ADVANCES IN X-RA Y CONTRAST Collected Papers ADVANCES IN X-RAY CONTRAST Collected Papers Edited by P. Dawson Department of Imaging Royal Postgraduate Medical School Hammersmith Hospital London, UK and W. C'auss Schering AG Clinical Development Monomeric X-Ray Contrast Media Berlin, Germany .... " SPRINGER SCIENCE+BUSINESS MEDIA, B.V. Library of Congress Cataloging-in-Publication Data is available. ISBN 978-0-7923-8741-1 ISBN 978-94-011-3959-5 (eBook) DOI 10.1007/978-94-011-3959-5 Printed on acid-free paper AII Rights Reserved © 1998 Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers in 1998 No pari of this publication may be reproduced or utilized in any form or by any means, electronic, mechanical, including photocopying, recording or by any information storage and relrieval system, without wrillen permission from the copyright owner. Contents Preface Peter Dawson On the nephrotoxic potential of the iodinated intravascular contrast agents Peter Dawson 3 Nephrotoxicity related to X-ray contrast media Knut Joachim Berg and Jar! AJ acobsen 11 The role of contrast agents in thromboembolic phenomena in clinical angiography Peter Dawson 20 Delayed reactions to intravenous injections of urographic contrast media Peter Davies 29 Contrast media use in paediatrics Paul Babyn 34 Cardiac use and effects of contrast agents Michael Bettmann 46 Contrast agents in interventional radiology Peter Dawson 52 Contrast enhancement in computed tomography of the liver, pancreas and spleen Andreas Adam 57 Spiral computed tomography - a short overview Mathias Langer 63 Electron Beam Computed Tomography (EBCT) R Knapp, I Banger!, D zur Nedden 67 Iodinated contrast agents in neuroradiology Ronald J Zagoria 81 Development of intravascular contrast agents: the first 100 years Ronald G Grainger 89 Risk factors, prophylaxis and therapy of X-ray contrast media reactions William H Bush, Jr 97 Contrast medium administration in spiral computerised tomography: an overview of a consensus meeting in radio diagnosis S Feuerbach 107 Index 111 P Dawson and W Clauss, (eds.), Advances in X-Ray Contrast: Collected Papers. 1 [:) 1998 Kluwer Academic Publishers. Introduction For all that new non-X-ray technologies such as agents; the important organ-specific toxicities, car MR and ultrasound and its various manifestations diac toxicity, neurotoxicity and nephrotoxicity and have made an enormous impact in recent years on high-dose toxicity as encountered in complex pro the practice of medical imaging, the use of X-rays cedures; the sometimes special circumstances and and X-ray contrast-enhancing agents has retained occasional extreme conditions to which contrast an important position at the heart of the process, agents may be exposed in Interventional Radiol Indeed, with its frequent requirements for high total ogy; the special in several ways case of paediatric dose regimes, CT has increased the the use of con radiology; the controversial subject of thrombo trast agents. Even helical/spiral CT which, it was embolic phenomena in clinical angiography; and initially argued, should reduce contrast as well as the precise role of contrast agents. As regards the radiation loads may actually require just as much practicalities of contrast administration regimes or more of both cause of the potential it offers for and imaging protocols it is really only in the area multi-phase scanning. ofCT that there is debate and controversy, and arti Iodinated intravascular X-ray contrast agents, cles are included which cover CT of the liver, spleen especially the more recently developed non-ionic and pancreas, and protocols for the new spiral! agents, continue therefore to playa pivotal role in helical technology and even for the much less widely clinical imaging. available electron-beam CT technology visualiza These succinct and authoritative articles, origin tion, and pulmonary embolus diagnosis, and proto ally appearing in the Advances in X-ray Contrast cols for contrast administration with this technol journal series, range sufficiently widely for their ogy are also discussed. compilation in this volume to be considered a This book should provide either a good general mini-textbook on the water-soluble iodinated X introduction to the subject of X-ray contrast agents ray contrast agents and their applications. Each is for the radiology trainee, or a quick and readable written by an acknowledged and experienced refresher course for the established radiologist or expert in the field. They usefully cover the develop for clinicians such as cardiologists, nephrologists mental history of the agents; defined risk factors, and neurologists with an interest in contrast agents. approaches to prophylaxis and, ultimately, of the treatment of adverse reactions; the interesting sub Dr Peter Dawson ject of supposed delayed reactions to contrast P. Dawson and W. Clauss, (eds.), Advances in X-Ray Contrast: Collected Papers. 3-10 (j';) 1998 Kluwer Academic Publishers. On the nephrotic potential of the iodinated intravascular agents P Dawson, PhD, MRCP, FRCR Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK A little more than 60 years ago, a young American, realization that, with a sufficiently high dose of contrast Moses Swick, working in the department of the agent in renal failure, it was usually possible to produce urologist von Lichtenberg in Berlin, used a mono a nephrogram and to exclude obstruction, important iodinated pyridine compound to perform an intra information capable of changing patient management. venous urogram [1]. Since then, there have been Macewan et al [4] and Schwartz et al [5] demonstrated several generations of iodinated intravascular contrast this in children and adults, and a number of others agents, the latest being the low osmolality ionic and reported similar findings [6-9]. These latter authors non-ionic types [2,3]. In spite of the development of reported no evidence of reduced renal function and by new imaging techniques, the scale of use and, the mid 1970s high-dose urography was accepted as relevantly, the doses used in many examinations have useful and safe, provided that the patient was hydrated. tended to increase. However, this early evidence for the safety of contrast Contrast agent -associated nephrotoxicity, broadly administration as regards renal function is a little defined as an acute impairment of renal function questionable, particularly in the light of subsequent associated with the administration of radiological work and in the context of more widely accepted use of contrast media, other factors having been eliminated, high doses. In some of the studies no data on renal was first recognized in the 1930s after the widespread function were actually presented [8]; some used urine adoption of urographic and angiographic contrast output only, with serial blood urea measurements, as an procedures using the (then) new agents. In the earliest indication of renal function; in others, only a small days, the general systemic adverse reactions (pain, number of patients was included [7] so a relatively low vomiting, etc.) to these agents dominated the clinical incidence of impaired renal function might easily have picture and contrast medium-induced nephropathy remained undetected. In none of the studies were received little attention until about 1970. Even in the controls established. This lack of proper control, in period from the mid 1950s to the mid 1970s, the heyday fact, dogs the debate about the incidence, and even the of the ionic, high osmolar, ratio 1.5 contrast media, the very existence, of contrast agent -associated nephro number of reported contrast-medium associated renal toxicity up to the present day. In more recent years, the events was apparently in single figures. safety of contrast agents administered against a However, the general toxicity profile of these agents background of pre-existing renal failure has become was considerably better than that of previously used less certain, following a considerable number of reports materials and this obviously led to a more liberal use of of deteriorating renal function associated with such contrast media, including the use of higher doses. This administration. In some prospective studies, contrast trend has continued further with the more recent media were reportedly involved in up to 10% of all introduction of 'low osmolality' agents [2,3]. In this cases of renal failure occurring in hospitalized patients, context, it is worth noting that over the last half century thus apparently exceeding aminoglycoside antibiotics there have been several changes in the perception of in nephrotoxic potential. The incidence of reported this whole subject. In the 1950s it was widely believed renal problems has been increasing since 1970, perhaps that urography was relatively contraindicated in the as a result of the use of increasing doses, because of a face of renal impairment because the contrast agents heightened awareness of the problem and, paradoxi were likely to engender a further deterioration in renal cally, with the tendency to undertake contrast studies function and, in the case of urography, unlikely to yield with newer contrast agents on sicker patients than in the any useful information. By the early 1960s came the past. 4 However, problems arise in evaluating all these toxicity is a very difficult concept to pin down. Patients reports as much as in evaluating the earlier ones. They in or visiting hospital and undergoing contrast are retrospective and uncontrolled and, to complicate enhanced diagnostic and interventional procedures matters more, a wide range of definitions of contrast may be subject to a number of nephrotoxic insults: they agent-induced nephropathy is used. Table I shows just may be dehydrated; they may be receiving other some of the different degrees of serum creatinine definitely nephrotoxic drugs; they may have already accepted as the criteria for a diagnosis of contrast impaired renal function and, unknown to their doctors, associated nephropathy by various authors [10-15J. may be on a declining curve of renal function before contrast is administered. Just as hospitals are some Table 1: Various criteria for nephrotoxic events times said, in general, to be dangerous for patients' health, so perhaps we may consider hospitals to be Reference Serum creatinine concentration fundamentally nephrotoxic! Indeed, perhaps there is an important message in the only study which utilized Eisenherg et al [10] 1980: > 1.0 mg/dl (90 [lmoIlL) controls. Patients attending for CT were randomly Carval\o et al [I I] 1977: >2.0 mg/dl (180 [lmollL) assigned to a contrast enhancement or non-contrast D'Elia et al[12] 1982: >1.0 mg/dl (90 [lmollL) enhancement group and their renal function before and Byrd and Sherman [13] 1979: >2.0 mg/dl (180 [lmollL) Older et al[14J 1980: >0.6 mg/dl (> 55 )lmollL) and at after the procedure was studied. The incidence of least 40% of preconlrasl level apparently procedure-related disturbance of renal Rao et al [15] 1980: >1.0 mg/dl (90 [lmoIlL) function was the same in both groups. Nevertheless, it is on such essentially anecdotal evidence that all our dogma in this area is built. Not Clinically, the glomerular filtration rate (GFR) is only is it accepted as an article of faith by both usually assessed indirectly by measuring serum radiologists and nephrologists that contrast agents creatinine concentrations or, more precisely, by possess a nephrotoxic potential, but associated measuring creatinine clearance. This definition may increased risk factors are dogmatically cited: dehydra greatly underestimate toxicity not severe enough to tion, pre-existing renal impairment, old age, diabetes affect such relatively insensitive markers of renal [J6]. Below, we discuss the relationship between function. Serum creatinine concentration, which is intravascular iodinated contrast agents and the kidney used most often as an indicator of renal dysfunction, and the known interactions between them. Thereby, may not be elevated above the normal range until the possible mechanisms by which contrast agents might GFR falls significantly below 50%. In the majority of be expected adversely to affect renal function are reported cases, the serum crcatinine level returns to indicated. We then briefly discuss the animal model baseline values within 7-10 days but renal failure, data and the role of the modem low osmolality contrast requiring short- or even long-term dialysis, is an agents. Finally, empirical approaches to the avoidance outcome which occurs in some groups. An unchanged of contrast agent -associated renal problems are serum creatinine concentration cannot, of its nature, proposed. exclude any more subtle and long-term effects such as loss of functional capacity in the kidney and no one has yet studied whether these apparently transient adverse CONTRAST HANDLING BY THE KIDNEY effects of contrast agents on renal function in any way affect the rate of progression towards endstage renal Following intravascular injection, the iodinated failure. It is certain that the true incidence of non contrast agents are rapidly distributed throughout the oliguric renal impairment associated with contrast whole extracellular fluid space of the body, intra-and agent administration is not known because it is by no extravascular. The materials are passively filtered by means routine to monitor renal function systematically the glomeruli and are excellent markers of glomerular following contrast agent administration. filtration rate. There is no active secretion or It is important to understand in any discussion of reabsorption of contrast agent by the tubular cells. these matters that contrast agent-associated nephro- Less than 1% of administered agent is non-renally 5 excreted if renal function is normal. Filtered contrast reduced nephron population excrete the contrast agent proceeding along the nephron is concentrated. In material, or the foreign or toxic substances, through the proxi mal tubule some 85% of water in the filtrate is the smaller number of nephrons, thereby increasing the automatically reabsorbed. In the distal and collecting 'dose' per nephron. Volume depletion of patients or tubules, water reabsorption is under the control of any obstruction to the flow of urine may lead to antidiuretic hormone (ADH/vasopressin). In the exposure to a greater concentration for a longer period. presence of normal renal function and dehydration, Furthermore, since contrast media are excreted very high concentrations indeed of contrast agent may primarily by glomerular filtration, renal insufficiency be achieved in the distal tubules. These concentrating results in a longer plasma half-life of the contrast mechanisms are opposed by the osmotic effects medium and a greater exposure, therefore, for the produced by the contrast agents themselves, and the kidney. higher osmolality agents in high doses may overwhelm Immediately after administration of a contrast agent the concentrating mechanisms. This occurs more into the circulation the size of the kidneys changes. The readily, and at lower doses, when, in patients with decrease and subsequent increase are similar whether a impaired renal function, the same contrast load is high osmolar or low osmolar agent is used [ 191. Within filtered by a diminished number of functioning seconds, a powerful osmotic diuresis begins when high glomeruli. The lower osmolality agents, both ionic osmolar agents are used and a less marked diuresis and non-ionic, are only able to override the concen following non-ionic agents [20]. Since the distension of trating mechanisms in any given patient at a higher the kidney is similar following both types of media the administered dose and, at any dose in a given patient, phenomenon seems unrelated to osmolality, and no will be found in higher concentrations in the urine than entirely convincing explanation is currently available. the higher osmolality agents. In the past, and to some extent still, active dehydration was inflicted upon patients in order to obtain high urinary concentrations Renal pelj:usion and denser pyelograms in intravenous urography. Most centres, however, have abandoned this practice because of the alleged association between dehydra Immediately after the contrast agents reach the kidney tion and the adverse effects of contrast agents on the there is an initial increase followed by a more kidney [16-18]. prolonged decrease in renal blood flow. These changes are greater in dehydrated animals than in normally hydrated ones and greater following high PATHOPHYSIOLOGY OF ADVERSE osmolality agents than low osmolality agents [21]. The CONTRAST EFFECTS IN THE KIDNEY decrease in blood flow may be long-lasting, especially in the dehydrated animal, and may severely affect renal Since 99% of an intravascularly administered function. Indeed, during renal angiography in dogs, it iodinated contrast medium is excreted by the renal has been shown that high osmolality agents may affect route, the kidney may be legitimately seen as a target renal blood flow so severely as to produce a patchy organ for these agents, more so since normal kidneys contrast medium retention effect [22]. What appears to actively increase their concentration after filtration. be the same phenomenon has been observed by Love et Indeed, while the kidneys represent less than 0.5% of al [231 in some patients having CT, 24 hours or so after total body mass, they receive up to 25% of the resting an arteriogram (Figure I). cardiac output and have a high oxygen consumption, The effect appears in Love's work [24] to be rendering them sensitive to any events or agents correlated with degree of impairment of renal function. impairing oxygen uptake in any way. Furthermore, as Indeed, these observations are, in this writer's opinion, indicated, it is one ofthe basic purposes of the kidney to far more convincing than the wealth of other, largely excrete foreign and toxic substances while preserving anecdotal case reports, based on measurements of water - in other words, to increase the concentrations of creatinine, that contrast agents really do have a these materials as they pass through it. Patients with a nephrotoxic potential of clinical importance. 6 Vasopressin response to central injection of contrast media 4 lopromide 370 Diatrizoate 370 3 Figure 1 CT scan the day after angiography. Notice the renal cortical enhancement though no contrast has been given for more than 12 hours. (Images kindly loaned by Dr. Leon Love of Loyola Medical Centre.) Glomerular injury o Trewhella et al [17,18] have reported that contrast o 5 10 o 5 10 agents administered as rapid bolus injections result in a Time (mins) after injection of contrast medium rapid rise in circulating vasopressin levels, which has an adverse effect on renal perfusion (Figure 2). In dog experiments, not only are vasopressin Figure 2 Vasopressin responses in normally hydrated concentrations appropriately elevated in dehydration patients to bolus administration of 'high' [Diatrizoate] and but the administration of materials such as contrast 'low' [Iopromide] osmolality contrast agents. The rises agents, increasing the osmolality of body fluids, associated with the 'high' osmolality agent are from normal range to dehydration ranges. Much higher base levels and produces an exaggerated vasopressin rise response. larger rises could be anticipated in the dehydrated patient. The authors suggested that vasopressin is consequently an important mediator of contrast agent-associated nephrotoxic effects. The hypothesis would certainly explain the alleged association with dehydration as a risk factor. Other factors which may impair renal blood flow glomerular protein leak is seen [22,25-27] and, in this include the well-recognized red cell rigidification sense, are undoubtedly nephrotoxic. The effect is engendered by contrast agents [3]. Table 2 sum greater with the higher osmolality agents than with the marizes various levels at which contrast agents have, or lower osmolality agents but osmolality is clearly not may be expected to have, adverse effects on the kidney. the only factor since metrizarnide produces much the When contrast agents reach the glomeruli they same degree of albuminuria as do the high osmolality undoubtedly are capable of producing injury since a agents. 7 Table 2: Some possible mechanisms of contrast based on an obstructive nephropathy. Contrast agents nephrotoxicity might precipitate with Tamm-Horsfall protein, with abnormal proteins in, for example, myeloma, or with (a) Impainnent of (i) Vasopressin-mediated proteinaceous material resulting from the above Perfusion (ii) Red cell rigidification effects (iii) Intrarenal pressure changes discussed injury to tubular cells. The evidence for (iv) Systemic hypotension this, however, is slim. Saxton and colleagues were (b) Glomerular Injury (i) Osmolality-mediated unable to obtain precipitation of contrast agents with (ii) Chemotoxicity-mediated abnormal myeloma proteins and Dawson and (iii) Hypoxic colleagues were unable to demonstrate precipitation (c) Tubular Injury (i) Osmolality-mediated with Tamm-Horsfall protein [16]. Microscopic (ii) Chemotoxicity-mediated changes are seen after the administration of both ionic (iii) Hypoxic and non-ionic contrast agent in tubular cells and have (d) Obstructive (i) 'Osmotic nephrosis' been described as osmotic nephrosis [29]. This is a Nephropathy (ii) Precipitation of contrast agents with: (a) Normal urinary proteins misnomer since it appears to be largely independent of (b) Abnormal urinary proteins osmosis. The vacuoles seen in the tubular cells seem to (c) Tubular cellular debris be pinocytosed contrast agent. It was once thought that the swelling of tubular cells associated with wide spread osmotic nephrosis might itself result in an obstructive nephropathy and explain a dense persistent TUBULAR CELL INJURY nephrogram. However, the effect, once again, appears When descending along the nephron and, in the normal to be routine rather than idiosyncratic and the kidney, being concentrated dramatically, contrast hypothesis has not stood up to the test of time and agents are clearly capable of injuring the tubular cells further study. since a variety of tubular cell-specific and tubular brush border enzymes may be seen in the urine [25,28,29]. This again clearly illustrates a potential for renal injury ANIMAL MODELS by contrast agents and, equally clearly, has to be A great variety of animal models has been studied and labelled nephrotoxicity. However, the relationship of such routine events to the occasional episodes in a few some of these and their uncertainties have been discussed by Thomsen et al [30]. One particular patients of significant changes in renal function is unclear. Nevertheless, not surprisingly, a large study, by Vaamonde et al [31], was an exhaustive one in the rat and, most interestingly, failed to elicit any literature has been spawned on this subject. One of the findings has been that, rather like the glomerular convincing evidence of nephrotoxic effects other than damage, high osmolality is involved but is not the proteinuria in animals with 'a remnant kidney' (pre exclusive mechanism. Low osmolality agents still existing renal dysfunction model), but this was not produce the phenomenon, though to a lesser degree and associated with any significant degree of renal not in simple proportion to their osmolality. It may be dysfunction. This brings us back to the point about that the magnitude of the effect may be exacerbated by tubular injury undoubtedly being an aspect of impairment of renal blood flow and tubular cell nephrotoxicity but not being in any way obviously hypoxia. related to clinically important events. This striking failure in carefully conducted experiments in a reasonable model moved Katzberg, in an editorial OBSTRUCTIVE NEPHROPATHY [32], to suggest that "there is a real possibility that the 'null hypothesis' may represent the truth". That is to Since, occasionally, a persistent dense nephrogram is say, there may be no such thing as genuine contrast said to be associated with impaired renal function agent-associated nephrotoxicity! This may be too following contrast administration (Figure 1), it has dogmatic a conclusion, but the failure to develop a been suggested that the whole phenomenon might be convincing animal model for contrast agent-associated