Marc Heinrich

Nephrotoxicity of Iso-osmolar Iodixanol Compared with Nonionic Low-osmolar Contrast Media: Meta-analysis of Randomized Controlled Trials

PURPOSE To compare the nephrotoxicity of iso-osmolar iodixanol with that of nonionic low-osmolar contrast media (CM) (LOCM) in randomized clinical trials. MATERIALS AND METHODS This meta-analysis was conducted with a systematic search of MEDLINE, EMBASE, BIOSIS, Web of Science, ISI Web of Knowledge, Current Contents Medizin, Cochrane Library (until August 2007), trial registers, conference proceedings, and reference lists to identify studies and with requests from all manufacturers of CM for unidentified studies. Randomized controlled trials assessing serum creatinine levels before and after intravascular application of iodixanol or LOCM were included. The primary outcome measures were the incidence of contrast medium-induced nephropathy (CIN) and change in serum creatinine levels. RESULTS Twenty-five trials were included. Iodixanol did not significantly reduce the risk of CIN (relative risk [RR], 0.80; 95% confidence interval [CI]: 0.61, 1.04; weighted mean difference in serum creatinine increase, 0.01 mg/dL [0.88 mumol/L]; 95% CI: -0.01, 0.03). There was no significant risk reduction after intravenous administration of the CM (RR, 1.08; 95% CI: 0.62, 1.89); subgroup with preexisting renal insufficiency (RR, 1.07; 95% CI: 0.56, 2.02) or after intraarterial administration (RR, 0.68; 95% CI: 0.46, 1.01); subgroup with preexisting renal insufficiency (RR, 0.59; 95% CI: 0.33, 1.07). However, in patients with intraarterial administration and renal insufficiency, the risk of CIN was greater for iohexol than for iodixanol (RR, 0.38; 95% CI: 0.21, 0.68), whereas there was no difference between iodixanol and the other (noniohexol) LOCM (RR, 0.95; 95% CI: 0.50, 1.78). CONCLUSION Iodixanol is not associated with a significantly reduced risk of CIN compared with the LOCM pooled together. However, in patients with intraarterial administration and renal insufficiency, iodixanol is associated with a reduced risk of CIN compared with iohexol, whereas no significant difference between iodixanol and other LOCM could be found.

Progression of Fibrosis in Usual Interstitial Pneumonia: Serial Evaluation of the Native Lung after Single Lung Transplantation

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Usual interstitial pneumonia (UIP) is the histopathological pattern identifying patients with the clinical entity of IPF. Despite aggressive immunosuppressive therapy the clinical course is usually dismal. For selected patients only lung transplantation improves prognosis and quality of life. After lung transplantation patients often receive a potent cyclosporine-based immunosuppressive therapy. Some reports suggest that cyclosporine has the potential to prevent progression of fibrosis. Objective: In patients with single lung transplantation (sLTx) for UIP we evaluated the effect of cyclosporine-based immunosuppressive therapy on progression of fibrosis using a high-resolution computed tomography (HRCT) scoring system. Methods: This retrospective observational study included 13 patients (24–64 years old) with histologically confirmed UIP who had HRCT scans preceding and following sLTx and who survived at least 6 months after sLTx. All patients were initially treated with cyclosporin A, prednisone and azathioprine. Three radiologists analyzed HRCT scans by setting a score regarding fibrosis [fibrosis score (FS); range 0–5 for each lobe] and ground-glass opacity [ground-glass score (GGS); range 0–5 for each lobe]. A comparison of serial changes (interval: 12–96 months posttransplant, 2–4 HRCT examinations/patient) was performed with the sign test. Results: Mean pretransplant FS and GGS of the nontransplanted lung were 1.80 and 1.61, respectively. Comparing pre- and posttransplant HRCT scans, mean lung FS significantly increased (0.35 ± 0.15/year; p = 0.00024), while GGS tended to decrease (0.06 ± 0.26/year; p = 0.5). Conclusion: A cyclosporin A based triple immunosuppressive regimen following sLTx does not seem to prevent progression of the fibrotic changes of the native lung in patients with IPF.

Ormond’s Disease or Secondary Retroperitoneal Fibrosis? An Overview of Retroperitoneal Fibrosis

Retroperitoneal fibrosis represents a rare inflammatory disease. About two thirds of all cases seem to be idiopathic (= Ormonds disease). The remaining one third is secondary and may be ascribed to infections, trauma, radiation therapy, malignant diseases, and the use of certain drugs. Up to 15 % of patients have additional fibrotic processes outside the retroperitoneum. The clinical symptoms of retroperitoneal fibrosis are non-specific. In sonography retroperitoneal fibrosis appears as a retroperitoneal hypoechoic mass which can involve the ureters and thus cause hydronephrosis. Intravenous urography and MR urography can demonstrate the typical triad of medial deviation and extrinsic compression of the ureters and hydronephrosis. CT and MRI are the modalities of choice for the diagnosis and follow-up of this disease. The lesion typically begins at the level of the fourth or fifth lumbar vertebra and appears as a plaque, encasing the aorta and the inferior vena cava and often enveloping and medially displacing the ureters. In unenhanced CT, retroperitoneal fibrosis appears as a mass that is isodense with muscle. When using MRI, the mass is hypointense in T 1-weighted images and of variable intensity in T 2-weighted images according to its stage: it may be hyperintense in early stages, while the tissue may have a low signal in late stages. After the administration of contrast media, enhancement is greatest in the early inflammatory phase and minimal in the late fibrotic phase. Dynamic gadolinium enhancement can be useful for assessing disease activity, monitoring response to treatment, and detecting relapse. To differentiate retroperitoneal masses, diffusion-weighted MRI may provide useful information.

Peripheral Intravenous Power Injection of Iodinated Contrast Media through 22G and 20G Cannulas: Can High Flow Rates Be Achieved Safely? A Clinical Feasibility Study

PURPOSE Modern examination protocols for computed tomography (CT) often require high injection rates of iodinated contrast media (CM). The purpose of this study was to evaluate the maximum achievable flow rates and stability of different peripheral intravenous catheters (IVC) in vitro and to assess the feasibility of higher injection rates through small IVC in vivo. MATERIALS AND METHODS For in vitro experiments flow measurements followed by high pressure testing of different types of IVC (22, 20, and 18 gauge [G]) were performed. For the in vitro study 91 patients with already inserted 22 or 20G IVC who had been referred for CT received Iopamidol (300 mg iodine/ml) at flow rates between 2 and 5 ml/sec. Complications were documented. RESULTS The maximal achievable flow rate of the tested IVC in vitro ranged from 5 to 8 ml/sec. No damage was observed during in vitro testing. The initially targeted in vivo flow rate was dropped in 33 of 91 (36 %) patients because the IVC could not be flushed adequately with saline before CM injection. Extravasation of CM occurred in 2 cases. In the remaining 58 patients the standard CT protocol was performed with flow rates of 3 ml/sec through 22G IVC and 5 ml/sec through 20G IVC, respectively. In this group, the extravasation of CM was observed twice (p > 0.05). CONCLUSION Even with highly viscous CM, high flow rates can be applied in vitro in 22, 20, and 18G IVC without risking material damage. In vivo power injection of iodinated CM through 22G and 20G IVC seems to be safely achievable in the majority of patients with flow rates of up to 3 ml/sec and 5 ml/sec. Extravasation rates do not differ significantly between patients with high-flow or low-flow injections.

Reversibility and Time-dependency of Contrast Medium Induced Inhibition of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (mtt) Conversion in Renal Proximal Tubular Cells In Vitro: Comparison of a Monomeric and a Dimeric Nonionic Iodinated Contrast Medium

Objectives:To evaluate the time-course and reversibility of toxicity of a low-osmolar and an iso-osmolar radiographic contrast medium on renal tubular cell cultures. Materials and Methods:LLC-PK1-cells were incubated with iomeprol, iodixanol, and mannitol (4.7–75 mg I/mL, 2–24 hours). Metabolic activity was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide-(MTT) assay. Results:Iomeprol and iodixanol induced a time- and dose-dependent inhibition of MTT conversion (75%–19% and 70%–23% of control for iomeprol and iodixanol, respectively, at concentrations ranging from 4.7 to 75 mg I/mL after an incubation time of 2 hours and 64%–14% and 65%–12% of control after 24 hours). The mannitol induced inhibition of the MTT conversion was significantly weaker than that induced by iomeprol (99%–47% of control at concentrations corresponding to 4.7–75 mg I/mL after an incubation time of 24 hours, P < 0.001). After 24 hours incubation with iomeprol, iodixanol, or mannitol and a recovery time of 2 hours after removal of the test-solutions, there was only a small inhibition of MTT-conversion (89%, 88%, and 95% of control at 75 mg I/mL). Conclusions:Contrast medium induced cytotoxicity consisted of a reversible part and an irreversible part. There was no difference in cytotoxicity between iomeprol and iodixanol over a broad range of concentrations and incubation-times.

[X-ray-induced DNA double-strand breaks after angiographic examinations of different anatomic regions].

PURPOSE The aim of this study was to investigate DNA double-strand breaks (DSBs) in blood lymphocytes as markers of the biological radiation effects in angiography patients. MATERIALS AND METHODS The method is based on the phosphorylation of the histone variant H 2AX (gamma-H2AX) after formation of DSBs. Blood samples were collected before and up to 24 hours after exposure of 31 patients undergoing angiographies of different body regions. Blood lymphocytes were isolated, fixed, and stained with a specific gamma-H2AX antibody. Distinct foci representing DSBs were enumerated using fluorescence microscopy. Additional in-vitro experiments (10 - 100 mGy) were performed for evaluation of DBS repair. RESULTS 15 minutes after the end of fluoroscopy values between 0.01 and 1.50 DSBs per cell were obtained. The DNA damage level normalized to the dose area product was 0.099 (cardiac angiographies), 0.053 (abdominal angiographies), 0.023 (pelvic/leg angiographies) and 0.004 excess foci/cell/mGym (2) (cerebrovascular angiographies). A linear correlation was found between gamma-H2AX foci levels and the dose area product (abdomen: R (2) = 0.96; pelvis/legs: R 2 = 0.71). In-vivo on average 46 % of DSBs disappeared within 1 hour and 70 % within 2.5 hours. CONCLUSION gamma-H2AX immunofluorescence microscopy is a sensitive and reliable method for the determination of X-ray-induced DSBs during angiography. The DNA damage level depends on the dose, the exposed anatomic region, and the duration/fractionation of the X-ray exposure.

Peripheral Intravenous Power Injection of Iodinated Contrast Media: The Impact of Temperature on Maximum Injection Pressures at Different Cannula Sizes

RATIONALE AND OBJECTIVES Modern computed tomographic scanners and examination protocols often require high injection rates of iodinated contrast media (CM). The purpose of this study was to investigate the maximum injection pressures (MIPs) with different CM at different temperatures in the most common intravenous cannula (IVC) sizes. MATERIALS AND METHODS Three IVC sizes, 22, 20, and 18 gauge, were evaluated. All examinations were performed with a pressure-limited (300 psi) power injector. The MIPs of three different CM (Solutrast 300, Imeron 350, and Imeron 400) were measured at room temperature (20 degrees C) and at 37 degrees C using increasing flow rates (1-9 mL/s). The intactness of the IVCs was checked after injection. RESULTS Heating the CM led to reductions in injection pressures (P < .001). Using constant flow rates, the difference in MIP between 20-gauge and 22-gauge IVCs was higher than that between 20-gauge and 18-gauge IVCs. By heating the CM, the manufacturers suggested operating pressure limit was exceeded at higher flow rates, such as with an 18-gauge cannula at 8 mL/s instead of 6 mL/s using warmed iomeprol 400. Even with pressures of up to 159.7 psi, none of the IVCs ruptured. CONCLUSIONS Heating of CM effectively reduces MIPs using power injection in common IVCs. Although the manufacturers suggested MIP was exceeded at higher flow rates, safe CM injection seems to be possible even in small cannulas using power injection. The compilation of the obtained data is meant to serve as guidance for future decisions on parameters of the power injection of iodinated CM.

Effects of dimeric radiographic contrast medium iotrolan on Swine renal arteries: comparison with monomeric contrast media iohexol and iomeprol.

Rationale and Objectives:To investigate whether the lower incidence of vasodilatation upon vascular injection of iotrolan, as compared with monomeric contrast media, is solely the result of its isotonicity. Materials and Methods:In an organ bath, isolated segments of swine renal arteries, uncontracted or precontracted by 10 &mgr;m phenylephrine, were incubated with increasing concentrations of iotrolan-300, iohexol-300, iomeprol-300, iomeprol-150, and mannitol solutions with the same molarity as the contrast media. Results:At equal iodine and equimolar concentrations, iotrolan-300 relaxed precontracted arteries less than iohexol-300, iomeprol-300, and iomeprol-150, which was, like iotrolan-300, iso-osmolar to blood (P < 0.05). There was no significant difference between iohexol-300 and iomeprol-300 (P > 0.05). Iotrolan had no significant effect on the basal tonus of the vessels whereas iohexol and iomeprol induced a slight relaxation. Conclusions:Iotrolan, even at equimolar concentrations, resulted in less vasorelaxation than iohexol and iomeprol. Both osmolarity and chemotoxicity contribute to the greater vasorelaxant effect on swine renal artery of monomeric contrast media when compared to that of the nonionic dimeric contrast medium, iotrolan.

Vergleich der Nephrotoxizität des iso-osmolaren Iodixanol mit der von nicht-ionischen, niedrig-osmolaren Röntgenkontrastmitteln: Eine Meta-Analyse randomisierter, klinischer Studien

Ziele: Ob das iso-osmolare Iodixanol weniger nephrotoxisch ist als niedrig-osmolare Kontrastmittel (KM) wird kontrovers diskutiert. Unser Ziel war es, die Nephrotoxizitat von Iodixanol mit der von nicht-ionischen, niedrig-osmolaren KM in randomisierten klinischen Studien zu vergleichen. Methode: Es erfolgte eine systematische Literatursuche in Medline, Embase, Biosis, ISI-Web-of-Science, CC-Medizin, Cochrane Library, Studiendatenbanken und Konferenzabstracts. 25 randomisierte Studien mit 3270 Patienten wurden eingeschlossen. Meta-Analysen erfolgten fur die Haufigkeit einer Kontrastmittel induzierten Nephropathie (CIN) und fur den Anstieg des Serumkreatinins von Patienten, die Iodixanol erhielten im Vergleich mit denen, die nicht-ionische, niedrig-osmolare KM erhielten. Sowohl Modelle mit festen als auch mit zufalligen Effekten wurden verwendet, um die Ergebnisse zu poolen. Ergebnis: Das Risiko zur Entwicklung einer CIN war bei Applikation von Iodixanol nicht signifikant geringer als bei Anwendung von nicht-ionischen, niedrig-osmolaren KM mit einem relativen Risiko (RR) von 0.80 (95% CI [0.61–1.04], p=0.10, Serumkreatininanstieg ≥25% als CIN-Definition, falls Daten fur diese Definition vorhanden waren). Es gab keine signifikante statistische Heterogenitat der Studienergebnisse bei Verwendung dieser CIN-Definition (I2=0%, p=0.55). Es zeigte sich auch keine signifikante Reduktion des RR unter Verwendung anderer CIN-Definitionen, beim Poolen der Differenz des Serumkreatininanstiegs (0.01 [-0.01–0.03], p=0.39) und bei Subgruppen- und Sensitivitatsanalysen. Meta-Regression und Subgruppenanalysen wiesen ein signifikant geringeres Risiko einer CIN fur Iodixanol im Vergleich mit Iohexol nach (0.45 [0.26–0.76], p<0.01), wohingegen es keinen Unterschied zwischen Iodixanol und den anderen niedrig-osmolaren KM gab (0.97 [0.72–1.32], p=0.86). Schlussfolgerung: Iodixanol ist weniger nephrotoxisch als Iohexol, wohingegen es keinen Unterschied zwischen Iodixanol und den anderen nicht-ionischen, niedrig-osmolaren KM gibt. Korrespondierender Autor: Heinrich MC Universitatsklinikum Erlangen, Radiologisches Institut, Maximiliansplatz 1, 91054 Erlangen E-Mail: marc.heinrich@uk-erlangen.de