Variable effects of radiological contrast media on thrombus growth in a rabbit jugular vein thrombosis model.

We studied the effect of an ionic high osmolar contrast medium (Ioxitalamate), an ionic low osmolar contrast medium (Ioxaglate) and various nonionic low osmolar contrast media (Iopamidol, Iopromide and Iohexol) on thrombus growth in a rabbit jugular vein thrombosis model. Thrombus growth was determined by the accretion of 125I-labeled fibrinogen onto autologous preformed thrombi in rabbit jugular veins at various time-intervals from 15 min up to 10 h after infusion of the study solution. The ionic low osmolar contrast medium markedly inhibited thrombus growth whereas all nonionic low osmolar contrast media promoted thrombus growth. The ionic high osmolar, contrast medium inhibited thrombus growth, but less than the ionic low osmolar contrast medium. Within the group of nonionic contrast media, the Iopamidol associated promotion of thrombus growth was significantly higher than the Iopromide or Iohexol associated effects. The simultaneous administration of the apparently most potent thrombus growth promoting contrast medium (i.e. Iopamidol) and heparin resulted in complete abolishment of the increase in thrombus growth. These results support the claims of prothrombotic properties of nonionic as compared to ionic contrast media and could explain the clinically encountered thromboembolic complications after the use of nonionic low osmolar contrast media.

Ventricular fibrillation during right coronary arteriography with ioxaglate, iohexol and iopamidol in dogs.

Radiograph contrast media (CM) are known to produce myocardial disturbances during cardiac angiography. The most severe electrical disturbance is ventricular fibrillation (VF). Previous studies using prolonged right coronary exposures have demonstrated a higher incidence of VF with dilute low sodium CM than with dilute CM containing more physiologic levels of sodium. In this study the incidence of VF was examined for more conventional concentrations of iopamidol, iohexol and ioxaglate and for sodium supplemented iohexol. The incidence of VF was determined during 25-second injections of contrast media into the canine right coronary artery at a rate of 0.4 mL/sec. Injections of iohexol and iopamidol at concentrations of 160, 240 and 320 mgI/mL produced significantly more VF (P less than .005, Fisher Exact Test) than meglumine/sodium ioxaglate or iohexol supplemented with 20 mM sodium chloride. The time required to produce a 50% incidence of VF with iohexol and iopamidol was significantly related to sodium concentration (r = .92, P less than .01).

Effect of contrast material osmolality on the electrocardiogram during intrauterine injection.

RATIONALE AND OBJECTIVES: In a previous study, intrauterine injection of meglumine-sodium diatrizoate (high osmolar contrast media) during hysterosalpingography was found to induce lengthening of the QTc interval on electrocardiography. To evaluate the relationship between high osmolality and electrocardiographic changes during intrauterine injection, the authors evaluated the effect on QTc of two ionic contrast agents with different osmolality during routine hysterosalpingography. METHODS: Forty-eight women undergoing routine hysterosalpingography were included in the study. Thirty-two women received meglumine-sodium diatrizoate (1500 mOsm/kg) and 16 received meglumine-sodium ioxaglate (600 mOsm/kg). QTc changes were evaluated using a 12 lead computerized electrocardiogram system during all the stages of the procedure. RESULTS: In the meglumine-sodium diatrizoate group, QTc interval was prolonged significantly from 419 +/- 19 msec at baseline to 447 +/- 30 msec during injection of contrast material, P < .001, and returned to baseline values in late phase (416 +/- 18 msec). The meglumine-sodium ioxaglate group showed no change in the QTc interval. CONCLUSION: As the single major difference between the two ionic agents is osmolality, we believe that QTc interval prolongation in the meglumine-sodium diatrizoate group is related to increased osmolality.

Contrast media-induced ventricular fibrillation. A comparison of Hypaque-76, Hexabrix, and Omnipaque.

Contrast media occasionally produce ventricular fibrillation during coronary angiography. We compared the fibrillatory propensity of the conventional ionic contrast medium, Hypaque-76 (H76) to the low osmolar ionic dimer Hexabrix (HB) and to the nonionic agent Omnipaque (OM) in 20 open chest anesthetized dogs. Intracoronary injection of 6 mL of contrast medium produced spontaneous ventricular fibrillation in four of ten dogs with H76, compared with two of ten with HB, and zero of ten with OM (P = .07). The induction of two premature beats by programmed stimulation of the myocardium during injection of 4 mL of contrast medium produced ventricular fibrillation in ten of ten dogs with H76, compared with three of ten with HB, and zero of ten with OM (P less than .001). Both H76 and HB produced ventricular fibrillation in ten of ten dogs when three premature beats were induced, compared with two of ten dogs with OM (P less than .001). Four mL H76 produced a 109 +/- 18 msec increase in the QT interval, compared with an 82 +/- 17 msec increase with HB, and a 45 +/- 12 msec increase with OM. We conclude that both low osmolar HB and OM are less fibrillatory than the conventional ionic medium H76, and that the nonionic medium OM is less fibrillatory than the ionic dimer contrast medium HB.

Evaluation of histamine release following intravenous injection of ionic and nonionic contrast media.

To evaluate histamine release (HR) following injection of radiocontrast media and to test the predictive value of peak-expiratory-flow rate (PEFR) in detecting high-risk patients, the authors performed in two series 90 intravenous pyelograms (IVPs). In the first group, HR was measured by a fluorometric method after injection of Hexabrix (25 patients) and Iopamiron (25 patients). In the second group, HR measured by a radioimmunoassay, and PEFR measured by a peak flowmeter were investigated after injection of Hexabrix (10 patients), Telebrix (10 patients), Omnipaque (10 patients) and Iopamiron (10 patients). Histamine release in groups 1 and 2, and PEFR in group 2, were not significantly modified by the injection of each radiocontrast media. For the four patients (two per group) who experienced minor allergic side effects, the levels of HR and PEFR were always within the normal ranges.

Extravascular extravasation of radiographic contrast media. Effects of conventional and low-osmolar agents in the rat thigh.

We compared the damage resulting from intradermal injection of four commonly used radiographic contrast media in laboratory rats. Sixty percent meglumine diatrizoate (Reno M 60) and ioxaglate (Hexabrix) produced significantly more ulceration and crusting on gross inspection and more necrosis, edema, and hemorrhage on histologic evaluation than iopamidol 300 (Isovue) or 0.9% (normal) saline. Thirty percent meglumine diatrizoate (Reno M Dip) had an intermediate toxicity, resulting in significantly more visible swelling and more microscopically detected hemorrhage than iopamidol or saline, but less ulceration/crusting and necrosis than Reno M 60 and ioxaglate. Since the three contrast agents of similar osmolality produced different degrees of tissue damage, our results suggest that factors other than high osmolality are partially responsible for determining the severity of injuries from extravasated contrast media.

Cutaneous ulceration due to contrast extravasation. Experimental assessment of injury and potential antidotes.

Severe cutaneous ulceration may occur as a result of contrast media extravasation. We established a definitive animal model for assessing the cutaneous toxicity of commonly employed agents and used this model to evaluate possible antidotes to the effects of contrast media extravasation. The contrast agents studied were: meglumine/sodium diatrizoate 76%, meglumine iothalamate 60% and 43%, meglumine/sodium ioxaglate 60%, iohexol 350, and iopamidol 370, in varying volumes and osmolalities. Hypertonic saline (950 and 1900 mOsm/kg) also was injected. Agents were injected intradermally into BALB/c mice. The higher osmolality agents produced dose-dependent skin ulcerations. The lower osmolality agents failed to produce any skin lesions after the same volume doses. Hypertonic saline produced skin toxicity in a dose-dependent fashion similar to hyperosmolar contrast agents. Three antidotes were tested: hyaluronidase, topical heat, and topical cold. Hyaluronidase significantly reduced skin toxicity when injected immediately following contrast injection. Cold also significantly reduced skin toxicity, while heat caused no improvement.

Incidence of ventricular fibrillation during coronary arteriography in the rabbit. A comparative study of isotonic ioxaglate and iohexol.

The incidence of major ECG changes, particularly ventricular fibrillation, was evaluated in rabbits during prolonged, selective right coronary injection of sodium/meglumine ioxaglate (Hexabrix 160) and iohexol (Omnipaque 140), two isotonic contrast media. The anesthetized animals (n = 12) per test solution) each received 1.5 ml of contrast material, delivered at a rate of 3 ml/minute. Both contrast media caused major ECG changes, which were reversible within seconds after administration. No fibrillation occurred with ioxaglate, but ventricular fibrillation was seen in seven animals given iohexol. There was a significant difference in the incidence of ventricular fibrillation between the contrast media (P less than .01). Both test solutions induced transient, more or less marked bradycardia, but without significant differences. The intracoronary injections produced similar decreases in blood pressure for both contrast agents. Reactive hypertension was observed only in those animals in which an episode of fibrillation occurred with iohexol. The causes underlying these effects are analyzed for both contrast agents.

Cardiac and hemodynamic tolerability of iodinated contrast media in the anesthetized rat.

RATIONALE AND OBJECTIVES: The study was designed to compare the hemodynamic effects of 11 iodinated contrast media (CM), including ionic (diatrizoate, ioxaglate), nonionic monomeric (iohexol, iopromide, iopamidol, iopentol, ioversol, iomeprol, ZK 139129), and nonionic dimeric (iotrolan, iodixanol) compounds. METHODS: Following left ventricular bolus injection of 1.2 g I/kg body weight in anesthetized rats, cardiohemodynamic parameters were measured. RESULTS: Compared with the control group, except for blood pressure (BP), all CM showed a similar response regarding the direction of the cardiohemodynamic changes after CM injection. A biphasic change in BP was observed for diatrizoate and iodixanol, whereas all other CM showed a transient increase in BP being most pronounced for ioxaglate. No arrhythmias were detected. The increase in LVEDP was lowest for the isotonic dimeric CM iotrolan and iodixanol. CONCLUSIONS: Only mild transient side effects were observed. Low osmolar, especially isotonic, dimeric CM show a clear benefit regarding cardiovascular side effects.

Effects of contrast media on myocardial function during acute left ventricular failure in the dog.

We studied the hemodynamic side effects of intracoronary injection of contrast media during acute ischemic heart failure by using anesthetized dogs. Induction of failure was performed by microembolization of the area supplied by the left main coronary artery. Six ml of iohexol (Omnipaque) increased contractility during the normal state, while this contrast medium induced no alterations in any of the recorded hemodynamic variables during left ventricular failure. Ioxaglate (Hexabrix) was also well tolerated during the normal state, while sodium-meglumine diatrizoate (Renografin) markedly decreased systolic variables. However, in the failing heart both ioxaglate and diatrizoate resulted in greater reduction in all systolic variables than in the normal heart. We conclude that both ionic contrast media may be harmful in acute ischemic heart failure. Non-ionic iohexol appears safer in this condition.

Effect on thrombus growth and thrombolysis of two types of osmolar contrast media in rabbits.

Thromboembolic complications have been reported after diagnostic or interventional radiological procedures. However, contrast media inhibit platelet function and blood coagulation in vitro. To investigate these characteristics in vivo, we determined the effect of nonionic and ionic low osmolar contrast media on thrombus growth and thrombolysis in rabbits in a randomized study design. Rabbits received either ionic low osmolar contrast medium (ioxaglate), nonionic low osmolar contrast medium (iohexol) or saline. Thrombus growth was determined by the accretion of 125I-labeled fibrinogen on to autologous, nonradioactive, preformed thrombi in rabbit jugular veins. Thrombolysis was assessed by measurement of the decrease in radioactivity of standard sized preformed 125I-fibrinogen labeled thrombi. Ioxaglate significantly inhibited thrombus growth (60% inhibition, P less than 0.005 vs. saline), in contrast to iohexol, which had no significant effect (33% inhibition, P less than 0.2 vs. saline). Neither ioxaglate nor iohexol affected thrombolysis.

Experimental tissue damage after subcutaneous injection of water soluble contrast media.

Various water soluble contrast media (WSCM) were injected subcutaneously into 970 hind feet of 485 rats. Gross morphologic changes were seen after the injection and analyzed as a function of various physicochemical characteristics of WSCM. The WSCM of larger volume, higher osmolality, higher iodine content, and meglumine salts rather than sodium salts caused more severe tissue damage; younger rats showed more severe tissue damage by WSCM of high osmolality.

Ioxaglate-induced light and electron microscopic alterations in the renal proximal tubular epithelium of rats.

Vacuolization of the proximal tubular epithelial cells was produced in rats by the intravenous administration of the radiographic contrast medium ioxaglate at high multiples of the human diagnostic dose. Samples of the renal cortex and outer zone of the medulla were examined by light and electron microscopy. We observed enlargement, confluence, and migration of vacuoles containing pleomorphic dense material and distinct inclusion bodies. With time, vacuolization disappeared, though single vacuoles partly engaged in extruding their contents into the tubular lumen were still visible. We concluded that radiographic contrast medium at high dose levels can produce a reversible disturbance in the transport vesicular system of the proximal tubular epithelial cells without affecting the specific cell organelles.

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.

Comparative cytotoxicity of low- and high-osmolar contrast media to human fibroblasts and rat mesangial cells in culture.

RATIONALE AND OBJECTIVES: The authors investigate the relative sensitivity of rat mesangial cells to iodinated contrast media (CM) and control solutions versus less differentiated cells (ie, human fibroblasts) and compare the effects of low-osmolar ionic (ioxaglate) and nonionic (iopamidol) and high-osmolar ionic (diatrizoate) CM on rat mesangial cells. METHODS: The cytotoxic effects of ioxaglate and control solutions of sodium chloride and mannitol were assessed by neutral red uptake in isolated rat mesangial cells and human fibroblasts. In a second series of studies, the cytotoxic effects of ioxaglate, iopamidol, and diatrizoate (0 to 100 mg I/mL) on rat mesangial cells were compared. RESULTS: Rat mesangial cells were more sensitive to the cytotoxic effects of ioxaglate than the less differentiated human fibroblasts between 70 and 100 mg I/mL. A similar discrepancy was observed in the case of control solutions, sodium chloride, and mannitol. Ioxaglate and iopamidol induced a similar level of cytotoxicity in rat mesangial cells whereas the high-osmolar agent diatrizoate was significantly more cytotoxic. However, the calculated inhibitory concentrations of 50% of all three CM were associated with similar osmolalities, suggesting a major role for this parameter in the case of such media. CONCLUSIONS: Rat mesangial cells are more sensitive to the cytotoxic effects of CM and hyperosmolar solutions than the less differentiated human fibroblasts. High-osmolar CM are more cytotoxic than ionic and nonionic low-osmolar CM to rat mesangial cells. Ionicity seems to play no deleterious role at similar iodine concentrations because ioxaglate and iopamidol had equivalent cytotoxic effects on mesangial cells.

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.

Modulation of the renal effects of contrast media by endothelium-derived nitric oxide in the rat.

RATIONALE AND OBJECTIVES: A possible involvement of endothelium derived relaxing nitric oxide (NO) in the pathogenesis of iodinated contrast media (CM)-induced nephrotoxicity was investigated in the rat. METHODS: Male rats (6 to 12 per group) were uninephrectomized. Six days later, the aorta was clamped above the renal artery and a low-osmolar contrast medium (CM), ioxaglate, was injected (1 mL/min; 3 minutes) via an aortic puncture in the single remaining kidney. Contrast medium was injected with or without the NO-synthase inhibitor L-NAME (100 mg/kg intravenously [i.v.] 5 minutes before CM). One group received L-Arginine, the physiological precursor of NO (100 mg/kg i.v.), 5 minutes before L-NAME. Phenylephrine (300 micrograms/kg; 30 min) was used as a vasoconstrictive NO-independent control. The effects of iohexol, another low-osmolar CM, on creatinine clearance (CrCl) were also studied with and without pretreatment with L-NAME. A control group was subjected to a 3-minute renal ischemia only. Creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion were determined before, and 24 and 48 hours after CM administration. Blinded histologic analysis was carried out after completion of the study. RESULTS: When administered alone, neither L-NAME nor L-arginine modified CrCl. Ioxaglate mildly but significantly decreased CrCl at 24 hours (-26.5% of preinjection value). This was similar to the effect observed in the control group subjected to ischemia only. When associated with L-NAME, ioxaglate markedly decreased CrCl (-58 + 11% at 24 hours, P < .05 vs. ioxaglate alone). A similar interaction was noted in the case of iohexol. L-NAME also markedly increased ioxaglate-induced urinary NAG excretion. Phenylephrine had a similar impact on renal function. L-arginine pretreatment reduced the increase in serum creatinine induced by L-NAME+ioxaglate (68 + 17 mumol/L vs. 175 + 59 mumol/L for L-NAME+ioxaglate; P < .05) and urinary NAG excretion. Ioxaglate alone induced only tubular epithelial vacuolization. When associated with L-NAME, this CM induced tubular and vascular lesions, as well as necrosis in the outer medulla. Such histologic effects were clearly inhibited by L-arginine. CONCLUSION: These data indicate that L-NAME, a specific inhibitor of NO-synthase, and phenylephrine, accentuate the nephrotoxicity of CM in the rat. This is consistent with results from the literature showing that CM-toxicity is enhanced by renal ischemia.

Experimental nephrotoxicity of the radiocontrast agents iohexol, ioxaglate, and iothalamate. An in vitro and in vivo study.

The authors compared the renal toxicity of the low osmolality radiocontrast agents, iohexol and ioxaglate, and the ionic agent, iothalamate, at equivalent iodine dose, using experimental models in vitro and in vivo. In isolated perfused rat kidneys, all agents induced comparable biphasic hemodynamic changes, associated with similar declines in glomerular filtration rate (GFR) and tubular necrosis. In two different in vivo models (using multiple insults combined with the administration of radiocontrast), iothalamate appeared to induce more severe morphologic injury. Despite similar nephrotoxic potential in vitro, the newer radiocontrast agents, iohexol and ioxaglate, cause in vivo less renal injury than iothalamate in the experimental models.

Tolerability of hypertonic and isotonic contrast media injected intravenously. A comparative study in the dog.

We examined the use of isotonic and hypertonic contrast media injected intravenously in the dog from the standpoint of cardiovascular tolerance after right atrial injections performed at 2.56 and 5.12 g I/second. The parameters measured were lead II of the electrocardiograph, heart rate, pulmonary and abdominal arterial pressure, and aortic flow. Three contrast media, ioxitalamate, ioxaglate, and iopamidol (two ionic and one nonionic), were compared, either concentrated (32% iodine) or dilute and isotonic with plasma (ioxaglate 160 mg I/mL and iopamidol 128 mg I/mL). At an injection rate of 5.12 g I/second, iopamidol-128 showed lower electrophysiologic tolerability and caused a higher increase in aortic flow than ioxitalamate 160 or ioxaglate 160. These effects may explain the lower radiographic efficacy observed with iopamidol-128 in previous digital subtraction angiography studies.

Carbazochrome attenuates pulmonary dysfunction induced by a radiographic contrast medium in rats.

The effects of carbazochrome sodium sulfonate (AC-17), a capillary stabilizer, on pulmonary edema and dysfunction induced by ioxaglate, an ionic radiographic contrast medium, were evaluated in rats. The pulmonary edema was evaluated by the extravasation of intravenously injected Evans blue into lung tissues, while pulmonary dysfunction was determined by monitoring blood gasses including pO(2). Ioxaglate (4 g I/kg, i.v.) caused a marked increase in vascular permeability and a decrease in arterial pO(2). AC-17 reversed the ioxaglate-induced vascular hyperpermeability in a dose-dependent manner. In addition, AC-17 (10 mg/kg) significantly inhibited the decrease in arterial pO(2). In isolated rat pulmonary mast cells, ioxaglate markedly enhanced the histamine release, which was not affected by AC-17. On the other hand, AC-17 did significantly blocked the hyperpermeability induced in cultured bovine endothelial cells by tryptase, thrombin and proteinase-activated receptor-2 agonist peptide (SLIGKV-NH(2)). These findings suggest that AC-17 blocks radiographic contrast medium-induced pulmonary dysfunction by maintaining the endothelial barrier function. Thus, the compound is potentially useful for the prophylaxis of contrast media-induced acute pulmonary adverse events during angiography.