Volume rendering of three-dimensional drip infusion CT cholangiography in patients with suspected obstructive biliary disease: a retrospective study.

The purpose of this study was to evaluate the diagnostic potential of prolonged drip infusion CT cholangiography (DIC-CT) using meglumine iotroxate (Biliscopin) and 3D volume rendering in patients with suspected obstructive biliary disease. From a material of 142 patients who had undergone a drip infusion CT, all cases with a verified surgical or endoscopic retrograde cholangiography (ERC) diagnosis (n=33) were selected. Age-matched controls were selected from the remaining examinations. Three radiologists reviewed all 66 examinations in retrospect, independently as well as in consensus. The image quality and the estimated diagnostic quality were rated as good or moderate in 91% of the 198 reviews. The consensus sensitivity and specificity for diagnosing biliary stones was 88% and 94%, respectively (with sensitivities ranging from 88% to 94% for individual observers, and specificities from 86% to 96%). Two out of three strictures were observed. No false positive strictures were described. The use of volume rendering technique (VRT) improved diagnostic certainty in 28/198 (14%) of the evaluations. The visualization of ductal stones was improved in 18/48 (38%). No differences in diagnostic quality between single and multislice CT were observed. We conclude that a detailed image of the biliary tree with good sensitivity and specificity can be obtained by means of bilirubin-governed infusion time DIC-CT with volume rendering reconstruction.

Accumulation and elimination of particulate iodipamide ethyl ester in the lungs and kidneys of the rat. A morphological study.

Particulate iodipamide ethyl ester, a new hepatolienographic x-ray contrast agent, was intravenously injected into rats. Lung and kidney biopsies taken at various intervals after the injection were examined by light and electron microscopy. IDE particles could be found in the lung capillaries phagocytized by polymorphonuclear neutrophils (PMNs). There were also free particles in the alveolar capillaries in the samples taken 5 min to 4 hours after the injection. No aggregates or emboli were seen. Two days or more after the injection no intra- and extracellular particles were present. The PMNs underwent transient local hydropic degeneration; the lung cells were morphologically intact. In the kidneys, the particles first appeared in both cortical and medullary capillaries. No emboli were observed. The kidney cells did not ingest IDE, but polymorphonuclear neutrophils (PMNs) with ingested IDE were often seen loosely attached to the glomerular capillary walls. In addition, free particles were evident in the capillaries in the samples taken up to 1 hour after injection. All particles in subsequent kidney samples were located in PMNs in the glomeruli. After three or more days the renal tissue was totally devoid of particulate IDE. No morphological evidence of kidney cell injury was observed.

Particulate suspensions as ultrasonic contrast agents for liver and spleen.

Ultrasonic backscatter and attenuation coefficients of a medium can be increased by the addition of solid, micron-size inhomogeneities. A potentially useful agent for ultrasonic contrast of liver images has been identified. Iodipamide ethyl ester (IDE) particles can be produced in the form of dense, relatively incompressible solids with high impedance mismatch to water. The chemical, biochemical, and pharmacologic properties of the small, uniform diameter IDE particles permit safe intravenous injection followed by rapid accumulation of reticuloendothelial (RE) cells of the liver and spleen, and later elimination from these organs. Since the particles are phagocytized by RE cells, present in normal liver but not in tumors and many lesions, the selective enhancement of ultrasonic backscatter should improve detectability of lesions that are hypoechoic or isoechoic compared with surrounding tissue. The mechanisms of particle-ultrasound interaction may be described by relative motion attenuation, and scattering from a cloud of dense, incompressible spheres for the case of IDE particles in agar. Thus, values of attenuation and backscatter can be controlled by choice of ultrasound frequency and particle concentration and size. When the particles are accumulated in rat and rabbit livers, additional mechanisms induce attenuation and backscatter in excess of that predicted by IDE in agar. This preliminary work demonstrates that solid, biocompatible particles may be useful as an ultrasonic contrast agent.

Uptake and dissolution of particulate iodipamide ethyl ester in the spleen. A morphologic study.

Iodipamide ethyl ester (IDE) is an experimental particulate contrast agent being developed for CT image enhancement of the liver and spleen. IDE particles are phagocytized by the reticuloendothelial cells after an intravenous injection. The uptake and dissolution of IDE particles were studied in the spleen with light and electron microscopy. Two minutes after injection, intra- and extracellular IDE particles were found in the red pulp of the spleen. Highest concentration of IDE was seen in the marginal zone surrounding the white pulp. Particles also were seen elsewhere in the red pulp but only occasionally between the outermost cells of the white pulp. The extracellular particles disappeared within 4 hours postinjection. At one day postinjection, the amount of intracellular IDE particles had begun to decrease. Electron micrographs showed that the intracellular particles dissolved gradually in the phagocytes and caused transient degenerative morphologic changes. At three days postinjection, practically all IDE particles had disappeared from the spleen. Polystyrene latex particles were used as controls. They were phagocytized like the IDE particles, but they did not disappear from the phagocytes. IDE particles caused no morphologic injuries in nonphagocytic cells of the spleen.

Computed tomographic enhancement of liver and spleen in the dog with iodipamide ethyl ester particulate suspensions.

Particulate suspensions have been developed for use as contrast agents to aid in the detection of hepatic lesions by CT. In several previous rodent studies, the toxicity and tissue concentrations of iodipamide ethyl ester (IDE) particles have been evaluated. The purpose of this study was to determine the pharmacokinetics of IDE in three dogs by evaluation of CT enhancement. Serum chemistry and hematologic parameters after intravenous administration were also followed. A dose of 75 mgI/kg IDE caused an increase of 40-60 Hounsfield units (HU) in liver attenuation, which persisted from 5 minutes to ten hours postinfusion. No enhancement of tissues other than liver and spleen was observed. IDE was completely eliminated from the liver within seven days. A mild transient elevation of liver enzymes may be attributable to the use of barbiturates rather than IDE. A transient depression of the white blood count was the only biochemical or hematologic change that was clearly in response to the infusion of IDE particulates.

Fractal analysis of renal cortical perfusion.

RATIONALE AND OBJECTIVES: Contrast-enhanced computed tomography (CT) images of canine renal cortex were analyzed to determine if the heterogeneous pixel intensity patterns met the requirements for fractal analysis and if the heterogeneity could be quantified by a fractal dimension, Df. METHODS: Contrast-enhanced CT images were obtained after injection of iodipamide ethyl ester (IDE), a vascular marker, or iohexol, a freely filtered interstitial marker, into the catheterized renal artery of an anesthetized dog. Images were mounted on a graphics workstation for analysis. A computer program was written to determine the fractal dimension of the pixel-intensity pattern within selected regions. RESULTS: All regions of renal cortex examined met the requirements for fractal analysis. Three seconds after injection of IDE, the mean fractal dimension decreased significantly from 1.21 +/- 0.05 to 1.12 +/- 0.06 (P < .05). Although the mean fractal dimensions were not significantly different, the variation in the fractal dimension around the renal cortex was significantly different with IDE as compared with iohexol at 3 seconds (P < .05). Differences in the change in fractal dimension over time were also observed with IDE as compared with iohexol. CONCLUSIONS: Fractal dimension measurement provides a new means to examine the in-vivo organization of renal vascular perfusion by quantifying pixel heterogeneity in contrast-enhanced CT. This may prove useful in understanding and quantifying the pathophysiologic changes in renal disease.

Biodistribution of a particulate hepatolienographic CT contrast agent: a study of iodipamide ethyl ester in the rat.

Particulate contrast agents have been shown to be efficacious in computerized tomographic detection of liver tumors. This article quantitatively defines the biodistribution of the experimental particulate agent iodipamide ethyl ester in the rat as a function of time after intravenous infusion. The contrast agent is actively accumulated in the liver and spleen with high selectivity compared to iodine concentrations in the blood or other organs. The contrast material remains at high concentration in the liver for more than 2 hours and then is slowly cleared from the organism in approximately two days. The high selectivity and retention of contrast in the liver are indicative of the value of particulate agents in contrast-enhanced computerized tomography.

New media. Particulate contrast media.

Particulate contrast agents, when compared to water-soluble media, offer the advantage of allowing the administration of high doses without creating hypertonicity gradients and ionic imbalances. Since these radiopaque particles are accumulated in the reticuloendothelial system, they could be ideal hepatic CT contrast agents. We have developed a method for making particles of 2 +/- 1 microns by precipitating from an organic solvent. Preincubation of these particles in human serum albumin overcomes the very serious problem of in vivo particle aggregation and embolization. The ethyl esters of iothalamic and iodipamic acid have been injected intravenously into mice, rats, and rabbits. Radiopacification of the liver is maximal within 2-3 hours postinfusion, with radiopaque material subsequently clearing through the biliary system. Elimination from the organism seems to be complete within a few days postinfusion. Efforts to decrease the subacute toxicity of these agents are underway.

Effect of elevated C1-esterase inhibitor concentrations on white blood cell-endothelium interactions: a potential mechanism for steroid protection in contrast material reactions.

Purified human C1-esterase inhibitor (C1INH) infused into the circulation of rabbits caused an immediate drop in white blood cell (WBC) count and, simultaneously, a marked decrease in WBC adhesion to the endothelium in the microcirculation. Infusion of iodipamide caused a marked "carpeting" of the venous endothelium by WBC, and this condition was reversed by subsequent infusion of C1INH. The relationship of elevated C1INH to the protective effect of prednisolone on iodipamide toxicity in the rabbit is discussed.

Glucocorticoid-induced elevations of C1-esterase inhibitor: a mechanism for protection against lethal dose range contrast challenge in rabbits.

Rabbits pretreated with methylprednisolone acquired significant protection against an intravenous challenge of meglumine iodipamide. In comparison to controls, the pretreated rabbits showed moderate elevations of Factor XII, and rather striking elevations of C1-esterase inhibitor. Treated rabbits also showed significantly less granulocytosis. It is believed that the protective effect can be ascribed to the modulation of acute phase reactants by increased concentrations of C1-esterase inhibitor.

Effect of intravenously administered iodipamide ethyl ester particles on rat liver morphology.

The effect of intravenously injected iodipamide ethyl ester (IDE) particles (150 mgI/kg) on the rat liver was studied by light and electron microscopy. IDE particles were phagocytized by Kupffer cells within a few minutes postinjection. After 4 hours particles began to dissolve in the Kupffer cells causing transient morphologic alterations resembling hydropic degeneration. The number of Kupffer cells seemed, however, to be unchanged and were ultrastructurally normal by 17 days postinjection. Hepatocytes contained large lipid droplets from one to four days after IDE injection. No changes were found in the hepatocytes from one week to one year after IDE injection. The fat-storing cells and endothelial cells remained ultrastructurally normal throughout the study.

Response of white blood cells to iodipamide ethyl ester particles.

The effect of intravenously injected iodipamide ethyl ester (IDE) particles (150 mgl/kg) on white blood cells was studied by light and electron microscopy. The clearance of IDE from rat plasma also was determined by analyzing free IDE particles in a counting chamber. The total white blood cell count remained essentially unchanged up to 40 minutes after the IDE injection, but the polymorphonuclear (PMN) neutrophil count decreased significantly. At 5 minutes postinjection, occasional PMNs contained ingested IDE particles, but by 40 minutes no intracellular particles could be found in the peripheral circulation. In vitro incubation experiments confirmed that human PMNs ingest IDE particles. In electron microscopy, the cells and particles seemed to be morphologically intact. Of the IDE particles counted at 5 minutes postinjection, only 4% remained in plasma at 30 minutes and none at 40 minutes. The decrease in PMN count apparently reflects sequestration of phagocytic cells from the circulation.

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.

The in vitro activation of complement by radiologic contrast materials and its inhibition with epsilon-aminocaproic acid.

Radiologic contrast materials activate complement by both the classical and alternative pathways. This activation is time, dose, and temperature dependent and is able to proceed with equal facility in either the presence or absence of Ca++ or Mg++ chelating reagents (EGTA, EDTA). All the components examined (C1, C4, C2, Factor B, C3, and C5) were consumed during complement activation. Immune complexes are produced during interaction of serum with contrast materials. The activation of complement by contrast materials appears to be principally initiated by the activation of plasminogen to plasmin. Inhibition of plasminogen activators by epsilon-aminocaproic acid affects complement activation markedly.

Release of serotonin from human platelets in vitro by radiographic contrast media.

Both ionic and nonionic, monomeric and dimeric contrast media were found to release serotonin from intact human platelets in vitro. The monomeric contrast media were compared at the concentration range of 25 mg I/ml. Iothalamate was the strongest and the statistically equal metrizamide iopamidol, and P-297 were the weakest releasers. Monomeric and dimeric contrast media were compared at concentration ranges of 50 and 100 mg I/ml. They ranked, in descending order of serotonin releasing potency: iodipamide, iothalamate, P-127, iopamidol, and a statistically indistinguishable group of the monoacid dimer P-286, the nonionic dimer ZK 74 435, and metrizamide. The capability of contrast media to release serotonin seems to be a composite result of their specific physical and molecular structural properties.

Biochemical characterization of x-ray contrast media.

RATIONALE AND OBJECTIVES: Eleven ionic and nonionic contrast media were compared in parallel regarding their effects on various biochemical parameters in vitro. Partition coefficient, protein binding, release of histamine, hemolysis inhibition and complement activation were determined as well as inhibition of various enzymes. Additionally, incompatibilities between contrast media and intravascular drugs that often are coadministered were determined. METHODS: Partition coefficients were determined in the system n-butanol/water by spectrophotometry. Protein binding was measured by equilibrium dialysis. Histamine release from rat peritoneal mast cells was measured by radioassay. Hemolysis inhibition and complement activation was determined in beagle dog serum using antibody-coated sheep erythrocytes. The inhibition of enzyme systems was measured photometrically. Incompatibility with coadministered drugs was registered by appearance of precipitations. RESULTS: Hydrophilicity as determined by partition coefficients was highest for iotrolan and lowest for iotetrol. Protein binding ranged from practically zero for most substances to 14% for ioxaglate. Histamine release was highest for diatrizoate (77% at 100 mg I/mL) and lowest for iodixanol (1%). Complement activation at 100 mg I/mL ranged from 0% (diatrizoate, iopamidol) to 77% (iopentol). The inhibition of the enzyme systems urokinase, streptokinase, collagenase, tissue plasminogen activator, and lysozyme was lowest for the nonionic dimers. CONCLUSIONS: All compounds influenced the parameters tested. However, the degree of interaction was different. Although there was no significant correlation between hydrophilicity (partition coefficient) or osmolality and the tested parameters, nonionic dimers seemed to be superior to nonionic monomers. The reason might lie in reduced chemotoxicity of this class of contrast media.

Elevation of serum lactate dehydrogenase-5 following methylglucamine iodipamide (Cholografin/Biligrafin) infusion for intravenous cholangiography.

Methylglucamine iodipamide (Cholografin-North America; Biligrafin-Europe, Squibb) is the only contrast medium in clinical usage for opacification of the biliary tree in intravenous cholangiography. We report two cases of elevation of serum lactate dehydrogenase-5 activity following infusion of 40 ml of Cholografin. This occurred without overt clinical signs of adverse reaction to contrast medium. This elevation was 65% of serum LD-5 activity in case one, 91% in case two. The elevation peaked at 12 h after administration of contrast medium in both cases and persisted for at least 24 h. These findings suggest that methylglucamine iodipamide causes transient hepatocellular toxicity, the mechanism of which is not known.

A particulate contrast agent with potential for ultrasound imaging of liver.

Ultrasonic backscatter and attenuation coefficients of a medium can be increased by the addition of solid, micron sized inhomogeneities. A potentially useful agent for ultrasonic contrast of liver images has been identified. Iodipamide ethyl ester (IDE) particles can be produced in the form of dense, relatively incompressible solids with high impedance mismatch to water. The chemical, biomechanical, and pharmacological properties of the small, uniform diameter IDE particles permit safe intravenous injection followed by rapid accumulation by reticuloendothelial (RE) cells of the liver and spleen, and later elimination from these organs. Since the particles are phagocytized by RE cells, present in normal liver but not in tumors and many lesions, the selective enhancement of ultrasonic backscatter should improve detectability of lesions which are hypo- or iso-echoic compared to surrounding tissue. The mechanisms of particle-ultrasound interaction may be described by relative motion attenuation, and scattering from a cloud of dense, incompressible spheres for the case of IDE particles in agar. Thus, values of attenuation and backscatter can be controlled by choice of ultrasound frequency and particle concentration and size. When the particles are accumulated in rat livers, additional mechanisms induce attenuation and backscatter in excess of that predicted by IDE in agar. This preliminary work demonstrates that solid, biocompatible particles may be useful as an ultrasonic contrast agent.

Lesion visualization by targeted computed tomography liver enhancement in dogs.

RATIONALE AND OBJECTIVES: We conducted a pilot study to determine the potential advantages of using liver-specific targeted computed tomography (CT) contrast agents for lesion detection. METHODS: Eight dogs had liver infarcts created by percutaneous injections of ethanol. Each dog underwent CT scans with four imaging techniques: unenhanced, intravenous contrast enhanced (IVCE), CT arterial portography (CTAP), and targeted liver enhancement with iodipamide ethylester (IDE) particles. Lesions were assessed quantitatively to determine liver-to-lesion density differences and the drop in density across liver edge as a quantitative measure of edge sharpness. Expert readers subjectively analyzed data to determine lesion visibility and edge sharpness. RESULTS: Liver-to-lesion density differences were greatest with CTAP (56.4 +/- 35.5 Hounsfield units [H]) followed by IDE (41.1 +/- 7.0 H), i.v. (22.7 +/- 6.0 H), and unenhanced scans (13.6 +/- 4.1 H; ps < .05 for CTAP versus unenhanced and IDE versus unenhanced). Edges were best defined both subjectively and quantitatively on IDE-enhanced scans. CONCLUSION: Targeted liver-specific contrast agents have potential to increase lesion visibility when compared with standard i.v. contrast enhancement of the liver by increasing lesion edge definition and liver-to-lesion attenuation differences. Further work in animal tumor models, and clinical trials as agents become available, appears justified.

Drip infusion cholangiography using iotroxamide. Double blind comparison with ioglycamide.

A double blind clinical trial was carried out in 200 unselected patients to compare the efficacy and tolerance of ioglycamide and iotroxamide as contrast media for intravenous cholangiography. The two agents were administered by slow infusion at a rate of 2.6 mumoles/kg bodyweight/minute for one hour. Radiological opacification of the bile duct was assessed independently by two radiologists. In patients with serum bilirubin levels of less than 34 mumoles/litre visualization of the bile duct was significantly better with iotroxamide than with ioglycamide (P < 0.001). Toxic side effects were observed in 8% of patients receiving ioglycamide and in only 3% of the patients given iotroxamide.