A comparison of the systemic responses to rapid intravenous injections of ioxilan, iohexol, and diatrizoate in rabbits

Rapid intravenous injections of contrast media are used for angiocardiography, intravenous digital subtraction angiography (DSA), and rapid scan computed tomography procedures. These rapid intravenous injections have been shown to produce significant hemodynamic changes that appear related to contrast media osmolality. In this study the systemic responses to 2-second injections at a dose of 1.5 mL/kg were compared for a new nonionic agent, ioxilan (350 mgI/mL), and for iohexol (350 mgI/mL), meglumine/sodium diatrizoate (370 mgI/mL), and saline. Ioxilan has a lower osmolality and viscosity than iohexol and is formulated with a 3 mM sodium citrate as a buffer and anticoagulant. All of the test solutions produced statistically significant changes in arterial pressure and respiratory rate (P less than .05, Student's t-test). The decrease in arterial pressure seen with diatrizoate (20.1%) was significantly greater than the decrease seen with either ioxilan (10.2%) or iohexol (10.2%). All of the responses observed were transient and would not be of clinical concern in a healthy patient. Ioxilan, which contains the calcium binding agent, sodium citrate, and iohexol appear to cause less systemic effects then diatrizoate.     

Contrast media-induced renal tubular vacuolization after dehydration. A light and electron microscopic study in rats.

Morphologic studies on the effect of dehydration on contrast media (CM)-induced renal changes were done. Sixty-six healthy Wistar rats were deprived of water for 24 hours before the intravenous (i.v.) injection of 1.0 or 3.0 g iodine (I)/kg of high-osmolal diatrizoate, low-osmolal iopromide or iohexol, iso-osmolal iotrolan, or 0.2 or 0.6 g/kg of high-osmolal magnetic contrast agent, gadolinium-DTPA (Gd-DTPA). Control animals received physiologic saline. After 2 hours, the kidneys were fixed by perfusion for light and electron microscopy, and the morphologic changes were semi-quantitatively reviewed by two independent observers blinded to the treatment. The smaller dose of iohexol or iotrolan and the larger dose of all the CM induced in the proximal convoluted tubule (PCT) cells a statistically highly significant (P less than .001) or significant (Gd-DTPA; P less than .01) cytoplasmic vacuolization. The changes were most prominent (P less than .001) after treatment with iohexol and iotrolan. The results might be related to the higher urinary CM concentration after low- and iso-osmolal agents. Dehydration further potentiates higher CM concentration. The morphologic injury, when compared with the author's earlier findings on normal rats, was clearly intensified by dehydration.     

Contrast media-induced renal morphologic changes in rats with acute edematous pancreatitis.

OBJECTIVES. Contrast media (CM)-induced renal morphologic changes were studied in rats during acute edematous pancreatitis. METHODS. The histologically verified, mild pancreatitis was caused in Wistar rats (n = 54) by an injection of peanut oil into the pancreatic duct. After 24 hours, the animals received an intravenous (IV) injection of 1.0 or 3.0 g iodine (I)/kg of high-osmolality diatrizoate, low-osmolality iopromide or iohexol, or 0.2 or 0.6 g/kg of high-osmolality magnetic resonance (MR) CM, gadolinium-DTPA (Gd-DTPA). The controls received physiologic saline. The kidneys were fixed by perfusion after 2 hours, and changes in renal morphology were analyzed semiquantitatively by two independent observers blinded to the treatment. RESULTS. The smaller dose of iohexol and the larger dose of all other CM induced a statistically significant (P less than .05) cytoplasmic vacuolization in the proximal convoluted tubule cells. The changes were most prominent after iohexol (P less than .001). When compared with the authors' earlier findings on healthy rats, the CM-induced renal structural injury was more severe. CONCLUSIONS. Pancreatitis potentiates the renal microstructural changes associated with CM; although the animals' fluid and electrolyte status was not specifically assessed, the enhanced abnormalities may be related to the hypovolemia associated with pancreatitis.     

Cytogenetic interactions of contrast media and antineoplastic drugs

The cytogenetic interactions of ionic (diatrizoate, ioxaglate) and nonionic (iohexol) contrast media (CM) with antineoplastic drugs cyclophosphamide (CPA) and carmustine (CARM) were evaluated in a rat bone marrow cell model. Male Wistar rats were anesthetized with a 6% chloral hydrate solution and divided into five groups of five rats each. In protocol 1, three groups of rats received diatrizoate, ioxaglate, and iohexol (2.5 mL/kg) intravenously within 30 seconds. The remaining two groups were similarly injected with CPA and CARM (10 mg/kg). Control animals were injected with nonpyrogenic sterile water or saline solution. After 12 and 24 hours, the animals were killed with an overdose of chloral hydrate, and bone marrow smears were prepared for determining chromosomal damage in polychromatic erythrocytes (PCEs) by a micronucleus test. In protocol 2, CPA and CARM were injected, and 15 minutes later, bolus injections of diatrizoate, ioxaglate and iohexol were given through the same route. Both ionic and nonionic CM induced significant numbers of micronuclei in PCEs (P less than .05). CPA caused a severe cytogenetic effect, whereas CARM did not produce a significant number of micronuclei in PCEs compared with control. In protocol 2 experiments, antagonism with CPA and synergism with CARM was demonstrable. Clinical implication of the cytogenetic interactions between CM and antineoplastic drugs remains to be established.     

Pretreatment with steroids before intravenous injection of diatrizoate or iohexol. Effects on urine and serum profiles.

The effects on urine and serum profiles of intravenous injection of diatrizoate, iohexol, or saline were studied in male rats pretreated with steroids or saline. Using urinary albumin, glucose, sodium, and the enzymes lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), and N-acetyl-beta-D-glucosaminidase (NAG) as markers of glomerular and tubular function, it was found that diatrizoate caused temporary glomerular and tubular dysfunction; the effect was independent of the kind of pretreatment. Iohexol did not cause increased glomerular permeability in steroid- and saline-pretreated rats. When used following saline, iohexol induced increased excretion of three tubular components, whereas iohexol plus steroids caused increased excretion of all five tubular components. The dysfunctional effect of iohexol plus steroids was less than that of diatrizoate plus steroids. The serum components revealed no abnormalities induced by either contrast media or methylprednisolone. Pretreatment with steroids has no effect on the glomerular or tubular dysfunctional effect of diatrizoate, whereas it worsens the temporary tubular dysfunctional effect of iohexol in rats.     

Nephrotoxicity of cyclosporin A and contrast media. A comparison between diatrizoate and iohexol in rats

Urine profiles (albumin, glucose, NAG, LDH, GGT and sodium) were followed for 22 h or 8 days after intravenous injection of diatrizoate, iohexol or saline in 30 adult Wistar rats in which nephrotoxicity was induced by daily peroral administration of 25 mg/kg body weight cyclosporin A over a 14-day period. Another 10 rats which had the vehicle of the cyclosporin A solution (placebo) and saline injected intravenously served as controls. The effect of iohexol and saline on the albumin excretion was similar, whereas diatrizoate increased it significantly. Both contrast media caused significantly increased excretion of all three enzymes. The contrast media had no effect on the excretion of glucose and sodium. Except for the fact that the excretion of NAG was significantly higher following iohexol than following diatrizoate 24 to 46 h after injection no significant differences between the two media were found from 24 h after injection among the rats given cyclosporin A. No contrast medium related changes were found by light microscopy of the kidneys. Neither iohexol nor diatrizoate potentiate acute cyclosporin A nephrotoxicity.     

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.     

Gentamicin nephropathy and contrast media. A comparison between diatrizoate and iohexol in rats

Urine profiles were followed for 3 or 9 days after intravenous injection of diatrizoate, iohexol or saline in 30 rats, where a tubulo-interstitial nephropathy was induced by gentamicin given over a 14-day period. Another 10 rats who had an injection of saline served as controls. Iohexol increased the excretion of lactate dehydrogenase significantly more than both saline and diatrizoate for the first 3 days, whereas diatrizoate had no effect. Both media caused significantly increased excretion of L-gamma-glutamyltransferase compared with saline, but iohexol significantly more than diatrizoate. Compared with saline S-creatinine was significantly increased following iohexol at 24 h, 3 and 9 days, and following diatrizoate only at 9 days. Among rats having gentamicin light microscopy revealed more severe changes in kidneys exposed to iohexol than to either diatrizoate or saline 3 days after their injection. Six days later no obvious differences were found between the 3 groups. In conclusion, iohexol induced more renal dysfunction than diatrizoate in this animal model of gentamicin induced nephropathy.     

Pharmacokinetics of three contrast media in experimental pancreatography

Diatrizoate, iohexol and ioxaglate were compared in experimental pancreatography in piglets. Outflow of contrast medium (CM) through the pancreatic papilla was permitted (n = 14) or impaired (n = 17) during examination. The CM concentrations were measured in portal and systemic plasma and in lymph to study the absorption of CM. Absorption of diatrizoate and iohexol was similar in both types of experiment, but radiographically, diatrizoate escaped significantly earlier from the pancreatic duct when outflow was permitted (p less than 0.01), suggesting that the CM was absorbed mainly during injection. Ioxaglate concentrations rose more slowly in systemic plasma and lymph, and fell more slowly in the portal plasma than those of diatrizoate and iohexol, which suggests that ioxaglate was absorbed over a longer period. When outflow was impaired, ioxaglate concentrations remained on a lower level, indicating less penetration in the pancreatic parenchyma. CM absorption varied markedly within each group, suggesting that variations in intraductal pressure and flow are more important in absorption than the type of CM used.     

Physiologic effects of contrast media in the rabbit

The intravenous administration of contrast media (CM) is often associated with alterations in blood pressure (BP) and heart rate (HR). Osmolality is thought to play a role, but the magnitude and even the direction of change may vary under similar osmotic conditions indicating the involvement of other mechanisms. Conscious rabbits received sodium-meglumine diatrizoate (76%, 1 mL/kg, ear vein) every 10 minutes for 1 hour. A similar injection protocol was performed with normal saline and mannitol (36%), equiosmotic to the contrast agent. BP and HR were monitored continuously. Blood samples were collected at the midpoint between each injection for determination of hematocrit, serum osmolality, and iodine concentration. Group parameters at each time point were compared with the Student's t-test. The administration of mannitol caused changes in serum osmolality, hematocrit, and HR as great or greater than the changes caused by equiosmotic diatrizoate. However, BP increased significantly in the diatrizoate group but not in the mannitol group, relative to normal saline. These results suggest that osmolality is important for certain physiologic changes induced by CM, but that BP changes involve mechanisms in addition to osmolality.     

Penetration of vascular contrast media into brain tissue and cerebrospinal fluid. An experimental study in rats

Recent studies suggest that intravenously administered contrast media (CM) penetrate into cerebrospinal fluid (CSF), and the concentration of CM in CSF increases significantly following acetazolamide or probenecid pretreatment. However, corresponding levels of CM in brain tissue and extracellular fluid (ECF) have not been reported. Adult anesthetized rats were injected intravenously with sodium/meglumine diatrizoate and iohexol. The control group received no pretreatment, and the pretreated group received acetazolamide and probenecid before the CM. The amount of each contrast agent was measured in brain tissue and in CSF by high performance liquid chromatography. Pretreated animals attained significantly higher CSF concentrations of diatrizoate and iohexol than control animals. However, tissue ECF concentrations in pretreated animals were not significantly different than in control animals for either agent. The results are consistent with the idea that a flushing action of CSF helps to remove CM from the brain ECF.     

Urine profiles and kidney histology following intravenous diatrizoate and iohexol in the degeneration phase of gentamicin nephropathy in rats. Effects on urine and serum profiles.

Urine chemical profiles were followed for three or nine days after intravenous injection of diatrizoate, iohexol, or saline in 30 rats, where a tubulointerstitial nephropathy was induced by gentamicin given over an eight-day period. Another ten rats injected with saline served as controls. Compared to injection of saline, both iohexol and diatrizoate induced dysfunction. The excretion of the cytoplasmic enzyme lactate dehydrogenase was significantly greater following iohexol than following diatrizoate. No significant differences between the two media were shown by the various serum components examined. Among the gentamicin-treated rats, light microscopy showed prolonged occurrence of tubular necrosis and a more intensive round cell infiltration following iohexol than following diatrizoate and saline. Both contrast media induced further temporary renal dysfunction in rats with gentamicin nephropathy; iohexol induced more morphologic changes than diatrizoate.     

Contrast media-induced renal tubular vacuolization. A light and electron microscopic study on rat kidneys

The morphologic changes in healthy rat kidneys (n = 102) were studied 2 or 48 hours after intravenous injection of 1 or 3 g iodine (I)/kg of high-osmolality diatrizoate, low-osmolality iopromide and iohexol, or iso-osmolality iotrolan, as well as after 0.2 or 0.6 g/kg of the high-osmolality magnetic resonance contrast medium gadolinium DTPA. Physiologic saline was injected in controls. The kidneys were fixed by perfusion and the specimens were analyzed semiquantitatively by two independent observers blinded to the treatment. A statistically significant (P less than .01) cytoplasmic vacuolization was noticed in the proximal convoluted tubule cells 2 hours after injection of 3 g I/kg of diatrizoate or iopromide. Iohexol and iotrolan induced an even more significant (P less than .01) and longer-lasting vacuolization, but gadolinium DTPA did not produce lysosomal alterations. Although the vital cell organelles remained intact, reversible lysosomal alterations may represent the first structural signs of a threatening cellular injury.     

Granulocyte adherence is inhibited by radiographic contrast media in vitro.

Different amounts of diatrizoate, ioxaglate, iohexol, iodixanol, NaCl 1,000 mOsm/kg, mannitol 1,098 mOsm/kg, and meglumine (meglumine concentrations corresponding to the content in the diatrizoate solutions) were added to either whole blood or a suspension of granulocytes in autologous plasma, and the adherence to nylon fibers was determined. At high concentrations all the investigated contrast media (CM) inhibited granulocyte adherence. The degree of inhibition was significantly greater when the ionic CM diatrizoate and ioxaglate were used, as compared with the nonionic media. Meglumine solutions at high concentrations also inhibited adherence but significantly less than diatrizoate solutions containing the same amount of meglumine. Diatrizoate showed the greatest inhibitory effect on granulocyte adherence, and significant inhibition could be detected even with a 1.25% solution.     

Effect of an iso-osmolar contrast medium on pulmonary arterial pressure at pulmonary angiography

A clinical comparison of the effects on pulmonary arterial pressure induced by contrast media with various osmolalities, iohexol 140 mg I/ml (300 mosm/kg H2O), iohexol 300 mg I/ml (690 mosm/kg H2O), and diatrizoate 292 mg I/ml (1480 mosm/kg H2O) following selective pulmonary angiography was made in 12 patients with normal pulmonary arterial pressure. A double-blind crossover study was performed and the contrast media were administered in random order. The pulmonary arterial pressure was recorded continuously before, during, and for 3 min after the injection. The effect of iohexol 140 on the pulmonary arterial pressure was significantly less marked than that of diatrizoate 292, whereas no statistical significance was shown between iohexol 140 and iohexol 300. These results indicate that iso-osmolar contrast medium (iohexol 140), as well as iohexol 300, would be better tolerated than diatrizoate 292, and is therefore a safer contrast medium for selective pulmonary angiography.     

Nephropathy induced by intramuscularly administered glycerol and contrast media in rats. A comparison between diatrizoate, iohexol and ioxilan

Urine profiles (albumin, glucose, NAG, LDH, GGT, sodium, and phosphate) were followed for 14 days after intravenous injection of either diatrizoate, iohexol, ioxilan, or saline in 24 Wistar rats with a glomerular and tubular dysfunction induced by intramuscularly (i.m.) administered glycerol. Another 6 rats exposed to neither glycerol nor contrast media served as controls. The effect of ioxilan and saline on the albumin excretion was similar, whereas diatrizoate and iohexol increased it significantly. The contrast media had no further inhibitory effect on the reabsorption of glucose. Iohexol caused significantly increased excretion of all three enzymes, ioxilan of NAG and LDH, whereas diatrizoate only increased the excretion of LDH. The sodium excretion was further increased by ioxilan and diatrizoate, whereas none of the contrast media affected the phosphaturia. Both ioxilan and iohexol caused a round cell response around the tubules shown by light microscopy whereas diatrizoate caused no further changes. It is concluded that diatrizoate and iohexol increase glomerular dysfunction induced by glycerol i.m.; all three contrast media cause some further increase in the tubular dysfunction. Neither diatrizoate, iohexol nor ioxilan prolong nephropathy induced by glycerol i.m. determined by the chemical analyses. The histologic finding indicates a direct toxic effect of non-ionic low osmolar contrast media in this animal model of nephropathy.     

Assays for plasma complement activation by x-ray contrast media

Hemolytic complement activity and a C3a radioimmunoassay (RIA) were investigated for their ability to characterize contrast media (CM) with respect to complement activation. The CM tested were commercial formulations of diatrizoate, iodamide, iothalamate, ioxaglate, iohexol, and iopamidol. When plasma was exposed to CM, the hemolytic complement activity decreased and the C3a concentration increased. The C3a assay had a larger dynamic range and therefore more ability to discriminate among the CM. Using C3a data from pooled plasma or from individual donors' plasma, nonionic iopamidol (as Isovue 300) had lower complement-activating potential (P less than .005 and P greater than .05, respectively) than all of the ionic media based on diatrizoate, iothalamate, iodamide, and ioxaglate. The ranges of mean C3a values generated by saline, nonionic CM, and ionic CM were 48 to 60, 65 to 173, and 807 to 3272 ng C3a/50 microL, respectively. Complement activation was found to correlate with osmolality (r = 0.945, all media) and with molarity (r = 0.994, diatrizoates).     

Intravenous injection of ioxilan, iohexol and diatrizoate. Effects on urine profiles in the rat

Effects of intravenous ioxilan, a new third generation non-ionic contrast medium, diatrizoate, iohexol and saline on urine profiles were compared. Albumin, glucose, sodium, phosphate, and the enzymes NAG, LDH and GGT were followed in 24 normal rats over 7 days. Diatrizoate significantly affected all profile components during the first two hours. Albuminuria was significantly greater after diatrizoate than after iohexol or ioxilan, and excretion of glucose, LDH and GGT was significantly higher than after ioxilan. Both iohexol and ioxilan increased the excretion of albumin, LDH and GGT, while iohexol also significantly increased excretion of glucose and sodium. There was a greater excretion of glucose and GGT after iohexol than after ioxilan. Saline did not induce any changes. At day 7, serum sodium, urea, creatinine, and albumin were normal for all test substances, and kidney histology revealed no difference between the groups of animals. It is thus concluded that both high osmolar ionic and low osmolar non-ionic contrast media may cause temporary glomerular and tubular dysfunction in rats. In this model, the kidney is affected most by diatrizoate, less by iohexol, and least by ioxilan.     

Effects of intravenous contrast media on cortical and medullary blood flow in the rat kidney

The effect of slow intravenous infusion of contrast medium (CM) (1600 mg I/kg body weight) on cortical blood flow (BF) and medullary BF in rat kidneys was investigated by laser-Doppler flowmetry on either renal cortex or exposed renal papillas (inner medulla). The effect on cortical BF was evaluated after infusion of either ioxaglate, iohexol, or ioxithalamate. Mannitol and Ringer's solution were used as control substances. The effect on medullary BF was examined after infusion of either ioxaglate, iohexol, iopamidol, ioxithalamate, or mannitol. BF was measured continuously during a 30-minute control period and a 60-minute experimental period, starting with the CM infusion. Cortical BF was unchanged in the ioxaglate group and significantly increased in the iohexol, ioxithalamate, and mannitol groups (P less than .05). Medullary BF was moderately increased in the ioxaglate group (P less than .05) but moderately decreased in the groups that received iohexol, iopamidol, ioxithalamate, or mannitol (P less than .05). The reduction in medullary BF following infusion of the ratio 3.0 nonionic CM and of the ratio 1.5 ionic CM might be one contributory mechanism to the pathogenesis of CM nephropathy, especially in the presence of microangiopathy in the kidney.     

High- and low-osmolar contrast agents in urography: a comparison of the appearances with respect to pyelotubular opacification and renal length

The incidence of pyelotubular opacification and the change in renal length during intravenous urography with iohexol (Omnipaque) was compared with sodium/meglumine diatrizoate (Urografin). Pyelotubular opacification was seen in 14 out of 29 urograms performed with iohexol compared with one out of 28 urograms performed with sodium/meglumine diatrizoate. This increased incidence is statistically significant and has not been previously documented. The increase in renal length following intravenous contrast medium was similar for both iohexol and sodium/meglumine diatrizoate. The significance of these findings with respect to the interpretation of urograms performed with iohexol is discussed.