Nonionic Iso-osmolar Contrast Research Articles

Anti-Apoptotic and Antioxidant Effects of 3-Epi-Iso-Seco-Tanapartholide Isolated from Artemisia Argyi Against Iodixanol-Induced Kidney Epithelial Cell Death.

Iodixanol is a non-ionic iso-osmolar contrast agent, but it is a risk factor for kidney damage and increases morbidity and mortality. In this study, we investigated the effect of 9 sesquiterpenes isolated from mugwort (Artemisia argyi) in contrast agent-induced cytotoxicity in LLC-PK1 cells. Cells were exposed to nine sesquiterpene compounds for 2 h, followed by incubation with iodixanol for 3 h. Cell viability was assessed using the Ez-Cytox assay. The level of reactive oxygen species was measured using 2′,7′-dichlorodihydrofluorescein diacetate staining. Apoptotic cell death was detected using annexin V/PI staining. In addition, immunofluorescence staining and western blotting were performed using antibodies against proteins related to apoptosis, oxidative stress, and MAPK pathways. The most effective 3-epi-iso-seco-tanapartholide (compound 8) among the 9 sesquiterpene compounds protected LLC-PK1 cells from iodixanol-induced cytotoxicity, oxidative stress, and apoptotic cell death. Pretreatment with compound 8 reversed iodixanol-induced increases in the expression of JNK, ERK, p38, Bax, caspase-3, and caspase-9. It also reversed the iodixanol-induced decrease in Bcl-2 expression. Furthermore, pretreatment with compound 8 caused nuclear translocation of Nrf2 and upregulated HO-1 via the Nrf2 pathway in iodixanol-treated LLC-PK1 cells. Thus, we demonstrated here that compound 8 isolated from A. argyi has the potential to effectively prevent iodixanol-induced kidney epithelial cell death via the caspase-3/MAPK pathways and HO-1 via the Nrf2 pathway.

One-year results of the ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) Study.

Long-term clinical outcomes after exposure to non-ionic iso-osmolar contrast medium (IOCM) or ionic low-osmolar CM (LOCM) in patients with chronic kidney disease (CKD) undergoing coronary angiography are unclear. The ICON trial was a prospective, double-blinded, multicentre study that randomly assigned 146 patients with CKD undergoing coronary angiography with or without percutaneous coronary intervention to the non-ionic IOCM Iodixanol or the ionic LOCM Ioxaglate. We report the 1-year clinical outcomes. After randomization, baseline and procedural characteristics were well-matched between the two groups. At 1 year, three deaths (4.1%) occurred in the ioxaglate and nine deaths in the iodixanol group (13.6%, P = 0.07). The cardiac death rate at 1 year was 2.7% in the ioxaglate group and 9.1% in the iodixanol group (P = 0.07). There were no significant differences in the rates of myocardial infarction (1.4% vs. 1.5%; P = 1.00) and repeated revascularization (6.8% vs. 9.1%; P = 0.75). The use of ionic LOCM ioxaglate was associated with a numerically lower mortality at 1 year as compared to iodixanol in patients who underwent cardiac catheterization. Future studies evaluating long-term safety following exposure to different types of CM are warranted.

Contrast nephropathy in children.

Contrast-induced nephropathy (CIN) remains a common and potentially serious complication in at risk patients after exposure to contrast agents. Risk factors for CIN include chronic kidney disease, hypotension, diabetes mellitus, recent previous exposure to contrast and all of these are potentially additive. Therefore, careful pre-procedural risk stratification is important. In high-risk patients, contrast should be avoided if possible. If avoidance is not possible, the volume of contrast should be minimized and the type of contrast used should if possible be non-ionic iso-osmolar contrast. In view of the clinical importance of CIN, numerous potential risk-reduction strategies have been evaluated. Adequate intravenous volume expansion with isotonic crystalloid (1.0-1.5 mL/kg per hr) for 3-12 hr before the procedure and continued for 6-24 hr afterward can lessen the probability of CIN in patients at risk. But there are insufficient data on oral fluids as a preventive strategy. Nephrotoxic drugs should be withdrawn before contrast administration in patients at risk for CIN. No adjunctive medical or mechanical treatment has been proved to be efficacious in reducing risk for CIN including prophylactic hemodialysis and hemofiltration, N-acetylcysteine, fenoldopam, dopamine, calcium channel blockers, atrial natriuretic peptide, and L-arginine. The CIN Consensus Working Panel considered that, of the pharmacologic agents that have been evaluated, theophylline, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), ascorbic acid, and prostaglandin E deserve further evaluation.

Decreased infarct volume and intracranial hemorrhage associated with intra-arterial nonionic iso-osmolar contrast material in an MCA occlusion/reperfusion model.

Infarct volume and intracranial hemorrhage after reperfusion with nonionic low-osmolar and iso-osmolar iodinated IRCM has not been previously compared. We postulated that iso-osmolar and low-osmolar iodinated contrast media exert varied effects on cerebral infarct after intra-arterial injection. We compared infarct volume and hemorrhagic changes following intra-arterial infusion of iodixanol, iopamidol, or normal saline in a rat MCA occlusion/reperfusion model. Infarct was induced in 30 rats by a previously validated method of MCA suture occlusion. Reperfusion was performed after 5 hours with either iodixanol (n = 9), iopamidol (n = 12), or saline (n = 9). MR images were obtained at both 6 and 24 hours after ischemia, followed by sacrifice. Infarct volume was measured with T2WI and DWI by semiautomatic segmentation. Incidence and area of hemorrhage were measured on brain sections postmortem. T2WI mean infarct volumes were 242 ± 89, 324 ± 70, and 345 ± 92 mm(3) at 6 hours, and 341 ± 147,470 ± 91, and 462 ± 71 mm(3) at 24 hours in the iodixanol, iopamidol, and saline groups, respectively. Differences in infarct volume among groups were significant at 6 hours (P < .03) and 24 hours (P < .05). In the iodixanol, iopamidol, and saline groups, mean areas for cortical intracranial hemorrhage were 0.8, 18.2, and 25.7 mm(2); and 28, 31, and 56.7 mm(2), respectively, for deep intracranial hemorrhage. The differences in intracranial hemorrhage area among groups were statistically significant for cortical intracranial hemorrhage (P < .01). Intra-arterial infusion of nonionic iso-osmolar iodixanol showed reduced infarct volume and reduced cortical intracranial hemorrhage areas in comparison with nonionic low-osmolar iopamidol and saline. Our results may be relevant in the setting of intra-arterial therapy for acute stroke in humans, warranting further investigation.

Torsade de pointes induced by ioxaglate intracoronary injection in patients with pre‐existent drug‐induced QT prolongation: case reports and review of literature

We report two cases of torsade de pointes directly related to intracoronary contrast media injection in patients without previous history of neither arrhythmia nor syncope but chronically treated with a drug prolonging ventricular repolarization. We discussed the effects of the contrast medium used on repolarization and concluded that three suggestions may be highlighted from the case reports presented and from the literature: (i) a QT prolongation should be systematically searched before coronary angiography; (ii) it seems important to correct QT prolongation when it results from a reversible cause (such as drug-induced) before nonurgent coronary angiography; and (iii) if there is no reversible cause explaining QT prolongation, contrast media should be used cautiously in such patient and nonionic iso-osmolar contrast media should be preferred.

Effect on renal function of an iso-osmolar contrast agent in patients with monoclonal gammopathies

To assess the safety of the non-ionic iso-osmolar contrast agent iodixanol on renal function in patients with monoclonal gammopathies undergoing CT. We explored the effect of iodixanol on renal function in 30 patients with monoclonal gammopathies and 20 oncological patients with a normal electrophoretic profile (control group). The parameters used to estimate renal function were: serum creatinine, eGFR (determined 24 h before and 48 h after the administration of iodixanol), and urinary excretion of Neutrophil Gelatinase-Associated Lipocalin (NGAL) determined 2 h and 24 h after. Serum creatinine was also determined 1 month after the administration of iodixanol. No significant increase in serum creatinine values were observed in the monoclonal gammopathies group and in 19/20 patients in the control group. Only 1 patient in the control group developed a transient contrast agent-induced nephropathy. We found no statistically significant difference between the two groups regarding the percentage variation from baseline values of serum creatinine, creatinine clearance, NGAL 2 h after, and eGFR. Whereas NGAL at 24 h showed a statistically significant increase in patients with Monoclonal gammopathies. The use of iodixanol appears to be safe in patients with monoclonal gammopathies and an eGFR≥ 60 ml/min/1.73 mq.

Ionic Low-Osmolar Versus Nonionic Iso-Osmolar Contrast Media to Obviate Worsening Nephropathy After Angioplasty in Chronic Renal Failure Patients: The ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) Study

This randomized, prospective, double-blind, multicenter study compared nephrotoxicity of the nonionic iso-osmolar contrast media (CM) iodixanol versus the ionic low-osmolar CM ioxaglate in patients with chronic renal insufficiency undergoing coronary angiography. The properties of iodinated CM might contribute to the incidence of contrast-induced nephropathy (CIN). Patients with renal impairment undergoing coronary angiography were randomly assigned to iodixanol (n = 72) or ioxaglate (n = 74). Baseline characteristics were well-matched between the 2 groups. The predicted risk score for CIN was similar in the iodixanol and in the ioxaglate groups (11.9 +/- 4.1 vs. 11.8 +/- 4.1), as was the use of N-acetylcysteine (70% vs. 73%). The primary end point of the study, median peak increase of serum creatinine from day 0 through day 3 after angiography, did not differ between the iodixanol (0.09 mg/dl; interquartile range 0.00 to 0.30 mg/dl) and the ioxaglate (0.15 mg/dl; interquartile range 0.00 to 0.40 mg/dl; p = 0.07) groups. The percentages of patients with a peak increase of serum creatinine >or=0.5 mg/dl (15.9% in iodixanol vs. 18.2% in ioxaglate), >or=1.0 mg/dl (1.4% vs. 4.5%), and >or=25% or >or=0.5 mg/dl (15.9% vs. 24.2%, respectively) also did not differ significantly between the 2 groups. In high-risk patients undergoing coronary angiographic procedures, use of the nonionic iso-osmolar CM iodixanol does not reduce renal deterioration in patients with renal impairment, compared with the ionic low-osmolar CM ioxaglate. Given that the study was underpowered to compare nephrotoxicity of the 2 groups under the active medical protection of CIN, a larger randomized study is warranted that will enroll patients with higher risks of CIN under a strict control of hydration regimens and adjunctive medications.

Renal Insufficiency Following Radiocontrast Exposure Trial (REINFORCE): a randomized comparison of sodium bicarbonate versus sodium chloride hydration for the prevention of contrast-induced nephropathy

For the prevention of contrast-induced nephropathy (CIN) after coronary angiography, hydration by 0.9% sodium chloride solution and N-acetylcysteine is currently recommended. However, it is unclear whether volume supplementation with sodium bicarbonate is better than with sodium chloride when used in conjunction with nonionic, low-osmolar iopamidol. The aim of this study was to analyze and compare the effects of sodium bicarbonate and sodium chloride on renal function in 145 patients exposed to nonionic iso-osmolar contrast medium iodixanol in a randomized study. Renal Insufficiency Following Radiocontrast Exposure is a prospective, randomized, single-center, double-blinded trial of 145 patients (age 72.6+/-6.7 years) with elevated baseline serum creatinine levels (mean 132.6+/-29.3 micromol/l). Eligible patients were randomized to either a 154 mEq/l infusion of sodium bicarbonate (n=71, group I) or sodium chloride 0.9% solution (n=74, group II). The primary endpoint was serum creatinine elevation beyond 25% or 44 micromol/l on the first or second day following exposure to the contrast medium. Serum creatinine, serum cystatin C, plasma viscosity, urinary enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase, and alpha1-microglobulin were measured at baseline and on days 1 and 2 after contrast medium administration. An overall proportion of five CIN (3.4%) was observed with equal distribution among the groups (4.2% in sodium bicarbonate group vs. 2.7% in sodium chloride group; P=0.614). Parameters of renal function demonstrated no differences between the two hydration regimens on day 1 after angiography; even on day 2 most parameters were similar in groups I and II. Renal Insufficiency Following Radiocontrast Exposure demonstrates a homogeneously low rate of CIN after exposure to nonionic, iso-osmolar iodixanol regardless of the use of either bicarbonate sodium or sodium chloride solution for volume supplementation. Low-toxicity contrast media and any hydration may offset potential antioxidant effects of sodium bicarbonate.

Stability of Balloon-Retention Gastrostomy Tubes with Different Concentrations of Contrast Material: In Vitro Study

The purpose of this study was to determine the performance of two balloon-retention-type gastrostomy tubes when the balloons are inflated with two types of contrast materials at different concentrations. Two commonly used balloon-retention-type tubes (MIC and Tri-Funnel) were inflated to the manufacturer's recommended volumes (4 and 20 cm(3), respectively) with normal saline or normal saline plus different concentrations of contrast material. Five tubes of each brand were inflated with normal saline and 0%, 25%, 50%, 75%, and 100% contrast material dilutions, using either nonionic hyperosmolar contrast, or nonionic iso-osmolar contrast. The tubes were submerged in a glass basin containing a solution with a pH of 4. Every week the tubes were visually inspected to determine the integrity of the balloons, and the diameter of the balloons was measured with a caliper. The tests were repeated every week for a total of 12 weeks. The MIC balloons deflated slightly faster over time than the Tri-Funnel balloons. The Tri-Funnel balloons remained relatively stable over the study period for the different concentrations of contrast materials. The deflation rates of the MIC balloons were proportionally related to the concentration of saline and inversely related to the concentration of the contrast material. At high contrast material concentrations, solidification of the balloons was observed. In conclusion, this in vitro study confirms that the use of diluted amounts of nonionic contrast materials is safe for inflating the balloons of two types of balloon-retention feeding tubes. High concentrations of contrast could result in solidification of the balloons and should be avoided.

Renal safety of iodixanol

Iodinated contrast is a mainstay for diagnostic and interventional procedures performed by cardiologists, radiologists and other specialists. With the emergence of computed tomographic techniques for the evaluation of cardiac disease, malignancies, trauma and a variety of other internal disorders, the use of iodinated contrast is expected to increase dramatically over the next few years. There has been considerable refinement over the past decades from ionic high-osmolar, to nonionic low-osmolar and finally to nonionic iso-osmolar contrast. Iodixanol is the only nonionic iso-osmolar contrast approved for intravascular use. This contrast agent has the lowest rates of systemic and renal adverse events. Clinical trials have demonstrated the lowest rates of contrast-induced nephropathy among all currently available forms of iodinated contrast. Specifically, iodixanol has been associated with a 71% relative risk reduction for contrast-induced nephropathy compared with low-osmolar agents in head-to-head randomized trials. This article reviews the structure, pharmacology and outcomes associated with iodixanol.

Optimal Contrast Agents for Vascular Imaging on Computed Tomography: Iodixanol Versus Iohexol 1

Dimeric nonionic iodinated contrast has a lower osmolality than monomeric nonionic iodinated contrast but is available at lower iodine concentrations. Less dilution of intravascular fluid by influx from the extravascular space is proposed to occur with decreasing osmolality. The purpose of this study was to determine if a dimeric nonionic iso-osmolar contrast agent (iodixanol) gives equal vascular enhancement compared with a monomeric nonionic hyperosmolar contrast agent (iohexol). A dynamic single-level computed tomography (CT) scan was performed of the abdominal aorta of 12 sedated rabbits using a four-row multidetector CT scanner following injection of 1.5 mL contrast/kg body weight at 2 mL/sec. The rabbits were injected with the dimeric contrast agent iodixanol (Visipaque 320; Amersham Health) or the monomeric contrast agent iohexol (Omnipaque 350; Amersham Health). The order of the type of contrast media injected was randomized for each rabbit, and the interval between injections was 2 weeks. Using the 2.5-mm detectors, four contiguous 3-mm contrast-enhanced scans were obtained at a single level every 5 seconds for 120 seconds (total of 24 scans) with a kVp of 120, mA.s of 110, field of view of 106 mm, and soft tissue reconstruction algorithm. A single level was chosen to measure the attenuation of the abdominal aorta at 5-second intervals. The mean attenuation and standard deviation values were recorded for the whole aorta, for the central half of the vessel, and for the peripheral half of the vessel. A log-log transformation of the data was performed and regression analysis was done on the outcomes of interest (e.g., mean, standard deviation) on time for each region. There was no statistically significant difference in mean attenuation for the whole aorta for iodixanol and iohexol (P = .918) even though the iodine content was 9.3% less with the dimeric iodixanol. The time-attenuation curve of iodixanol paralleled that of iohexol for all time points. The mean attenuation values of the central half of the aorta (P = .354) and peripheral half of the aorta (P = .758) were also not statistically different for the two contrast agents. The vascular attenuation provided by a 9.3% lower iodine concentration of iso-osmolar iodixanol is equal to that given by hyperosmolar iohexol. This suggests that there is less intravascular dilution of iso-osmolar contrast. The enhancement across the cross section of the vessel is also similar for both contrast agents. This suggests the vascular studies with iodixanol and iohexol are of equal quality even when a lower dose of iodine is given with iodixanol. It is relevant for patients with borderline or diminished renal function in whom less volume of contrast may be administered.

Recent advances in the prevention of radiocontrast-induced nephropathy

Radiocontrast nephropathy is a serious clinical problem associated with increased morbidity and mortality, particularly in patients with chronic renal failure. The optimal strategy to prevent radiocontrast nephropathy has not been established. This article reviews recent clinical researches concerning new developments in the prevention of radiocontrast nephropathy and analyzes unresolved issues. Among all prophylactic measures that have been proposed, periprocedural hydration with isotonic saline has demonstrated effectiveness in the prevention of radiocontrast nephropathy. Thus, it remains the most frequently applied measure in clinical practice. Recently, additional benefit has been shown to derive from the infusion of isotonic alkalizing (sodium bicarbonate), instead of isotonic (sodium chloride) solutions. The use of nonionic low-osmolar and, more recently, nonionic iso-osmolar contrast agents has been demonstrated to significantly reduce the risk of radiocontrast nephropathy in patients with renal impairment, in comparison with hyperosmolar contrast media. Recently, periprocedural hemofiltration has emerged as a safe and very effective strategy to prevent radiocontrast nephropathy and to reduce its associated poor outcome in patients with severe chronic renal failure. In the past few years, several trials with acetylcysteine have shown conflicting results. Nevertheless, most of them indicated that acetylcysteine, particularly when associated with adequate hydration, might be useful in preventing radiocontrast nephropathy in patients with renal impairment. A possible dose-dependent protective effect has been suggested by more recent trials that included patients undergoing coronary interventional procedures requiring large contrast volume. Adequate prophylaxis is needed to reduce the high morbidity and mortality associated with radiocontrast nephropathy in high-risk patients. By reviewing the available evidence from clinical trials, this article provides an overview of current strategies and unresolved issues concerning the prevention of radiocontrast nephropathy.

Intravenous single dose toxicity of iodixanol, a new nonionic iso-osmolar contrast medium, in mice, rats and monkeys

The single-dose intravenous toxicities of iodixanol, a new nonionic iso-osmolar contrast medium, were investigated in mice, rats and monkeys. The LD50 values were estimated to be 17.9 gI/kg for male mice and 16.2 gI/kg for female mice, 18.8 gI/kg for male rats and 22.0 gI/kg for female rats, and more than 10.0 gI/kg for monkeys. There was no marked sex difference in mice or rats, nor any significant difference observed between these two rodent species. Decrease in spontaneous locomotor activity, ptosis, respiratory depression and abdominal posture were observed in many mice and rats. These signs disappeared mostly by 8 days after dosing in surviving animals. Death occurred between immediately and 4 days after dosing in mice, and between immediately and 14 days after dosing in rats. Transient depression of body weight gain was observed in the surviving mice and rats by 7 days after dosing. Histological examinations revealed congestion or hemorrhage in the renal medulla, vacuolation or necrosis of the renal proximal tubular epithelium in mice and rats that died and vacuolation of the renal proximal tubular epithelium in surviving rats. There were no significant treatment-related changes in the laboratory and pathological examinations in monkeys.

Systemic, Pulmonary and Renal Haemodynamic and Renal Morphologic Effects of Intravenously Infused Iodixanol

The systemic, pulmonary and renal haemodynamic effects following an intravenous infusion (1 ml/s, 4 ml/kg) of a non-ionic iso-osmolar contrast medium (iodixanol) were investigated in 8 pigs. Histopathologic changes occurring after infusion of iodixanol were studied by repeated renal biopsies. Iodixanol caused a significant increase of cardiac output, mean right atrial pressure, mean pulmonary arterial pressure, mean pulmonary arterial occlusion pressure and mean arterial pressure. There was a decrease of the systemic and pulmonary vascular resistances. Most renal biopsies showed no pathologic findings after infusion of iodixanol but in 3 specimens proteinaceous content was observed 15 min after infusion.

Systemic, Pulmonary and Renal Haemodynamic and Renal Morphologic Effects of Intravenously Infused Iodixanol

The systemic, pulmonary and renal haemodynamic effects following an intravenous infusion (1 ml/s, 4 ml/kg) of a non-ionic iso-osmolar contrast medium (iodixanol) were investigated in 8 pigs. Histopathologic changes occurring after infusion of iodixanol were studied by repeated renal biopsies. Iodixanol caused a significant increase of cardiac output, mean right atrial pressure, mean pulmonary arterial pressure, mean pulmonary arterial occlusion pressure and mean arterial pressure. There was a decrease of the systemic and pulmonary vascular resistances. Most renal biopsies showed no pathologic findings after infusion of iodixanol but in 3 specimens proteinaceous content was observed 15 min after infusion.

Systemic, Pulmonary and Renal Haemodynamic and Renal Morphologic Effects of Intravenously Infused Iodixanol

The systemic, pulmonary and renal haemodynamic effects following an intravenous infusion (1 ml/s, 4 ml/kg) of a non-ionic isoosmolar contrast medium (iodixanol) were investigated in 8 pigs. Histopathologic changes occurring after infusion of iodixanol were studied by repeated renal biopsies. Iodixanol caused a significant increase of cardiac output, mean right atrial pressure, mean pulmonary arterial pressure, mean pulmonary arterial occlusion pressure and mean arterial pressure. There was a decrease of the systemic and pulmonary vascular resistances. Most renal biopsies showed no pathologic findings after infusion of iodixanol but in 3 specimens proteinaceous content was observed 15 min after infusion.