071_078_00_Thomsen:Thomsen 13-02-2008 9:32 Pagina 71 MDCT and Contrast Media: What are the Risks? Henrik S. Thomsen Department of Diagnostic Radiology, Copenhagen University Hospital Herlev, Herlev Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Denmark Introduction Renal Adverse Reactions With the advent of multi-detector computed to- Contrast-material-induced kidney damage is imme- mography (MDCT) technology, the number of pa- diate, starting as soon as the first CM molecule reach- tients undergoing contrast-enhanced CT (CECT) es the kidney; however, it takes several hours or days studies has steadily grown in the last 6 years. In for a deterioration of renal function to be detected. 2005, approximately 22 million CECT examinations Despite more than 30 years of research, the patho- were carried out in the European Union, and 32 mil- physiology of CM-induced nephropathy (CIN) is lion in the United States (The Imaging Market Guide poorly elucidated. Nonetheless, several risk factors 2005. Arlington Medical Resources, Inc., Philadel- are well-known and can be divided into CM- and pa- phia, PA). Unfortunately, post-contrast-material-re- tient-related factors. lated adverse events, i.e., all those unintended and unfavorable signs, symptoms, or diseases temporally associated with the use of an iodinated contrast ma- Contrast-Medium-Related Factors terial (CM), are a common occurrence in radiology departments. Most adverse events occur within the More than 25 years ago, Barrett and Carlisle [1] first 60 min following CM administration (“imme- showed that the incidence of CIN is significantly diate” or “acute” adverse events), with the greatest higher after the administration of high-osmolarity risk in the first 20 min. More-delayed CM adverse CM (HOCM, osmolality > 1,500 mOsm/kg) than af- events also occur, with some recorded up to 7 days ter low-osmolarity CM (LOCM, osmolality < 915 post-contrast administration (“delayed” or “late” mOsm/kg). Today, it is recommended to avoid the events) or even later (“very late” adverse events). use of HOCM in patients at increased risk of CIN. Adverse reactions to CM can also be classified as Are there differences in nephrotoxicity among the “renal” if the signs and symptoms are caused by other available CM, either LOCM or iso-osmolar CM-induced kidney damage, or they may be “non- CM (IOCM, osmolality always 290 mOSM/kg)? renal”. Some subjects are at higher than usual risk Eight non-ionic monomers (iohexol, iomeprol, for the development of post-CM complications. Risk iopamidol, iopentol, ioxilan, iopromide, ioversol, io- factors can be usually identified prior to the CECT biditrol), one ionic dimer (ioxaglate), and one non- exam; some are modifiable, but all require specific ionic dimer (iodixanol) are approved for intravas- measures to reduce or minimize the rate and sever- cular use (their use varies from country to country). ity of adverse events. This chapter addresses and dis- One non-ionic dimer is not approved for intravas- cusses the most common risk factors for adverse re- cular use (iotrolan) and another is under clinical test- actions to CM and provides practical recommenda- ing (iosimenol). tions aimed at improving the safety of CECT The appropriateness of grouping all LOCM into procedures. one class and considering all of them as equally © 2008. MDCT Technology and Applications – Selected Reviews (e-ISBN 978-88-470-0802-1 Springer-Verlag Milan Berlin Heidelberg New York). Published online at www.mdct.net 071_078_00_Thomsen:Thomsen 13-02-2008 9:32 Pagina 72 72 MDCT Technology and Applications nephrotoxic is heavily debated, as there may be dif- the analysis was carried by the NEPHRIC study, ferences in nephrotoxic potential between the vari- clearly an outlier among the various studies in the ous monomers [2, 3]. No side-by-side comparisons analysis [7]. A similar bias was described by Pan- of non-ionic monomers in risk patients, however, are nu et al. [10], who assessed the preventative effect yet available. of N-acetyl-cysteine in a meta-analysis and showed Several studies have instead compared LOCM that one study, published by Tepel et al. [11] in the with IOCM, most often following intra-arterial ad- New England Journal of Medicine, carried most of ministration of these agents, and a few following their the weight of the final results, showing a positive intravenous injection. In 2003, the results of a effect of the anti-oxidant. Tepel et al. [11] found a prospective study (the NEPHRIC study) conducted 2% incidence of CIN when acetylcysteine (600 mg by Aspelin et al. [4] in 129 patients with moderate × 2 daily × 2 days) was administered and 21% when chronic kidney disease and diabetes mellitus showed acetylcysteine was not given. Both groups received that, compared to iodixanol, the intra-arterial use of intravenous hydration with half-isotonic saline and iohexol resulted in a significantly higher incidence only 75 ml iopromide intravenously for CT. In the of CIN. The two groups differed significantly with 14 comparative studies included in the meta-analy- regard to interventional procedures and length of di- sis of Pannu et al. [10], the CM was given intra-ar- abetes, but in other aspects they were comparable. terially and at higher doses. The most striking as- The CIN endpoint was defined as an absolute in- pect is that both the study of Tepel et al. [11] and crease in serum creatinine (SCr) > 44 μmol/l (0.5 the study of Aspelin et al. [4] have had a great im- mg/dl) within 72 hours. The rate of CIN was 26% pact on the radiological world [12]. The 40–50 stud- of patients receiving iohexol and 4% of those ad- ies and more than 15 meta-analyses stimulated by ministered iodixanol intra-arterially (p < 0.001). Us- the Tepel study [11] have been of varying quality ing the same endpoint, Jo et al. [5] did not find sig- [13]. It is difficult to find two outlier studies so in- nificant differences between IOCM iodixanol and a fluential for daily routine practice. Thomsen and LOCM, the ionic dimer ioxaglate, in 275 patients Morcos [12] analyzed the various guidelines and with chronic kidney disease undergoing coronary found that, in principle, there was nothing new com- procedures. In a retrospective study of 225 patients pared with the 1999 guidelines from the European with moderate-to-severe renal impairment, Briguori Society of Urogenital Radiology (ESUR) [14] and et al. [6] could not find differences in the incidence concluded that evidence for using iodixanol and of CIN in patients receiving iodixanol or the LOCM acetylcysteine following the intra-arterial adminis- non-ionic monomer iobitridol. In these two latter tration of CM is lacking. As a matter of fact, the two studies, however, only a proportion of the study pa- first authors (M Tepel and P Aspelin) of those out- tients were diabetic. lier studies recently published a review paper [15] Recently, McCullough et al. [7] conducted a and concluded that “prospective, randomized trials... pooled analysis using a clinical trial database on significant differences between contrast agents due iodixanol, maintained by General Electric Health- to their physicochemical properties, and low-osmo- care (Waukesha, WI). This pooled analysis includ- lar or iso-osmolar contrast media should be used to ed prospective, double-blind, randomized controlled prevent contrast medium induced nephropathy in at- trials that compared iodixanol with LOCM in adult risk patients” and that there is limited evidence that patients undergoing angiographic examinations and any pharmaceutical intervention, e.g., acetylcysteine, reported SCr values at baseline and after CM ad- can prevent CIN. ministration. The vast majority of LOCM (> 89%) Regardless of the controversy about potential dif- patients had received iohexol or ioxaglate; only 5% ferences in nephrotoxicity between IOCM and had received iopamidol [8], and a similar percent- LOCM following their intra-arterial administration, age iopromide [9]. The results showed a significant it is clear that there is no difference at all following difference in CIN rates between the two groups. their intravenous injection. In a randomized, multi- Nevertheless, it was difficult to conclude that iodix- center trial (the IMPACT study), Barrett et al. [16], anol is less nephrotoxic than all other LOCM. For using the same endpoint as Aspelin et al. in the instance, the only study that included iopamidol in NEPHRIC study [4], recently showed a 2.6% inci- the analysis was conducted in patients with normal dence of CIN after intravenous injection of iodix- renal function who underwent femoral angiography, anol for CT and 0% after injection of iopamidol. All with SCr measured at baseline and at 4 and 18 h patients had reduced renal function even though the post-CM. In that study [8], there was only one case hydration regimen was left to the local centers (on- of CIN, following iodixanol. Most of the weight of ly ~65% of the patients received volume supple- 071_078_00_Thomsen:Thomsen 13-02-2008 9:32 Pagina 73 H. S. Thomsen • MDCT and Contrast Media: What are the Risks? 73 mentation). The results of the IMPACT study con- venous administration was 1.9% and after intra-ar- firmed the conclusions of previous, smaller studies terial administration 9.5%. Dialysis was necessary in by Carraro et al. [17] and Kolehmainen et al. [18], 40% of those developing anuria. However, the av- neither of which found any difference between iodix- erage dose of the gadolinium-based contrast agent anol and the non-ionic LOCM iopromide and io- was three fold or slightly higher in that study. Prince biditrol, respectively, in patients with chronic kid- et al. [20] used the standard dose. Thomsen [22] re- ney disease. Differences in nephrotoxicity due to ported a patient with diabetic nephropathy who de- iodixanol vs.