Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in pathological tissue damage. Mitochondrial manganese superoxide dismutase (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir (MnDPDP) as a magnetic resonance imaging (MRI) contrast agent, it was discovered that MnDPDP and its metabolite manganese pyridoxyl ethyldiamine (MnPLED) possessed SOD mimetic activity. MnDPDP has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. Whereas MRI contrast depends on release of Mn(2+), the SOD mimetic activity depends on Mn(2+) that remains bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn(2+) and has superior therapeutic activity. Ca4Mn(DPDP)5 is presently being explored as a chemotherapy adjunct in a clinical multicenter Phase II study in patients with metastatic colorectal cancer.

Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines.

PURPOSE: To update the guidelines of the Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) on nephrogenic systemic fibrosis and gadolinium-based contrast media. AREAS COVERED: Topics reviewed include the history, clinical features and prevalence of nephrogenic systemic fibrosis and the current understanding of its pathophysiology. The risk factors for NSF are discussed and prophylactic measures are recommended. The stability of the different gadolinium-based contrast media and the potential long-term effects of gadolinium in the body have also been reviewed.

Are intravenous injections of contrast media really less nephrotoxic than intra-arterial injections?

UNLABELLED: We oppose the opinion that the intra-arterial administration of iodine-based contrast media (CM) appears to pose a greater risk of contrast medium-induced nephropathy (CIN) than intravenous administration since 1) in intra-arterial coronary procedures and most other intra-arterial angiographic examinations, CM injections are also intravenous relative to the kidneys, 2) there is a lack of comparative trials studying the risk of CIN between intra-arterial and intravenous procedures with matched risk factors and CM doses, 3) a bias selection of patients with fewer risk factors may explain the seemingly lower rate of CIN after CT in comparison with coronary interventions, 4) the rate of CIN following intra-arterial coronary procedures may also be exaggerated owing to other causes of acute kidney failure, such as haemodynamic instability and microembolisation, 5) roughly the same gram-iodine/GFR ratio (≈1:1) as a limit of relatively safe CM doses has preliminarily been found for both intravenous CT and intra-arterial coronary procedures and 6) the substantially higher injected intravenous CM dose rate during CT relative to an intra-arterial coronary procedure might actually pose a higher risk of CIN following CT. KEY POINTS: • Most intra-arterial injections of contrast media are intravenous relative to the kidneys. • No evidence that intravenous CM injections should be less nephrotoxic than intra-arterial. • Considerably higher dose rates of CM are used for CT relative to intra-arterial procedures. • Higher dose rates may pose higher nephrotoxic risk for intravenous based CT studies.

Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines.

PURPOSE: The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 1999 guidelines on contrast medium-induced nephropathy (CIN). AREAS COVERED: Topics reviewed include the definition of CIN, the choice of contrast medium, the prophylactic measures used to reduce the incidence of CIN, and the management of patients receiving metformin. Key Points • Definition, risk factors and prevention of contrast medium induced nephropathy are reviewed. • CIN risk is lower with intravenous than intra-arterial iodinated contrast medium. • eGFR of 45 ml/min/1.73 m (2) is CIN risk threshold for intravenous contrast medium. • Hydration with either saline or sodium bicarbonate reduces CIN incidence. • Patients with eGFR ≥ 60 ml/min/1.73 m (2) receiving contrast medium can continue metformin normally.

Late adverse reactions to intravascular iodine based contrast media: an update.

DEFINITION: Late adverse reactions (LAR) to contrast media (CM) are defined as reactions occurring 1 h to 1 week after exposure. NEED FOR REVIEW: In view of more prospective studies of LAR and new data about their pathophysiology, the Contrast Medium Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) reviewed the literature on LAR and updated their guidelines. CLINICAL FEATURES AND PATHOLOGY: LAR after CM include symptoms such as nausea, vomiting, headache, itching, skin rash, musculoskeletal pain, and fever. Skin reactions are well-documented LAR to CM with an incidence of approximately 2%-4% after nonionic monomers. LAR are commoner by a factor of three to four after nonionic dimers. The commonest skin reactions are maculopapular rashes, erythema and skin swelling. These reactions are T cell-mediated immune reactions, and the diagnosis may be confirmed using skin tests (patch or delayed reading intradermal). The main risk factors for LAR are a previous reaction to contrast medium, a history of allergy, and interleukin-2 treatment. Most skin reactions are mild or moderate and self-limiting. MANAGEMENT: Management is symptomatic and similar to the management of other drug-induced skin reactions. To reduce the risk of repeat reactions avoidance of the relevant CM and any cross-reacting agents identified by skin testing is recommended.

Iodine contrast iso-attenuating with diagnostic gadolinium doses in CTA and angiography results in ultra-low iodine doses. A way to avoid both CIN and NSF in azotemic patients?

OBJECTIVES: To establish iodine (I) contrast medium (CM) doses iso-attenuating with gadolinium (Gd) CM doses regarded diagnostic in CTA and percutaneous catheter-angiography/vascular interventions (PCA/PVI) in azotemic patients. METHODS: CT Hounsfield units (HU) were measured in 20-mL syringes containing 0.01/0.02,/0.05/0.1 mmol/mL of iodine or gadolinium atoms and placed in phantoms. Relative contrast were measured in 20-mL syringes filled with iohexol at 35/50/70/90/110/140 mg I/mL and 0.5 M gadodiamide using radiofluoroscopy (RF), digital radiography (DX) and x-ray angiography (XA) systems. Clinical doses of Gd-CM at CTA/PCA/PVI were reviewed. RESULTS: At CT 91-116 and 104-125 mg I/mL in the chest and abdominal phantoms, respectively, were iso-attenuating with 0.5 M Gd at 80-140 kVp. At RF/DX/XA systems 35-90 mg I/mL were iso-attenuating with 0.5 M gadodiamide at 60-115 kVp. Clinically, 60 mL 91-125 mg I/mL (5.5-7.5 gram-iodine) at 80-140 kVp CTA and 60 mL of 35-90 mg I/mL (2.1-5.4 gram-iodine) at 60-115 kVp PCA/PVI would be iso-attenuating with 60 mL 0.5 M Gd-CM (=0.4 mmol Gd/kg in a 75-kg person). CONCLUSIONS: Meticulous examination technique and judicious use of ultra-low I-CM doses iso-attenuating with diagnostic Gd-CM doses in CTA and PCA/PVI may minimise the risk of nephrotoxicity in azotemic patients, while there is no risk of NSF.

Reducing the risk of iodine-based and MRI contrast media administration: recommendation for a questionnaire at the time of booking.

This paper presents a practical questionnaire to be used when a contrast medium examination is requested. The questionnaire is based on the guidelines from the European Society of Urogenital Radiology. Its aim is to identify patients at increased risk of clinically relevant renal and non-renal adverse reactions to iodine-based and MRI contrast agents. The questionnaire should be completed by the referring physician when the examination is requested.

Iodixanol 320 results in better renal tolerance and radiodensity than do gadolinium-based contrast media: arteriography in ischemic porcine kidneys.

PURPOSE: To prospectively compare nephrotoxicity and radiodensity of plasma hyperosmotic gadolinium chelates (attenuation-osmotic ratio of 1:1) with those of plasma iso-osmotic iodine-based contrast media (attenuation-osmotic ratio of 3:1 or 6:1) after renal arteriography in ischemic porcine kidneys. MATERIALS AND METHODS: The local animal care committee approved this study. The following contrast media were used: (a) iodixanol (150 mg of iodine per milliliter and 320 mg I/mL, 0.29 osm/kg H(2)O), (b) iopromide (150 mg I/mL, 0.34 osm/kg), (c) 0.5 mol/L gadodiamide (0.78 osm/kg), and (d) 1.0 mol/L gadobutrol (1.6 osm/kg). After left-sided nephrectomy, contrast media (3 mL per kilogram of body weight) were injected (20 mL/min) in a noncrossover design into the right renal artery of pigs during a 10-minute ischemic period. There were eight pigs in each group and one group for each contrast medium. We compared histomorphology, radiographic contrast medium excretion, subjective radiodensity of nephrograms (70 kVp) at the end of injection, and contrast medium plasma half-life elimination times 1-3 hours after injection. Longer elimination times resulted in lower glomerular filtration rates. RESULTS: Gadobutrol caused extensive tubular necrosis and moderate glomerular necrosis; gadodiamide and iopromide, minimal to mild tubular necrosis; and iodixanol, no necrosis. Gadobutrol was the only contrast medium to show no sign of excretion, and its plasma half-life elimination time (median, 1103 minutes; P < .001) was significantly longer than that of other contrast agents. Gadodiamide had a significantly longer plasma half-life elimination time (median, 209 minutes; P = .01) than did iodine-based contrast media (median, 136-142 minutes). The 320 mg I/mL dose of iodixanol had the highest radiodensity, whereas gadodiamide had the lowest radiodensity. The radiodensity of the 320 mg I/mL dose of iodixanol was greater than that of the 150 mg I/mL dose of iodixanol, which was equal to the radiodensities of the 150 mg I/mL dose of iopromide and 1.0 mol/L gadobutrol, which in turn were greater than that of 0.5 mol/L gadodiamide. CONCLUSION: Plasma iso-osmotic iodine-based contrast media used at commercially available concentrations have superior attenuation and nephrotoxic profiles compared with equal volumes of hyperosmotic nonionic 0.5-1.0 mol/L gadolinium-based contrast media when performing renal arteriographic procedures.

Signs in vector-electrocardiography (VECG) predicting the fibrillatory propensity of iodixanol and mannitol solutions after injection into the left coronary artery of pigs.

RATIONALE AND OBJECTIVES: To find signs in vector-electrocardiography (VECG) predicting the ventricular fibrillatory propensity (VF-PROP) of iodixanol and mannitol solutions after injection into the left coronary artery (LCA) of pigs. MATERIALS AND METHODS: Five plasma-isotonic solutions perfused LCA: Iod 320 + Na/Ca (iodixanol 320 mg I/mL, 19 mM NaCl, 0.3 mM CaCl(2)), Iod 320 + Mann (iodixanol 320 mg I/mL, 50 mM mannitol), Mann + Na/Ca (240 mM mannitol, 19 mM NaCl, 0.3 mM CaCl(2)), Mann (275 mM mannitol), and Ringer (representing "physiologic electrolytes"). The first two solutions have at 37 degrees C viscosity 13 mPas and the others <1 mPas. In eight pigs, 20 mL of each solution was injected twice for 10 seconds, and in 15 pigs, each solution was injected for 11-40 seconds (0.5 mL/second) through a wedged catheter in the LCA. If ventricular fibrillation (VF) occurred, injection was stopped and heart was defibrillated. If VF did not occur, perfusion period was 40 seconds. A higher frequency of VF and a shorter period from start of injection until start of VF gave a solution a higher ranking of VF-PROP. RESULTS: The 10-second injections caused no VF. Ringer and Iod 320 + Na/Ca caused no VF after 40-second injections, whereas the other solutions caused VF. Ranking the solutions from lowest to highest VF- PROP gave: Ringer = Iod 320 + Na/Ca < Iod 320 + Mann < Mann + Na/Ca < Mann. Prolongation of QRS time and QTc time were the only VECG signs that showed significant differences (P < .05) between all solutions and correctly ranked the VF-PROP of all solutions in both animal groups. CONCLUSION: The results fit with the concept that a more physiologic electrolyte composition and a higher viscosity of a test solution will, after start of injection of that solution into LCA, delay changes in the electrolyte composition in myocardial interstitial fluid and also delay start of VF. If a plasma isotonic contrast medium (CM) with lower viscosity than that of iodixanol at 320 mgI/mL were created, we conclude that such a CM should have electrolyte composition closer to that of Ringer than present composition (19 mM NaCl and 0.3 mM CaC1(2)) to counteract the effects of faster diffusion of nonphysiologic electrolyte composition from the low-viscosity CM to myocardial interstitial fluid.

Gadolinium contrast media are more nephrotoxic than iodine media. The importance of osmolality in direct renal artery injections.

A study was undertaken of the role of osmotoxicity in gadolinium (Gd) and iodine contrast media (CM) nephrotoxicity in ischemic porcine kidneys. Test solutions: mannitol iso-osmotic to 0.5 M: gadopentetate (1.96 Osm/kg H2O), 0.5 M: gadodiamide (0.78 Osm/kg H2O) and 0.5 M: iohexol (190 mg I/ml, 0.42 Osm/kg H2O). Each solution was injected [3 ml/kg body weight (BW)] into the balloon-occluded (10 min) renal artery of eight left-sided nephrectomized pigs. The plasma half-life of a glomerular filtration rate (GFR) marker was used to compare their effects on GFR 1-3 h post-injection. The median half-lives of the GFR marker after injection of gadopentetate (1,730 min) and mannitol 1.96 Osm/kg H2O (2,782 min) did not differ statistically (P = 0.28), but were significantly longer than after all other solutions (P < 0.001). There was no significant difference (P = 0.06) between gadodiamide (218 min) and mannitol 0.82 Osm/kg H2O (169 min), while there was (P = 0.03) between iohexol (181 min) and mannitol 0.43 Osm/kg H2O (148 min). The difference between gadodiamide and iohexol was significant (P = 0.01). Reduction in GFR, as a marker of nephrotoxicity, induced by gadopentetate correlated with its high osmolality, while the effect of gadodiamide and iohexol may include chemotoxicity. Iohexol molecules were less nephrotoxic than the Gd-CM molecules and contain three-times the number of attenuating atoms per molecule.

Gadolinium contrast media are more nephrotoxic than a low osmolar iodine medium employing doses with equal X-ray attenuation in renal arteriography: an experimental study in pigs.

RATIONALE AND OBJECTIVES: To investigate in a unilaterally nephrectomized porcine model whether gadolinium contrast media (Gd-CM) are less nephrotoxic than iodine media (I-CM) in x-ray arteriography of a kidney made temporarily ischemic by arterial balloon occlusion. MATERIALS AND METHODS: In a noncrossover design, 3 mL of each test solution were injected in eight pigs (mean weight 19 kg) at a rate of 20 mL/min into the right renal artery at the start of a 10-minute period of ischemia. In group 1 (40 pigs) we injected 0.5 M gadopentetate, 0.5 M gadodiamide, 0.5 M iohexol (190 mg I/mL), 0.18 M iohexol (70 mg I/mL; with an x-ray attenuation equal to that of 0.5 M Gd-CM at 80 kV), and saline. In group 2 (24 pigs), we tested 0.18 M iohexol with ischemia and saline with and without ischemia. Gd- and iodine contrast media functioned as markers of glomerular filtration rate (GFR). When saline was tested, a low dose of iohexol (3 mL per pig; 300 mg I/mL) was injected as GFR marker intravenously in group 1 and into the renal artery in group 2. The plasma half-life elimination times of the CM 1-3 hours after injection were used to compare the effects of the different test solutions on GFR. Longer half-life means lower GFR. RESULTS: Group 1: median plasma half-life elimination time of the GFR marker was 3 340 minutes after injection of 0.5 M gadopentetate, 256 after 0.5 M gadodiamide, 179 after 0.5 M iohexol, 143 after 0.18 M iohexol, and 133 minutes after saline. All differences except that between 0.18 M iohexol and saline were statistically significant (P < .01). Group 2: median plasma half-life was 174 minutes after 0.18 M iohexol with ischemia, 196 minutes after saline with ischemia, and 195 minutes after saline without ischemia. There were no significant differences between the test solutions in group 2 (P > .05). CONCLUSION: In pigs, 0.5 M Gd-CM were more nephrotoxic than both equal-attenuating (70 mg I/mL) and equimolar (190 mg I/mL) concentrations of the I-CM iohexol. These results do not support the "off-label" use of Gd-CM for renal x-ray arteriography in man instead of commercially available concentrations of iodine contrast media at 140, 150 and 180 mg I/mL or diluted to 70 mg I/mL.

Adding sodium and calcium ions to the contrast medium iodixanol reduced the risk of ventricular fibrillation during perfusion of the left coronary artery in pigs: effects of electrolytes, viscosity, and chemotoxicity of an isotonic perfusate.

RATIONAL AND OBJECTIVES: The effects of electrolytes, viscosity, and chemotoxicity of a plasma-isotonic iodine contrast medium iodixanol were compared with regard to its propensity to cause ventricular fibrillation (VF). MATERIALS AND METHODS: The left coronary artery of pigs was perfused with five isotonic solutions: iodixanol 320 mg I/mL with 19 mmol/L NaCl + 0.3 mmol/L CaCl2, Iod 320+Mann (iodixanol 320 mg I/mL + 50 mmol/L mannitol), Mann+Na/Ca (240 mmol/L mannitol with 19 mmol/L NaCl + 0.3 mmol/L CaCl2), Mann (275 mmol/L mannitol) and Ringer. The first two solutions have at 37 degrees C a viscosity of approximately 13 mPa x s while the others have a viscosity < 1 mPa x s. In eight pigs, each test solution was injected twice into the left coronary artery in random order for 10 seconds (injection volume, 20 mL). In 15 pigs, each of the solutions was injected in random order for 11-40 seconds through the end-hole of a wedged 5F balloon catheter in left coronary artery. Injection rate was 0.5 mL/sec until VF occurred. If VF occurred, injection was stopped and the heart was defibrillated. If VF did not occur, the perfusion period was 40 seconds. RESULTS: The 10-second perfusions caused no VF. The 40-second perfusions with iodixanol 320 mg I/mL with 19 mmol/L NaCl + 0.3 mmol/L CaCl2 or Ringer caused no VF (0%). Iod 320+Mann caused nine VF (60%) after 35 +/- 4 seconds (SEM). Mann+Na/Ca caused 14 VF (93%) after 30 +/- 2 seconds. Mann caused 15 VF (100%) after 24 +/- 2 seconds. Iodixanol 320 mg I/mL with 19 mmol/L NaCl + 0.3 mmol/L CaCl2 and Ringer caused fewer VF than all other solutions (P < .05-.001). Iod 320+Mann caused fewer VF than Mann (P < .05). Iod 320+Mann caused VF later than Mann+Na/Ca or Mann (P < .02 and P < .01). Mann+Na/Ca caused VF later than Mann (P < .05). CONCLUSION: The results fit with a concept that VF starts when the electrolyte composition of the interstitial fluid in the myocardium is sufficiently nonphysiologic. The more physiologic the electrolyte composition of the perfusion fluid, and the higher its viscosity, the slower the composition of the interstitial fluid will be changed, and VF will occur later (or not at all).

Gadolinium-containing contrast media for radiographic examinations: a position paper.

Recently, it has been suggested that gadolinium-based contrast media could be used for radiological examinations in patients with significant renal impairment, previous severe generalized reaction to iodinated contrast media or thyroid disease about to undergo radioactive iodine treatment; however, the indications for and risks of using gadolinium agents in this way are not well known; hence, the Contrast Media Safety Committee of The European Society of Urogenital Radiology reviewed the literature to issue a position paper on this subject. A comprehensive literature review was performed and the resulting report was discussed at the Ninth European Symposium on Urogenital Radiology in Genoa, Italy, June 2002. Review of the literature indicates that according to experimental data on animals gadolinium-based contrast media have more nephrotoxic potential than iodinated contrast media in equivalent X-ray attenuating doses; therefore, gadolinium-based contrast media should not replace iodinated contrast media in patients with renal insufficiency for radiographic examinations. For patients with previous severe generalized reactions to iodinated contrast media, and in patients about to undergo thyroid treatment with radioactive iodine gadolinium-based contrast media in approved intravenous doses, up to 0.3 mmol/kg body weight will not give diagnostic radiographic information in most cases. Gadolinium-based contrast media are not approved for radiographic examinations.