Incidence of ventricular fibrillation during left coronary arteriography in pigs: comparison of a solution of the nonionic dimer iodixanol with solutions of five different nonionic monomers.

BACKGROUND: Solutions of iodine contrast media (CM) used for selective coronary arteriography (CA) should have minimal propensity to cause ventricular fibrillation (VF). Commonly used CM for CA are nonionic monomers or dimers. PURPOSE: To compare VF propensity of ready-to-use solutions of one nonionic dimer, iodixanol, and five nonionic monomers, iobitridol, iopamidol, iomeprol, iopromide, and ioversol. MATERIAL AND METHODS: Twenty milliliters of each CM was injected into the left coronary artery (LCA) through an inflated balloon catheter (0.5 ml/s) in 14 pigs; the longest period of injection was 40 s. If VF occurred before 40 s, the injection was stopped and the heart was defibrillated. After VF, there was a delay of 40 min before the next injection. Hemodynamic parameters and vector electrocardiography (VECG) were monitored. A CM with a lower frequency of VF and a longer period between start of injection and start of VF was considered to have a lower VF propensity. RESULTS: Following 14 injections, each of the five nonionic monomers caused 14 VF, whereas iodixanol caused three VF (P<0.01). When VF occurred after iodixanol, it occurred later than after the other CM (P<0.001). Iodixanol caused less prolongation in QRS time (P<0.01) and QTc time (P<0.05) than the other CM. Prolongations in QRS and QTc times caused by CM parallel the VF propensities of the CM. CONCLUSION: Ready-to-use solutions of the dimer iodixanol have lower VF propensity than solutions of the five monomeric CM. This is related to the fact that the solutions of the dimer iodixanol have lower osmolality, higher viscosity, and higher concentrations of NaCl and CaCl2 than solutions of the five monomers.

Histomorphological changes after renal X-ray arteriography using iodine and gadolinium contrast media in an ischemic porcine model.

BACKGROUND: Gadolinium contrast media (Gd-CM) are regarded as non-nephrotoxic or considerably less nephrotoxic than iodine contrast media (I-CM), and have therefore come to be used as a substitute for I-CM in patients with renal insufficiency in a variety of radiographic examinations. PURPOSE: To investigate renal histomorphological changes caused by Gd-CM in comparison with I-CM after renal X-ray arteriography in an ischemic porcine model,and to evaluate these changes in relation to the nephrotoxicity of the CM used. MATERIAL AND METHODS: Test solutions: gadopentetate, gadodiamide, iohexol, gadobutrol,iopromide, iodixanol, mannitol, and saline. The experiments were performed on 152 animals. Each pig was randomized to receive one test solution injected into the balloon occluded(10 min) right renal artery. The kidneys were evaluated histomorphologically.The severity of histomorphological changes was graded subjectively: 15 minimal, 25 mild, 35 moderate, and 4=marked. RESULTS: The main histological changes were 1) proximal tubular and glomerular necrosis,2) hemorrhage/congestion of the cortex, medulla, and glomeruli, 3) proximal tubular vacuolation, and 4) protein-filled tubules in the cortex and medulla. Necrosis and hemorrhage/congestion were more frequent after injections with gadopentetate, mannitol solution iso-osmotic to gadopentetate, and gadobutrol compared to all other groups(P<0.001). The degree of necrosis and hemorrhage/congestion was related to the degree of impairment of renal function, but inversely related to vacuolation and tubular protein filling. CONCLUSION: In ischemic porcine kidneys, the histomorphological changes caused by Gd-CM are similar to those caused by I-CM. Vacuolation appears to be independent of the osmolality and viscosity of the CM, and does not seem to be an indicator of renal impairment. "High-osmolal" Gd-CM are more nephrotoxic than "low- and iso-osmolal" I-CM when compared in equal volumes of concentrations, resulting in equal X-ray attenuation.

Behavioral effects of melanocyte stimulating hormone release-inhibiting factor-1 (MIF-1).

Consideration of the isolation, structure, localization, and behavioral effects of melanocyte stimulating hormone release inhibiting factor (MIF-1) is followed by a review of its opiate antagonistic and clinical effects. Evidence pertaining to various hypotheses offered in explanation of these behavioral effects is examined and evaluated. It is concluded that MIF-1 affects behavior in many instances with possible antagonistic effects as well as clinical possibilities.

Contrast media: the relation of chemical structure, animal toxicity and adverse clinical effects.

Chemotoxicity and osmotoxicity of contrast media (CM) are determined by chemical structure. The lower the chemotoxicity and osmotoxicity of the CM, the less animal toxicity and higher clinical tolerance in humans will be achieved. Nonionic monomers such as iohexol and iopamidol in iodine-equivalent concentrations have approximately half the osmolality and therefore half the osmotoxicity of ionic monomers such as diatrizoate, iodamide, iothalamate and metrizoate. Absence of carboxyl groups in nonionic CM, as opposed to the presence of carboxyl groups in ionic CM, results in a lower chemotoxicity in nonionic CM. Similarly, a larger number of hydroxyl groups in nonionic CM than in ionic CM result in a lower chemotoxicity. The lower chemotoxicity of nonionic CM is reflected as a higher subarachnoid and intravenous tolerance both in animals and in the clinical setting.

New media. Experience from 10 years of development of water-soluble nonionic contrast media.

Some experiences are presented from 11 years of work within a group trying to develop better water-soluble contrast media for myelography, urography, and angiography. The group consisted of chemists, pharmacologists, neurophysiologists, and radiologists interested in research. The first nonionic water-soluble contrast medium in clinical use, metrizamide (Amipaque), was developed within the group. Some data obtained within the group are presented. Interest is focused on effects of clinical and experimental contrast media on the central nervous system, arachnoid membrane, and blood-brain barrier.

Development of nonionic contrast media.

In this brief history, the author reviews the observations that led to his developing a nonionic contrast medium. Current knowledge suggested that if a water-soluble medium could be made isotonic to human plasma, it would cause less pain and toxicity than the ionic media then in use. The principles and design of such a medium are discussed, as well as the subsequent chemical development and testing in animal models of first generation (metrizamide) and second generation (iohexol) nonionic media. Iohexol, which is described as a nonionic, monomeric ratio 3 contrast medium, was selected for clinical testing from among competing substances due to its low toxicity in a number of animal models. The results from these experimental models predicted that iohexol would cause fewer and less severe adverse reactions in clinical use than ionic ratio 1.5 media.

Cardiovascular effects of ionic monomeric, ionic dimeric and non-ionic contrast media. Effects in animals on myocardial contractile force, pulmonary and aortic blood pressure and aortic endothelium.

Three different types of contrast media, monomeric ionic, dimeric ionic and monomeric non-ionic, were tested and compared concerning their toxicity on three experimental models: I. Pulmonary artery and aortic pressure after contrast medium injection into the right atrium in rabbits: II. Ventricular contractile force and heart rate after perfusion of the coronary arteries on the isolated rabbit heart: III. Aortic endothelium of rats. Non-ionic contrast medium was, in all three experiments, less toxic than monomeric ionic; thus it caused less rise in pulmonary artery pressure (I) and caused less reduction in ventricular contractile force and heart rate (II) and caused less damage on aortic endothelium of rats (III). The non-ionic contrast medium also gave less toxic reaction in two (I and II) of the three models compared to the dimericionic contrast medium. In experimental model III there was no difference between these two agents. Also, the dimeric ionic contrast medium caused less toxic reactions in all three models than the monomeric ionic contrast medium.

Contrast media-induced nephrotoxicity. Survey and present state.

Reports of renal failure induced by contrast media are increasing. Adverse effects of contrast media on kidney function include diuresis, changes in renal blood flow, osmotic nephroses, albuminuria, enzymuria and, most important, glomerular filtration rate. Animal studies indicate that the new nonionic contrast medium, iohexol, has fewer adverse effects on kidney function than the ionic media currently used. Three clinical studies offer some evidence of the effect of iohexol on renal function, but it is not yet possible to conclude that lower nephrotoxicity found in animals will also be found in man. Further clinical studies are warranted, and careful monitoring of contrast media clearance is recommended in all high-risk patients.

Studies on the acute toxicity of ionic and non-ionic contrast media following rapid intravenous injection. An experimental study in mice.

The influence of the injection rate on the acute intravenous toxicity (LD50) on mice of the ionic high osmotic contrast medium Isopaque Coronar (370 mg I/ml) and the non-ionic low osmotic Amipaque (370 mg I/ml) was investigated. At slow injection (0.1 ml/sec). Amipaque had a significantly higher LD50 than Isopaque Coronar (17.3 respectively 9.8 gm I/kg). Also at rapid injection (2 ml/10 sec). Amipaque was significantly less toxic than Isopaque Coronar (13.4 respectively 6.1 g I/kg). Thus Isopaque Coronar increased approximately 60% in toxicity while Amipaque increased 28% when the rate of injection was increased. This difference was statistically significant (p less than 0.001). Several possible mechanisms that might explain this difference, with special interest in the disturbances on the pulmonary circulation following contrast media injection, are discussed.

Liver toxicity of ionic (Diatrizoate) and nonionic (C-29) contrast materials: effects of serum enzymes after hepatic artery injection in the rat.

Catheters were placed in the retrograde direction in the surgically exposed gastroduodenal arteries of rats. There was an early postoperative mortality of one-third of the animals. The catheter was exteriorized at the tail and was used for arterial perfusion of the liver with one experimental, nonionic contrast medium (C-29) and one ionic contrast medium (diatrizoate). Both contrast media (370 mg I/ml) were injected in a dose of 4 ml/kg rat. The contrast medium injections caused no significant changes in serum levels of the enzymes ALAT, ASAT, or GT.

Addition of calcium or other cations and of oxygen to ionic and non-ionic contrast media. Effects on cardiac function during coronary arteriography.

Metrizamide is a new non-ionic water soluble contrast agent. Isolated rabbit hearts were perfused with solutions of 1) metrizamide, 2) metrizamide with plasma equivalent amounts of cations, 3) oxygenated metrizamide, 4) oxygenated metrizamide with cations, 5) diatrizoate. Solutions of 1) metrizamide, 2) metrizamide with plasmaequivalent amounts of cations, 3) metrizamide with calcium ions, 4) metrizoate (ionic medium) with calcium ions, metrizoate with 5) low and 6) high sodium content and 7) diatrizoate were injected into the left coronary artery of dog hearts in vivo. Maximal change of myocardial contractile force was measured with a strain gauge arch. Changes in aortic blood pressures were also recorded. In both sets of experiments metrizamede affected these parameters less than the ionic contrast media. The addition of calcium ions to both ionic and non-ionic media reduced the adverse effects on the observed cardiac funcitons, while simultaneous addition of plasma equivalent amounts of four cations as metrizoate salts had no beneficial effects. Sodium ions had in high concentration deleterious effects on cardiac performance. Oxygen saturation of the contrast medium had no observable effect. The adverse effects on cardiac mechanical function of sodium ions and possibly other cations contained in a contrast medium solution might be counterbalanced by the addition of calcium ions to the solution.

Effect of ionic and non-ionic contrast medium on aortic and pulmonary arterial pressure. An angiocardiographic study in rabbits.

Effects in angiocardiography from injections into the right atrium of rabbit hearts of a new, non-ionic contrast medium (Amipaque) were studied and were compared with the effects from injections of an ionic medium (Isopaque Coronar) at a dose of 3 ml/kg rabbit and concentration of 370 mg I/ml. Forty-seven experiments in 11 rabbits are reported. Amipaque produced a significantly (p less than 0.001) smaller increase in pulmonary arterial pressure (29%) than Isopaque Coronar (82%). Simultaneously (within 12 seconds from the beginning of an injection) Amipaque produced an increase in aortic pressure of 21%. About 10-15 seconds later when the contrast media had reached peripheral vessels Amipaque produced a significantly (p less than 0.001) smaller decrease of aortic pressure (12%) than the decrease produced by Isopaque Coronar (40%). The differences found between the two types of contrast media are believed to be related to, among other factors, their different osmolality. The osmolality of Amipaque was about one third of the osmolality of Isopaque Coronar.

Metrizamide in urography. II. A comparison of 51Cr-EDTA clearance and metrizamide clearance in man.

In nine subjects undergoing urography with metrizamide measurements of total serum clearance of 51Cr-EDTA have been made before, during, and after the urography. During the urography both total serum clearances and renal clearances were determined for 51Cr-EDTA and metrizamide. The present study in man confirms the previous results from investigations in rabbits, that most of the intravenously injected metrizamide is excreted through the kidneys, that tubular reabsorption of metrizamide occurs and suggests that metrizamide might be used with advantage for urography.

Metrizamide in experimental urography. IV. Effects of bilateral ureteric stasis on urine iodine concentration after intravenous infection of an ionic and a non-ionic contrast medium.

The non-ionic contrast medium metrizamide was compared to the sodium salt of diatrizoate to investigate the potential usefulness of metrizamide in clinical urography when ureteric stasis is applied. After intravenous injection of the contrast media to rabbits at dose level 175 mg I/kg, the kidneys were subjected to temporary bilateral ureteric stasis. Urine was collected through ureteric catheters and analyzed for its concentration of iodine, sodium and potassium. After metrizamide injection the urine iodine concentration was twice as high as after sodium diatrizoate injection. This difference between one non-ionic and one ionic contrast medium was larger than what has been reported earlier during free flow of urine at the same dose. Furthermore, during the periods of ureteric stasis metrizamide was excreted faster than diatrizoate. When diatrizoate was given as its sodium salt, the sodium given was excreted at about the same rate as the diatrizoate given.

Noninvasive estimation of kidney function by x-ray fluorescence analysis: biological half-time and clearance of contrast material in rabbits.

A noninvasive method for glomerular filtration rate-determination, in which the use of radioactive tracers and sampling of plasma and urine can be omitted, is described. After injection of iodinated contrast material in rabbits, the iodine content of tissue, serum, and urine is measured by means of x-ray fluorescence analysis. The disappearance rates of iodine in tissue and serum are found to be the same, and a strong correlation is found between clearance values calculated from serum and tissue measurements. This indicates the possibility of evaluating kidney function by x-ray fluorescence analysis of contrast material in tissue only.

Noninvasive estimation of kidney function by x-ray fluorescence analysis. Elimination rate and clearance of contrast media injected for urography in man.

A noninvasive method for the estimation of kidney function is described. The use of radioactive tracers and the sampling of plasma and urine are omitted. The method has been used in patients referred for urography and who had therefore been injected with routine amounts of iodine-containing urographic contrast medium. After urography, the elimination rates of urographic contrast medium from both serum and finger tissue were determined and compared during a 2-hour period that began two hours after injection of contrast medium. The elimination of iodine in finger tissue was measured noninvasively using x-ray fluorescence analysis. A strong degree of correlation was found between the elimination rates from serum and finger tissue and between the total clearances calculated from the serum and finger measurements. Thus, after urography estimation of kidney function may be obtained as a fringe benefit by x-ray fluorescence measurements of the elimination rate of an iodine-containing contrast medium from tissue or from serum.

A magnetic resonance imaging contrast medium for the liver and bile.

A pharmacokinetic investigation of a paramagnetic Cr-HIDA derivative was performed. Blood, bile, and urine were collected during the first 2 hours after injection of Cr-HIDA 0.01, 0.05, and 0.25 mmol/kg in rats or rabbits. The pharmacokinetics of the substance were found to be similar to those of the biliary iodinated contrast media in common use. Magnetic resonance imaging performed at 10 minutes after injection into the animals revealed that it was necessary to use doses higher than 0.01 mmol/kg to obtain a diagnostically significant increase in signal intensity from the liver. The gallbladder, however, was clearly defined at this dose level.

Interactive effects on renal function between renal ischemia and intravascular contrast media.

This review deals with some recent animal and clinical investigations that show that small amounts of intravascular contrast media (CM) that remain in the body at the time of surgery and are the residual from a preoperative roentgen examination may increase (potentiate) the renal injury resulting from temporary intraoperative renal artery occlusion. Such interaction (potentiation) may occur in each of the following clinical situations: (1) aortorenal reconstructive surgery after angiography; (2) kidney harvesting after cerebral angiography in cadaver donors; and (3) percutaneous dilatation of a stenotic renal artery that includes a sequence of CM injections and balloon inflations that occlude the renal artery. It is concluded that such a potentiation may be decreased by prolonging the time interval between CM injection and the subsequent temporary renal arterial occlusion because such a prolongation decreases the amount of CM that remains in the kidney at time of occlusion.

Recent advances in the treatment of childhood obesity.

The multidisciplinary, four-phase approach, which includes PSMF, BEM, and MPE is successful in treating mild, moderate, and severe degrees of childhood and adolescent obesity. The MPE program is appropriate for use with PSMF and BEM due to its progressive nature, variety of options, and moderate intensity level. In addition, the MPE program is of sufficient intensity, duration, and frequency to promote a significant increase in estimated aerobic capacity (VO2max) and to promote the maintenance of lean body mass and resting energy expenditure. The short-term intervention of PSMF, BEM, and MPE also results in an improvement in body composition, lipid profiles, and IGF-1 and T3 levels. The 1200-calorie balanced diet, MPE, and BEM also provide a successful method of weight maintenance in children and adolescents, as indicated by further improvement in body composition at the 26-week measure. Additional studies are needed to assess the contribution of exercise to the maintenance of lean body mass and resting energy expenditure in obese children and adolescents. In addition, it will be important to assess long-term weight maintenance in obese adolescents who effectively lose weight in this multidisciplinary program.