the rabbit kidney.

We have examined the effect of dose on contrast medium-induced reductions in glomerular filtration in anesthetized rabbits. The fraction of renal plasma flow that is filtered, the filtration fraction, was directly measured by the renal arteriovenous difference method using technetium-99m (99mTc) (Sn) DTPA as the tracer, arterial and renal venous extracorporeal shunts, a gamma camera and a computer. Filtration fraction (FF) was measured each 30 seconds before and after contrast medium (sodium/methylglucamine diatrizoate) was injected in 15 seconds at a dose of 0.5, 1.0 or 2.0 ml/kg, IV. In six animals that had a control FF of 0.19 +/- 0.01 there was a dose-related decrease in FF. The largest dose reduced FF by 53.3%. In three other animals that had a low control FF (0.07 +/- 0.01), the largest dose induced an even greater 71.0% decrease in FF. These data suggest that attempts at increasing contrast excretion by injecting larger doses will be offset, at least in part, by larger reductions in glomerular filtration, and that this effect may be greater when glomerular function is impaired.

Animals↗

Mechanism of renal excretion of various X-ray contrast materials in rabbits.

The excretory behavior of nine nephrotropic contrast agents with varying physicochemical properties such as charge, lipophilicity, and molecular size was investigated. Renal clearance in comparison with inulin was determined by means of the continuous infusion method. Each contrast agent was infused at three dose levels in four to six rabbits. The investigations show that tubular transportation in proportion to glomerular filtration decreases with increasing dosages of all the contrast agents. Thus, with the highest concentration in plasma all contrast agents are eliminated at more or less the glomerular filtration rate (GFR). After administration of the low dosages the following differences are found: 1) Net tubular secretion increases for the monomeric contrast agent acids with increasing lipophilicity, in the order diatrizoate congruent to iothalamate less than iodamide less than acetrizoate. 2) The clearance studies do not reveal any tubular secretion or reabsorption for a hydrophilic cationic contrast agent. 3) The nonionic contrast agents do not show net secretion. The more lipophilic they are, the more they are reabsorbed. 4) Two dimeric contrast agents also do not reveal any tubular secretion. They seem to be reabsorbed more than monomers with the same charge.

Acetrizoic Acid↗

Iohexol cerebral angiography. Multicenter clinical trial.

Ionic contrast media currently used in cerebral angiography frequently cause discomfort due to hyperosmolality. This double-blind, multicenter trial compared two ionic media, meglumine iothalamate and meglumine-Na diatrizoate, with the new nonionic agent, iohexol, in 277 patients undergoing cerebral angiography. Vital signs, cardiovascular changes, and neurologic status were evaluated before, during, and after injection. Patients were observed for adverse reactions for up to 24 hours following studies. Patient discomfort and image quality were evaluated. Visualization was good or excellent with all media studied. No significant physiological differences were observed between the ionic and iohexol groups, but fewer iohexol patients experienced large increases (greater than 20 mmHg) in systolic blood pressure. Iohexol patients experienced significantly less discomfort; ionic patients reported severe discomfort 21/2 times more often. This finding was attributed to iohexol's low osmolality. Iohexol may be indicated particularly for use in selective angiograms where discomfort is a factor and for patients suspected of having blood-brain barrier disruption.

Adult↗

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.

Contrast Media↗

Immediate effects of graded ionic and nonionic contrast injections on coronary blood flow and myocardial function. Implications for digital coronary angiography.

The comparative immediate effects of ionic and nonionic contrast agents on coronary blood flow and regional function have not been studied. Therefore, subselective intracoronary injections of iohexol and sodium meglumine diatrizoate (Renografin 76) were compared at different rates (1, 3, and 4 mL/sec) and volumes (2 and 4 mL). Open chest dogs were instrumented with electromagnetic flow probes, subendocardial ultrasonic crystals, and a subselective intracoronary catheter. The 2- and 4-mL volumes of Renografin infused at 3 mL/sec, caused reductions in coronary blood flow that were maximal at 2 to 3 seconds after injection. These changes were significant for the 4-mL dose (61 +/- 19 at control vs. 23 +/- 12 mL/min, mean +/- SD, P less than .01) but not for the 2-mL dose. Iohexol produced identical flow responses but regional function was not significantly altered, whereas Renografin caused significant depression at both dose levels. Injections of 4 mL of Renografin at 1 and 4 mL/sec caused maximal flow decrements at 4.5 and 2 seconds after injection, respectively. Again, iohexol caused identical responses. At these doses, the effects of iohexol on regional function were also identical to those of Renografin. Thus, despite differences in physical properties, no significant differences in early blood flow changes were detected between these two agents.

Animals↗

Contrast media-induced blood-brain barrier damage. Potentiation by hypertension.

Large doses of an ionic contrast medium (CM) can disrupt the blood brain barrier (BBB) osmotically. Acute hypertension (HT) also is known to open the BBB. We tested the hypothesis that these two factors potentiate each other in a rat model. Adult male Wistar rats, anesthetized with pentobarbital, underwent tracheostomy. An external carotid artery catheter was placed so that it opened into the patent common carotid artery; arterial blood pressure was recorded continuously. Of three groups of animals, two (HT) groups received metaraminol to elevate and maintain blood pressure in the range of 165 to 190 mm Hg. The third (normotensive) group received an equivalent volume of saline. Five minutes after injection of Evan's blue, either sodium/meglumine diatrizoate or saline was infused into the carotid cannula (2 mL in 30 seconds). Twenty minutes later the cardiovascular system was flushed with saline, and the brain was removed, frozen, and sectioned for gross and histofluorescent microscopic examination of BBB opening. The carotid injection of CM at a concentration of 1000 mosm/kg water did not produce gross evidence of BBB opening in the normotensive group. Similarly, hypertension at levels below 190 mm Hg did not produce gross evidence of opening in the carotid saline group. However, the combination of carotid CM and HT produced significant BBB opening. These results suggest that the risk factor of acute HT potentiates CM-induced BBB opening.

Animals↗

Water-soluble contrast media compared with barium in enteric follow-through. Urinary excretion and radiographic efficacy in rats with intestinal ischemia.

The local effects and radiographic efficacy of four water-soluble contrast media, barium and saline were evaluated in 91 anesthetized rats with a ligature applied to the anterior mesenteric artery and vein via laparotomy. The rats were observed for 8 hours after instillation of 3 mL of test substance via oro-gastric tube. Radiographs were taken after 1, 4 and 8 hours of observation. After 8 hours, the intestines were weighed, a biopsy was done for light microscopy, and blood and urine were sampled for testing. The roentgen contrast media caused dehydration and increased influx of fluid into the small bowel lumen in proportion to their osmolality. They diluted the bowel contents, enhanced their progression and distended the bowel walls. The diagnostic qualities of radiographic films were better using the new, low-osmolal contrast media than using either barium or sodium diatrizoate. The water-soluble contrast media were excreted in the urine, as demonstrated by dense opacification of the urinary bladder on abdominal films, and increased iodine concentrations at x-ray fluorescence analysis of the urine. This may be useful clinically in detecting bowel ischemia.

Animals↗

Vicarious excretion of water-soluble contrast media into the gallbladder in patients with normal serum creatinine.

Ten patients with normal serum creatinine and no evidence of acute cholecystitis were found to have vicarious excretion of water-soluble contrast media into the gallbladder 20 minutes to 72 hours after injection. Eight of the ten had unilateral renal pathology. Two patients, however, had bilaterally normal kidneys. The patients had been injected with either diatrizoate, iothalamate, or iodamide. The mechanisms and pathophysiology of vicarious contrast excretion are discussed. The vicarious excretion of intravascular contrast in the gallbladder does not in itself indicate renal or hepatobiliary disease. Although commonly associated with unilateral renal pathology, vicarious gallbladder excretion of urographic contrast may be a normal variant in some patients.

Adolescent↗

Does dilution of contrast media affect contrast enhancement? An experimental study in rats.

The effect of contrast media (CM) dilution on contrast enhancement was studied using CM representing four structurally different molecular types at osmolalities ranging from 135 to 1340 mosm/kg. Diatrizoate (ionic monomer), iopamidol (nonionic monomer), ioxaglate (ionic dimer), and iodecol (nonionic dimer) were each given at a dose of 500 mgI/kg and at concentrations of both 300 and 150 mgI/mL. Contrast media concentrations were measured using iodine 125I. Tissue blood volumes were determined using human serum albumin labeled with 131I. For each of the four CM at each of the two concentrations and after each of five time intervals following injection (0, 15, 40, 120, and 300 seconds), five rats were killed (total = 200 rats). Blood and 14 other tissues were studied. Dilution of the CM did not lead to any lower iodine tissue concentrations, iodine distribution volumes, plasma volumes, or hematocrit. The authors conclude that lowering CM osmolality by dilution with water should improve tolerance without affecting CT contrast enhancement.

Animals↗

Comparison of water-soluble contrast media and barium in rats with small bowel obstruction or ischemia.

The experimental results from comparing the low-osmolar radiographic contrast media (CM) iohexol, iodixanol, and ioxaglate to the hyperosmolar CM sodium diatrizoate or barium for enteric follow-up examination in rats, suggest that low-osmolar CM are the better alternatives for use in examinations of obstructed small intestine. Excretion of iodine to the urinary bladder in rats with acute intestinal ischemia indicates that water soluble CM may be helpful in the discrimination between this serious disease and simple obstruction of the small intestine.

Animals↗

Nonionic contrast agents and coagulation.

The chemotoxicity of nonionic and ionic contrast media is discussed with reference to chemical structure. Second-generation nonionic contrast media have the lowest chemotoxicity of any agents because of the uniform distribution of hydrophilic groups around the molecule, which mask the hydrophobic iodine atoms. Previous investigations show that second-generation nonionic agents have the same qualitative hematologic effects as other contrast agents. The less marked quantitative hematologic effects of second-generation contrast media compared with conventional agents are consistent with the low toxicity profile of these agents. A study was conducted in which a nonionic and a conventional ionic contrast medium were observed on microscopic slides after small drops of nonanticoagulated blood were added to each. The disordered aggregations of red cells observed were larger in the nonionic agent but easily dispersed with minimal disturbance, suggesting limited clinical significance. A series of coagulation experiments was conducted in which two types of plastic syringes and glass syringes, containing either iohexol or diatrizoate, were contaminated with blood and inspected for blood clots. An ELISA assay for fibrinopeptide A also was performed. Clot formation was uncommon and appeared to be related to syringe material.

Blood Coagulation↗

Acute and chronic renal effects of radiocontrast in diabetic rats. Role of anesthesia and risk factors.

The acute and chronic renal effects of the intravenous injection of meglumine diatrizoate sodium 76% (CM), 5 mL/kg body weight were studied in diabetic (DM) and age-matched normal (C) female Sprague-Dawley rats. In acute studies, the effect of anesthesia was assessed for 2 hours. Although anesthesia decreased 14C-inulin clearance (Cin) in both DM and C rats (P less than .001 vs. conscious values), there was no impairment of Cin in either group after administration of CM. In chronic studies, creatinine clearance (Ccr) was followed for 3-4 days after CM administration. Four protocols to assess risk factors in DM and C were used: adult rats with normal hydration (2A); old dehydrated rats with DM of long duration (2B); rats with prior decreased Ccr (remnant kidney, 2C); and DM rats treated with insulin (2D). No clear-cut nephrotoxicity was apparent in these studies, except that proteinuria increased with CM in Study 2C. A greater severity of renal dysfunction, renal disease, or the association of multiple risk factors may be necessary to induce CM-related nephrotoxicity in the experimental animal. The rat, diabetic or not, may have an inherent resistance to CM-induced renal injury.

Aging↗

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.

Animals↗

Iodinated contrast media effects on extravascular lung water, central blood volume, and cardiac output in humans.

Intravascular contrast media produce pulmonary edema in one rat model, but not in dogs or pigs. In humans, pulmonary edema after contrast media is rarely diagnosed, but subclinical edema could be more frequent than believed previously. Therefore, the authors prospectively studied the effects of diatrizoate (n = 5) and ioxaglate (n = 5) on extravascular lung water, central blood volume, and cardiac output in ten patients undergoing routine radiographic procedures. Variables were measured by thermal-dye dilution before and every 5 minutes after completion of the procedure for four repetitions. Extravascular lung water and central blood volume did not change significantly, indicating that pulmonary edema or pulmonary congestion did not occur. Cardiac output was elevated by 10.6% immediately after the procedure, but returned to baseline during the 10 following minutes. The authors conclude from this preliminary study in a small number of patients that intraarterial contrast media (less than 1.5 g/kg body weight of iodine) did not produce pulmonary edema or pulmonary congestion, even at a subclinical level.

Blood Volume↗