High osmolar contrast agents

Contrast-induced nephropathy has been defined as an increase in serum creatinine of at least 25% or an absolute increase in serum creatinine of at least 0.5 mg/dL within 48 to 72 hours of iodinated contrast administration and is associated with significant morbidity and mortality (75). Important risk factors include diabetes mellitus, chronic renal insufficiency, administration of large volumes of high osmolar contrast agents, and intravascular volume depletion. Numerous pharmacologic preventive measures have been studied, but consistent benefits have not been demonstrated. In a recent large retrospective study, preprocedural statin therapy was independently associated with a lower risk of contrast nephropathy and nephropathy requiring dialysis (76). 

Adverse reactions to intravascular iodinated agents are usually classified as minor, intermediate, or severe life-threatening. All types of reactions to low-osmolar contrast media are five times less common than reactions to high-osmolar contrast agents (SEDA-22, 489) (SEDA-23, 494) (SEDA-24, 519), and very severe adverse reactions to contrast media are rare, with a frequency of about 0.04% with high-osmolar agents and 0.004% with low-osmolar agents. However, there are no important differences in the safety profiles of the different low-osmolar non-ionic monomers (18). 

Ionic monomeric contrast agents are known as high osmolar contrast agents (HOCAs) and are not much used nowadays because of the risk of adverse effects. 

In another survey, the incidence of contrast media reactions after intravenous administration was evaluated over 14 years (25). The incidence of all reactions to contrast media was 6-8% with high-osmolar contrast media and only 0.2% with low-osmolar non-ionic agents. Most of the reactions (over 90%) were aUergic-like, and severe reactions were rare (0.05%). One death was reported after the use of a low-osmolar agent. These data are compatible with previous reports, which showed that low-osmolar contrast media have a much better safety profile than high-osmolar media and that there is no significant difference in the incidence of acute adverse reactions between non-ionic dimeric and monomeric contrast media. 

There are wide variations in the reported incidence of contrast nephrotoxicity because of differences in patient selection, the type of radiological procedure, and the definition of renal impairment. Contrast nephrotoxicity is relatively uncommon in people with normal renal function, in whom it is 0-10%. Pre-existing renal impairment increases the frequency, with a reported incidence of 12-27% in several prospective controlled studies. In some studies the incidence was as high as 50%, in spite of the use of low-osmolar contrast agents and adequate hydration. Dialysis may be required in some of these patients (SEDA-22, 502). 

There are four types of iodinated water-soluble contrast media, classified according to their physicochemical properties (Table 1). They are mainly used intravascularly but can also be injected into body cavities, particularly the low-osmolar contrast agents. Some are also used for oral or rectal administration, and the high-osmolar water-soluble contrast agent diatrizoate is suitable only for these purposes. Low-osmolar and iso-osmolar iodinated contrast media have almost completely replaced high-osmolar agents for intravascular use and administration into body cavities. 

The analysis of X-ray contrast agents has not been described in too much detail in the hterature. Only scattered data for individual compounds can be found. In the following paragraphs, we will concentrate both on the determination of physicochemical characteristics, which allow for a classification of different contrast agents, e.g. into high and low-osmolar substances, and on the separation from by-products or biological material and on the determination of concentrations. Structural aspects of iodinated contrast agents have been described by Toennessen et al. [81]. 

Currently available contrast agents can be classified into three different groups, high-osmolar compounds with osmolalities in the order of 1500 mosm kg low-osmolar agents with 600 - 700 mosm kg and isotonic substances with osmolaH-ties similar to that of blood (300 mosm kg ). Data for individual contrast agents are summarized in Table 2. 

Reticulated purpura has been reported after the use of diatrizoate meglumine, a high-osmolar water-soluble contrast agent, for hysterosalpingography (212). 

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