High-osmolar Contrast Media Research Articles

Profound platelet degranulation is an important side effect of some types of contrast media used in interventional cardiology.

Thrombotic complications occurring during coronary angiography and percutaneous transluminal coronary angioplasty (PTCA) are relatively frequent and can be influenced by the type of radiographic contrast media used. Low osmolar contrast media (LOCM), both ionic and nonionic, have been considered to be safer than the older high osmolar contrast media (HOCM), causing less haemodynamic and symptomatic side effects. Recently, however, nonionic LOCM have been associated with an increased incidence of thrombotic events, including coronary occlusion and stroke. The effects of commonly used contrast media on platelets in native blood were investigated using immunolabeling and flow cytometry to detect platelet activation in vitro. A nonionic LOCM (Omnipaque) caused profound platelet degranulation in nearly 80% of platelets compared with 2 to 3% of platelets in the control. Conversely, an ionic HOCM (Urografin) caused only 25% degranulation, whereas an ionic LOCM (Hexabrix) caused no platelet activation and, furthermore, it inhibited the effects of thrombin on platelets. Platelet degranulation, quantified by immunolabeling, was paralleled by release of beta-thromboglobulin and platelet factor 4 from platelet alpha-granules. Blood from patients anticoagulated with heparin and pretreated with standard-dose aspirin in preparation for PTCA showed the same pattern of contrast media-induced platelet activation as normal subjects. These results suggest that the type of contrast media used during invasive imaging of the vasculature could have a significant effect on platelets. Platelet degranulation within a PTCA-damaged vessel would be increased by a nonionic contrast medium, releasing procoagulant molecules and platelet-derived growth factors into the damaged vessel lumen, which might contribute to acute thrombosis and the initiation of the restenosis process.

Incidence and risk factors of adverse reactions to ioxithalamate in patients with computed tomography

A prospective study was conducted from February 1989 to January 1991, on 5,000 consecutive patients, undergoing CT studies of the head and brain, to evaluate the adverse reactions to sodium meglumine ioxithalamate, a high-osmolar contrast medium (HOCM). The overall incidence of moderate or severe reactions was 2.8%. Severe reactions occurred in 0.06% and moderate reactions in 2.74% of the contrast media examinations. It is interesting to note that the risk of adverse reactions was multiplied by 7.6 in patients with the acquired immune deficiency syndrome (AIDS). No deaths occured. It is concluded that the incidence of adverse reactions to Ioxithalamate is low. Although the occurrence of adverse reactions is lower with low osmolar contrast media (LOCM), the routine use of HOCM appears justified by the best cost-efficacy ratio in low-risk patients.

Net costs from three perspectives of using low versus high osmolality contrast medium in diagnostic angiocardiography

Objectives. We conducted an economic analysis to assess the extent to which a reduction in adverse drug reactions induced by low osmolality compared with high osmolality contrast media during diagnostic angiocardiography would result in savings to hospitals, society and third-party payers that would offset the substantially higher price of low osmolality contrast medium.Background. Substitution of low osmolality for high osmolality contrast media in the approximately 1 million diagnostic angiocardiographic procedures performed each year in the United States could substantially increase health care costs. Costeffectiveness estimates should include savings that might occur through reduced costs of managing adverse drug reactions.Methods. In a randomized clinical trial of 505 persons undergoing diagnostic angiography with either high osmolality or low osmolality contrast medium, we measured and compared 1) material costs of contrast media, and 2) costs from three perspectives of incremental resources used to manage contrast-related adverse drug reactions. We also performed sensitivity analyses to examine the effect of different assumptions with regard to relative risk, absolute risk and costs of adverse drug reactions on estimates of net cost of use of high osmolality and low osmolality contrast media.Results. One-hundred thirty-seven (54.2%) of 253 patients receiving high osmolality contrast medium and 44 (17.5%) of 252 patients receiving low osmolality contrast medium experienced adverse drug reactions. The average cost (from society's perspective) of resources used to manage adverse drug reactions per patient undergoing angiography was significantly (p = 0.0001) greater for high osmolality (mean $249) verus low osmolality (mean $92) contrast medium. Differential costs (from the hospital's perspective) were $67 greater for high osmolality contrast medium. Charges and professional fees (from the payer's perspective) were $182 greater for high osmolality (mean $312) than for low osmolality (mean $130) contrast medium (p = 0.42, NS). The higher differential and average costs of managing adverse drug reactions with high osmolality contrast medium offset 33% and 75%, respectively, of the $207 difference in mean material costs, but these estimates are sensitive to infrequent high cost cases.Conclusions. Although low osmolality contrast medium is not cost-saving in diagnostic angiocardiography, its higher price is partially offset by lower management costs of adverse drug reactions. The cost offset for the hospital is lower than that for society and may not be realized by third-party payers. These methods and results may be useful in establishing clinical and payment guidelines for use of alternative contrast media in diagnostic angiocardiography.

High-Osmolar and Low-Osmolar Contrast Media

During the past 3 years a great number of papers about adverse drug reactions to intravascular injection of high-osmolar and low-osmolar iodinated contrast media (CM) have been published. They include observational studies, randomized trials, meta-analyses and committee reports. Thorough analysis of this material substantiates an improvement in safety of at least 6-fold using nonionic low-osmolar CM compared with ionic high-osmolar CM. The point where only a small minority is continuing to argue effectively that low-osmolar CM are not better than conventional high-osmolar CM has now been reached. High-osmolar CM are used less and less for intravascular purposes, and, in fact, have been totally replaced by low-osmolar CM in 4 countries.

In Vivo Fluorescence Microscopy of Microcirculation in the Renal Cortex of Mice

In vivo fluorescence microscopy was used for experimental studies of renal cortical microcirculation in 46 mice. The cortical circulation was studied after i.v. infusions of mannitol of various osmolalities as well as nonionic low osmolar (iohexol) and ionic high osmolar (metrizoate) contrast media. All infusions produced an increase in the number of capillaries with increased blood flow, significantly more pronounced after the infusion of iohexol, metrizoate and mannitol 1.46 mol/l than after the infusion of mannitol 0.3 mol/l. However, the renal cortical blood flow was inhomogeneous with respect to different capillaries. While the blood flow was increased in some capillaries it was to some extent simultaneously decreased in others, significantly more after infusion of metrizoate than after infusion of mannitol 0.3 mol/l.

Optimum utilisation of intravascular radiological contrast media

The major current problem related to radiological contrast media is how best to achieve the optimum cost benefit efficiency in the deployment of contrast agents. Low osmolar contrast media (LOCM) are more comfortable for the patient and cause less adverse reactions than high osmolar contrast media (HOCM), but there is no statistically proven reduction in mortality. There is no improvement in diagnostic intravascular imaging when LOCM replaces HOCM. LOCM are 4–5 times more expensive than HOCM.

Low-osmolality versus high-osmolality contrast material

Universal use of low-osmolality contrast agents for intravascular diagnostic procedures has been limited to a large extent by the high cost of these agents, which is generally 10 to 20 times that of high-osmolality contrast media. The question for the radiologist, therefore, is the definition of selected populations and situations for the use of low-osmolality agents to achieve the greatest patient benefit at the least cost. The authors examine controversial issues including the incidence of significant contrast reactions, the definition and incidence of nephrotoxicity, and the effects of contrast media on coagulability.

Decision analysis to assess cost-effectiveness of low-osmolality contrast medium for intravenous urography

Decision analysis was used to compare the cost-effectiveness of a conventional ionic high-osmolality contrast medium with that of a nonionic low-osmolality contrast medium when used for i.v. urography. The patient populations considered in the model were those with a low risk and those with a high risk of contrast medium-associated adverse effects. Mean toxicity rates for the contrast media were obtained from the literature. To estimate the average cost of adverse effects, the probability of a patient in each population developing a mild, moderate, or severe reaction was multiplied by the respective estimated cost for each level of severity, and the products were summed. The incremental cost of the low-osmolality medium per case of adverse effects prevented was calculated by dividing the difference between the average costs of the two media by the difference between the frequencies of toxicity associated with the agents. According to the 1990 cost data used, combined mean drug and toxicity costs were $68 and $13 for the low- and high-osmolality contrast media, respectively, per high-risk patient and $67 and $10 per low-risk patient. The incremental costs of the low-osmolality medium per case of severe adverse effects prevented was $17,974 in the high-risk population and $77,027 in the low-risk population. Sensitivity analysis showed the results to be stable over a range of data used in the model.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of low-osmolality contrast medium does not increase prevalence of medullary sponge kidney.

To assess the prevalence of intrapapillary linear collections of contrast medium as well as of homogeneous papillary blush on excretory urograms obtained with a low-osmolality contrast medium, iohexol was used in 300 patients. Intrapapillary linear collections of contrast medium (ie, three or more linear collections of contrast material within a papilla) were found in 10 (9.5%) of the 105 patients with renal stone disease and two (1.0%) of the 195 patients without nephrolithiasis (P less than .001). These prevalences are similar to those found in a previous study with use of a high-osmolality contrast medium (sodium amidotrizoate). The difference in the prevalence of homogeneous papillary blush between stone formers and non-stone formers was nonsignificant. The authors conclude that intrapapillary linear collections of contrast medium on excretory urograms obtained with use of a low-osmolality contrast medium should be considered to have the same clinical significance as those on excretory urograms obtained with use of a high-osmolality contrast medium, that is, as indicating the presence of medullary sponge kidney.

Nephrotoxicity of contrast media following cardiac angiography: pathogenesis, clinical course, and preventive measures, including the role of low-osmolality contrast media.

To review the incidence, definition, clinical course, risk factors, pathogenesis and prevention of contrast-associated nephropathy (CAN) following cardiac angiography with emphasis on differences between high-osmolality contrast media (HOCM) and low-osmolality contrast media (LOCM). Investigations in animal models and in patients following cardiac angiography. Animal models of the pathogenesis of CAN are presented. Human studies describing the incidence, clinical course, risk factors, and prevention of CAN are reviewed. Comparative clinical trials of HOCM (diatrizoate, metrizoate) and LOCM (iohexol, iopamidol, ioxaglate) nephrotoxicity following cardiac angiography are critically evaluated. All clinical studies comparing CAN of HOCM versus LOCM following cardiac angiography have some methodologic limitations (e.g., small sample size, lack of control for other factors) that may affect renal function, lack of stratification for other reported risk factors, and variable or short follow-up periods. Whether the incidence of CAN following cardiac angiography is reduced with LOCM remains controversial. The incidence of CAN in patients with normal renal function does not appear to differ in patients treated with LOCM versus HOCM because few patients in each group develop renal failure. Additional controlled clinical trials comparing CAN of LOCM and HOCM in patients with renal dysfunction are needed. Because of greater product cost and scarcity of documented benefit compared with HOCM, selection of LOCM based on the presence of renal dysfunction cannot be recommended at this time.

Contrast Media-Induced Renal Tubular Vacuolization

The morphologic changes in healthy rat kidneys (n = 102) were studied 2 or 48 hours after intravenous injection of 1 or 3 g iodine (I)/kg of high-osmolality diatrizoate, low-osmolality iopromide and iohexol, or iso-osmolality iotrolan, as well as after 0.2 or 0.6 g/kg of the high-osmolality magnetic resonance contrast medium gadolinium DTPA. Physiologic saline was injected in controls. The kidneys were fixed by perfusion and the specimens were analyzed semiquantitatively by two independent observers blinded to the treatment. A statistically significant (P less than .01) cytoplasmic vacuolization was noticed in the proximal convoluted tubule cells 2 hours after injection of 3 g I/kg of diatrizoate or iopromide. Iohexol and iotrolan induced an even more significant (P less than .01) and longer-lasting vacuolization, but gadolinium DTPA did not produce lysosomal alterations. Although the vital cell organelles remained intact, reversible lysosomal alterations may represent the first structural signs of a threatening cellular injury.

The effects of high (sodium meglumine diatrizoate, Renografin-76) and low osmolar (sodium meglumine ioxaglate, Hexabrix) radiographic contrast media on diastolic function during left ventriculography in patients

Although a majority of studies indicate superior hemodynamic and clinical profiles of low osmolar compared with high osmolar contrast media, the effect of these agents on diastolic left ventricular function has not been examined. We prospectively examined hemodynamic, electrocardiographic, and echocardiographic indices of left ventricular function in patients undergoing contrast ventriculography with a high osmolar, ionic, monomeric contrast, diatrizoate (Renografin-76) compared with a low osmolar, ionic, dimeric contrast, ioxaglate (Hexabrix). Thirty patients were randomized to each group. There were no clinical differences between the two groups. The decrease in systemic pressures was significantly greater with diatrizoate after left ventriculography (−38.5 ± 3.5 versus −18.2 ± 2.3, p < 0.001) and selective left coronary angiography (−29.5 ± 2.4 versus −17.4 ± 2.6, p < 0.001). In addition, left ventricular end-diastolic pressure increased significantly more with diatrizoate (7.3 ± 0.9 versus 2.7 ± 0.8 mm Hg for ioxaglate, p < 0.001). QT interval prolongation occurred in both patient groups. Diatrizoate decreased systemic vascular resistance, and increased cardiac output and left ventricular ejection fraction more than ioxaglate, while simultaneously increasing left ventricular end-diastolic volume and altering the peak atrial filling velocity. Negative dp dt ( p < 0.05), but not Tau, computed by the logarithmic or derivative methods, was reduced by diatrizoate. These data indicate that significant alteration of diastolic filling patterns occurs with high osmolar compared with low osmolar contrast agents. Although the clinical significance of this observation is currently unknown, these data further support the reported hemodynamic superiority of the low osmolar, dimeric contrast agent ioxaglate during contrast angiography.

Prediction of severe adverse reactions to ionic and nonionic contrast media in Japan: evaluation of pretesting. A report from the Japanese Committee on the Safety of Contrast Media.

In a nationwide prospective study of adverse reactions to intravenous contrast media (CM), the Japanese Committee on the Safety of Contrast Media compared high-osmolar ionic CM with low-osmolar nonionic CM. A total of 337,647 cases were analyzed. The reliability of pretesting with an intravenous injection of a small amount of CM as a means of predicting severe or fatal reactions was also evaluated. The predictive values of the pretest were 1.2% for ionic and 0.0% for nonionic CM, and the sensitivity values were 3.7% and 0.0%, respectively. Such low values render this test meaningless for predicting which patients are at risk of a severe adverse reaction. A comparison of the incidence of severe adverse reactions between the nonpretested and pretested patients, as well as between the nonpretested and pretested patients with negative results, disclosed no statistically significant differences. Also, no beneficial effects of premedication in patients with a positive pretest were proved. The authors therefore conclude that pretesting with an intravenous injection of a small amount of CM is not useful in predicting severe reactions to ionic or nonionic CM.

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.

Effects of High- and Low-Osmolar Contrast Media on Renal Plasma Flow and Glomerular Filtration Rate in Euvolaemic and Dehydrated Rats

The effects of a slow intravenous injection of contrast media (CM) on renal function and haemodynamics were investigated in euvolaemic and dehydrated rats. Iodine-equivalent doses (1600 mg I/kg body weight) of ioxithalamate, ioxaglate, iopamidol and iohexol were used. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed with clearance techniques. In euvolaemic rats no statistically significant decrease in GFR or RPF was found after CM injections. In the dehydrated rats the changes in GFR were more pronounced and this was significantly decreased in the ioxithalamate and iopamidol groups while RPF was still not decreased. This study indicates that dehydration potentiates adverse effects of CM on GFR and that there may be differences between the effects of low-osmolar and high-osmolar CM on GFR and also between different low-osmolar CM.

Morphological dynamics of ureteral transport. I. Shape and volume of constituent urine fractions.

Ureteral transport was studied in 50 urinary systems by urography with video recording in the upright and recumbent positions using low-osmolality and high-osmolality contrast media. Morphometry and volumetry were applied to right urinary systems in which the urine-filled segments had a circular cross section at maximum peristaltic distension. The filling of the lumbar segment was composed of four fractions, each entering that segment by a specific mechanism: 1) the residual urine left behind by the preceding contraction ring, 2) the postcontraction injection from the pyelocalyceal system, 3) the extraperistaltic flow, and 4) the peristaltic injection produced by the pyelocalyceal contraction rings. The variations in the precontraction filling by fractions 1-3 and in the volume of fraction 4 gave rise to four types of transport. The junction between the lumbar and pelvic segments constituted a constant point of resistance to flow that prevented fractions 1-3 from entering the pelvic segment, the peristaltic injection into that segment being determined solely by the resistance at the junction and the volume of the bolus in the lumbar segment. Extraperistaltic flow to the bladder constituted a separate type of transport.

Normal collecting ducts: visualization at urography.

In 21 of 636 patients with normal renal function and without obstruction of the upper urinary tract, urograms showed that contrast medium filled thin cylindrical structures in the renal pyramids with the same course as that of the collecting ducts. The prevalence of cylinders when the low-osmolality contrast medium iohexol was used was 21 of 158 studies (13.3%) and with the high-osmolality contrast medium amidotrizoate, two of 529 studies (0.4%). The cylinders were more distinct and more numerous with iohexol, while with amidotrizoate most cylinders appeared as striations. The cylinders appeared within 4 minutes from the start of contrast medium injection and remained distinct for 35-50 minutes. The diameter of the cylinders varied between 0.05 and 0.30 mm; their course was almost straight and closely followed the shape of the pyramid. The cylinders proved to consist of the highly opacified collecting duct lumina. Their configuration indicated that a single cylinder might be an individual collecting duct, but conclusive evidence was lacking.

Contrast medium-induced adverse reactions: economic outcome.

Because the cost of managing an expected greater number of adverse reactions when high-osmolality contrast media (HOM) are used could offset the higher material cost of low-osmolality contrast media (LOM), a prospective study was done of 795 inpatients undergoing any of four procedures involving intravascular injection of HOM: cardiac catheterization, peripheral angiography, head computed tomography (CT), or body CT. The resources used in managing HOM-induced adverse reactions were measured, and the costs of these resources were estimated. Four hundred five patients (51%) had adverse reactions. Reactions were grouped into three classes according to their severity. Class 1 (mild) reactions occurred in 358 patients (45%), class 2 (moderate) reactions occurred in 44 patients (6%), and class 3 (severe) reactions occurred in three patients (0.4%). Ninety-nine patients (12%) consumed resources as a result of an adverse reaction. The average cost of these resources per patient undergoing examination was $1.07 to the radiology department, $5.83 to the hospital, and $12.93 to a charge-paying insurer. Mean (+/- standard deviation) cost to the hospital for managing class 1, class 2, and class 3 reactions were $2.52 +/- $5.33, $24 +/- $54, and $910 +/- $749, respectively. By comparison, the difference in material cost of HOM versus LOM ranged from $93 for body CT to $179 for cardiac catheterization. Even if LOM were to induce no adverse reactions, the increased material cost associated with universal substitution of LOM for HOM would be greater than the expected cost of managing adverse reactions when HOM are used.

EFFECT OF CONTRAST MEDIUM INFUSION ON COLLOID OSMOTIC PRESSURE (COP) AND OSMOLARITY IN THE NEWBORN DURING CARDIAC CATHETERIZATION

The injection of extremely high osmolar contrast medium into a newborn infant undergoing angiocardiographic study has been a concern. We studied the effect of contrast medium on COP and osmolarity changes in the newborns during a six month period in 1983. Twenty-two infants underwent cardiac catheterization and angiocardiography during this period. The average gestational age was 39.6 weeks and the mean birthweight 3266 gms. Ages ranged from one to 28 days of life. Diatrizoate sodium 50% solution (MD-50) was used at a dose of 3.3 ml/kg. Direct measurement of MD-50 revealed COP of 7.0 mmHg and osmolarity of 1497 mOsm/L. Blood samples were obtained before and at one hour and 4 hours after injection of MD-50. COP was determined by Wescor 4100 Colloid Osmometer. Serum osmolarity was measured by Wescor 5100 C Vapor pressure Osmometer. There was no significant change in COP before and after injection. However, there was significant although small overall change in osmolarity before and after infusion of MD-50 (one way analysis of variance p=0.0021). This small alteration in osmolarity probably does little harm in our cases but larger doses may cause osmolar imbalance.