British Journalof Urology (1990), 66,561-567
0007-1 331/90/006&0561 /$IO.OO
01990 British Journal of Urology
REVIEW
Intravenous Urography Revisited P. DAWSON Department of Diagnostic Radiology, Royal Postgraduate Medical School, Hammersmith Hospital, London
Intravenous urography remains the most frequently Historical Background performed, contrast agent-enhanced procedure in diagnostic radiology. Newer contrast agents have The first intravenous urogram was performed in made the procedure more comfortable and safer for 1923 at the Mayo Clinic by Osborne et al. (1923). patients, though at a significantly higher cost and These workers noted that the urine in the bladder with changes in the quality and pace of the was opaque to X-rays in some patients with syphilis examination. The historical development of this who had been treated with large intravenous doses important technique is reviewed and the physiology of sodium iodide. However, they had little success of contrast agent handling, essential for understand- in obtaining good visualisation of the renal pelvis ing of image formation, is outlined. The problems and sodium iodide was much too toxic to be of anaphylactoid reactions and contrast agent- administered in enormous doses. It was some 5 years later that the first really associated nephrotoxicity are discussed and the successful IVU was performed using an agent of a place of the newer agents in this picture is indicated. not too dissimilar to the agents of today (Fig. type Despite some dramatic developments in recent years of new technology and techniques of diagnos- 1A). These were mono-iodinated pyridine comtic imaging, such as magnetic resonance imaging pounds which had been synthesised, along with a (MRI), computed tomography (CT), ultrasound large number of others, by Binz and Rath in Berlin and isotope studies, the intravenous urogram (IVU) in their search for an anti-syphilitic agent (Grainremains an important and simple means of visual- ger, 1982). Some of the compounds were found to king the renal tract. It has been performed for more be not exclusively, but rather selectively, excreted than 60 years, during which time the chemistry of in the urine (‘Uroselectans’) and in 1928/9 were the essential contrast agents has changed and the used by a young American, Moses Swick, working sophistication and reliability of radiological and in the Berlin department of the urologist, von film technology have markedly improved but during Lichtenberg, to perform IVUs in animals and man which time the basic technique of the examination (Marshall, 1977; Swick, 1978; Grainger, 1982). Within 2 or 3 years these mono-iodinated has remained unchanged. When carried out with pyridine compounds were replaced by more soluble the most modern of the contrast agents it is a safer versions, carrying 2 iodines and therefore offering procedure than ever before but should, of course, a greater contrast punch (Fig. IB). Because these be used appropriately and always with a thought to agents were very effective tWy held sway until the the alternative techniques which may be available. The interpretation of any radiological examina- early 1950s, when the tri-iodinated benzoic acid tion requires a knowledge of anatomy. Where the group of agents (also based on an idea of Swick) IVU is concerned, a full understanding of the (Grainger, 1982) were introduced (Fig. 2). Just how images also requires some knowledge of physiology. good the second generation pyridine compounds were may be judged from Figure 3, which shows an This essential physiology will be discussed below. IVU obtained in 1934 using one of them. When it is noted that this is a print of a copy of a copy of an old original from a time when radiograpic and film Accepted for publication 15 June 1990 561
562
BRITISH JOURNAL OF UROLOGY CH,COO-Na’
I
I
Do
I Selectan neutral
I
Do
Uroselectan
C H 2 C O O - Meg’
CHI +
I
I
0 0 - Na+
N a 00C
I
0
Uroselectan B
XAI 0
Diodone
Fig. 1 (A) Mono-iodinated pyridine compounds used by Swick to perform the first IVU. (B) Diodinated pyridine compound successors of greater water solubility introduced in the early 1930s.
R2
R3
Proper name Commercial name
H
NHCOCH,
Acetrizoate Urokon, Diaginol
CH,CONH
NHCOCH,
Diatrizoate
CH,CONH
CONHCH,
lothalamate Conray
CH,CONH
NCOCH,
~-
Metrizoate
I
Urografin, Hypaque
Isopaque, Triosil
CH, ~
Fig. 2 The tri-iodinated benzoic acid derivative salts introduced in the 1950s. Still in use today, they are now known as the ‘conventional ionic agents’.
Fig. 3 An IVU performed in England in the 1930s using a second generation pyridine compound (‘Uroselectan B’). Right renal carcinoma. (The author is grateful to Dr L. S. Carstairs for a copy of this film from the R.C.R. Museum).
technology were not what they are now, it will be realised how effective they were. The benzene ring based agents introduced in the 1950s were a further distinct improvement both in terms of contrast density and tolerance, but these ionic agents were all of high osmolality-up to 7 times plasma osmolality-a fact responsible for some of their toxic effects. In recent years they have been superseded but not entirely replaced by a new generation of ‘low osmolality’ agents (Dawson et al., 1983b). These are of 2 kinds, non-ionic and mono acid dimeric. The former are much better tolerated intravenously than either the earlier agents or the latter monoacid dimeric agents (Manhire et al., 1984). Some non-ionic compounds are illustrated in Figure 4. These are not only associated with a reduced incidence and severity of subjective side effects than any other intravenous agents but are also significantly safer in terms of
being associated with a reduced incidence of major idiosyncratic adverse reactions.
Technique As indicated already, the basic technique of the
IVU has changed very little since the subject was put on a rigorous scientific basis in the 1960s (Saxton, 1969). A bolus of an iodinated contrast agent is administered rapidly intravenously (typically 300 mg iodine/kg body weight over min) and an ‘immediate’ film of the renal areas obtained (nephrogram phase). (In the past some radiologists preferred to give a slow infusion but this is now rarely done in Europe). More films are obtained of the renal areas at about 5 min to demonstrate the contrast-filled pelvicaliceal system (pyelogram phase). At about 10min a full length abdominal film is obtained to demonstrate ureters and bladder
-
-+
563
INTRAVENOUS UROGRAPHY REVISITED
OH
CH,OH
I
I CONHCHCH~OH
CONHCHl-
CH - CHZOH
I
CH,CO, CONH - CH - CHZOH
CH,CHCOHN
I
OH
I
CONHCH,CHCH,OH
N
I
CH,OH
H c c H,cA
I
c H,
I
I
OH
OH
~ M O L
IOPAMIDOL CH,
I
OH
I
CONHCH,CHCH,OH I
CH3-O-CH;-C-N II
I
II
I
O
H
I
CONHCHZCHCH,OH II OH
IOPROMIDE Fig. 4 The non-ionic 'low osmolality' contrast agents in use in the UE:. Iopamidol (Niopam) (Merck), iohexol (Omnipaque) (Nycomed), iopromide (Ultravist) (Schering Health Care).
and finally, when appropriate, a post-micturition film of the bladder may be taken. Variations on the theme include tomograms when appropriate, administration of a diuretic to precipitate and demonstrate a pelviureteric junction obstruction, prone films and delayed films to try to demonstrate the level of an obstruction. The review of Saxton (1969), though 20 years old and having nothing to say about low osmolality contrast agents, remains a key source of basic information on all aspects of the procedure. More recently, Hattery et al. (1988) have provided a technique update and Strautman et al. (1989) have investigated the possibility of performing digital intravenous urography, taking advantage of the high contrast sensitivity of such systems to use lower doses of contrast. Unfortunately, the latter authors found that no amount of post-acquisition image manipulation could compensate for the diminished image quality obtained using a low dose rather than a conventional dose of contrast agent. They did not use any low osmolality contrast agents in their investigation, leaving unanswered the question of whether some aspects of low dose digital IVUs might be adequate with low osmolality agents in view of the higher urinary concentrations these achieve (see below). Traditionally, patients have been dehydrated
prior 'to the examination in order to increase urinary contrast concentrations and pyelographic density. This is still widely practised but should be abandoned in view of its importance as a factor increasing the risk of nephrotoxic events associated with contrast agents (Dawson, 1985; Trewhella et al., 1987; Dawson and Trewhella, 1990). In summary, other than a greater range of choice of contrast media the technique remains essentially unchanged since the 1960s, and very little changed for half a century.
Physi'ologyand Contrast Handling Following rapid bolus injection, iodinated contrast agents are rapidly diluted in the circulating blood volume and begin immediately to diffuse across the blood vessel walls into the extravascular extracelM a r space. The agents do not significantly enter the iritracellular space. Within about 2 min some 70% of the administered dose has disappeared from the plasma. Strictly speaking, an equilibrium is never reached, for although distribution throughout the extracellular fluid space is very rapid, the plasma levels begin to fall immediately because of renal excretion. Contrast molecules are excreted by the kidneys entirely by passive glomerular filtration with no significant tubular secretion or reabsorp-
564
BRITISH JOURNAL OF UROLOGY
tion. The plasma half-life of contrast agents is of the order of 2 h.
The Nephrogram The nephrogram is an essentially simple phenomenon. It represents X-ray absorbing iodinated contrast agent in the renal vasculature, in the extravascular extracellular space and in the proximal tubules. Radiographic density obtained in an ‘immediate’ nephrogram is a function of the total dose injected and the size of the patient. The Pyelograrn The pyelogram is based on a more complex series of physiological events. If there is normal renal tubular function, 85% of water in the glomerular filtrate is reabsorbed from the proximal tubules. In the distal and collecting tubules more water is reabsorbed with further concentration of the urine, but this process is active and under the control of
vasopressin. It is, of course, in order to increase the amount of absorption here that vasopressin levels have been traditionally raised in patients attending for IVU by dehydration. This should now be abandoned, as will be discussed below. The presence in the glomerular filtrate of nonreabsorbable foreign molecules such as urea or contrast agent will engender an osmotic diuretic effect opposing the urine concentrating mechanisms. The osmotic effect will increase in accordance with the total dose of contrast agent (Fig. 5). As this dose increases, so does the amount of contrast material delivered into the urine. The osmotic diuresis increases and the urine concentration and pyelographic density therefore increase. However, at a certain dose level, the urine concentration reaches a plateau as the osmotic diuretic effect begins to dominate. After this point, pyelographic density cannot be enhanced further by any increase in contrast dose. With conventional ionic
Diuresis
A
Iodine concentration
A
i I
B
300 mg I/kg
600 mg I/kg
Fig. 5 (A) The osmotic diuresis increases with increasing contrast load. (B) With increasing dose of contrast agent the urinary concentration and pyelographic density increase up to a point beyond which the osmotic diuresis dominates and a urinary iodine concentrationplateau is reached. Concentrationsare always higher for the low osmolality agents and the dose to achieve maximum is approximatelytwice as high because of their lower osmolality.
565
INTRAVENOUS UROGRAPHY REVISITED
contrast agents the maximum pyelographic density is achieved with a dose of approximately 300 mg iodine/kg body weight (Saxton, 1969; Dawson et al., 1984), this being the sort of dose which is given clinically in the UK for urography. However, with the low osmolality agents the diuretic effect, which is based on osmolality, is less marked and larger doses of contrast continue, to a higher level, to increase the urinary iodine concentration and therefore the pyelographic density. It is not until approximately 600 mg iodine/kg body weight that the plateau is reached (Dawson et al., 1984). Thus, for any given iodine dose administered, the low osmolality agents will produce higher urinary concentrations and pyelographic densities ; they are also capable, in principle, for basic physiological reasons, of producing higher urinary concentrations and pyelographic densities than could be achieved by the conventional high osmolality agents at any dose. A strong osmotic effect with a large osmotic diuresis will assist in the distension of the collecting system of the kidney, a desirable feature in an IVU. In the early days it was predicted that the low osmolality agents might produce a dense but rather poorly distended pelvicaliceal system with consequent loss of diagnostic information. However, at the iodine doses used in the UK and certainly with the use of abdominal compression, this anxiety has not been borne out in practice. However, it may be that there is a dose-dependent factor to be considered and if a low dose IVU is performed with a low osmolality agent there might, even with abdominal compression, be poor distension of the pelvicaliceal system. Another consideration, predictable on simple physiological grounds, is that there will be slow filling of the bladder when the low osmolality agents are used, the reduced osmotic diuresis being responsible. Clinical Experience The non-ionic agents have been in use in the UK for about 8 years. It was clear from the outset that they were better tolerated by patients and it was also realised that the IVU they produced was different in its details and in its style and pace, facts which are explicable on the basis of the analysis outlined above. Nephrograms appeared to be comparable, allowing for any difference in total iodine dose administered, but pyelograms seemed to be denser. At least when abdominal compression was used, there was no significant loss of pyelo-
graphic distension. These observations were first p1ace:d on a sound basis in a double-blind study by Dawson et al. (1984). The change of pace of the examination, arising from the lesser diuretic effect of the low osmolality agents, is seen in the relatively slow filling of the bladder. To the extent that the cystogram is an important part of the examination, it is a. slower examination. Other authors have made similar observations but with differences in detail and emphasis. Kay et al. (1988) found a difference in the pyelographic quality and density between 2 non-ionic agents but no simple explanation for this is readily to hand. Rawllinson et al. (1988) studied a large number of infants with a conventional agent and with 2 nonionic agents. It was found that conventional ionic agenit yielded slightly better nephrograms and pyelograms but the authors thought the differences had no significant effect on the information obtained. The explanation for this deviation from both theory and other clinical practice was not obvious but may be related to the lower dose used in children. It may be that there is a dose threshold which must be passed if good pyelographic density and distension are to be achieved. Safely of New Agents Other than the general question of exposure to radiation, there are 2 significant problems associated with the IVU or, indeed, with any administration of an intravascular contrast agent. These are the severe (and occasionally fatal) iodiosyncratic adverse reactions to the agents (Ansell, 1970) and the nephrotoxic potential associated with them (Dawson, 1985; Dawson and Trewhella, 1990). Anaphylactoid Reactions The mechanisms of these severe adverse reactions remain obscure, though a number have been postulated (Dawson, 1985). Perhaps the only thing which is clear is that most of them are not truly anaphylactic. There are some established risk factors, which will significantly increase the likelihood of such a major adverse reaction. These include previous reactions to contrast material, allergy to other materials, asthma, atopy and cardiac disease (Ansell, 1970; Grainger, 1984). Apart from the interesting matter of pathophysiology, however, a crucially important question is : are the non-ionic agents safer in this regard? Certainly the nlon-ionics are biologically more inert (Dawson, 1985), as is reflected in their greater tolerance, and so greater safety would not be too surprising.
566 Early evidence of their greater safety as compared to the conventional agents, in terms of a reduced degree of subclinical bronchospasm and a reduced number of electrocardiographic changes associated with their administration, was observed by Dawson et al. (1983a) and Heron et al. (1984). The general impression in Europe was that the incidence of severe reactions was reduced with their use but it was felt that formal studies to establish this firmly would be difficult, if not impossible, to organise. This was because of the difficulty of controlling the very large scale multicentre trial which would be necessary and because a policy had been widely implemented of using non-ionic agents in all patients with definable risk factors on the working assumption that they were safer (Grainger, 1984). This would skew the data against the non-ionic agents; in addition, many radiologists would have misgivings from the ethical and medico-legal standpoint about giving conventional agents to any (control) patients who had definable risk factors. In spite of such considerations, large scale studies have been performed in Australia (Palmer, 1988) and in Japan (Katayama et al., unpublished observations). Both of these studies confined themselves entirely to intravenous injections of their conventional or non-ionic agents and so the results are directly relevant to the IVU. The Japanese data on 330,000 patients revealed an approximately 6fold reduction in the incidence of severe and very severe reactions when non-ionics rather than conventional agents were used. The Australian data on 169,000patients indicated a similar finding. In the groups definably at high risk there was a 12fold reduction in the likelihood of a severe reaction in the Australian series. In both studies an interesting paradox emerged. If a patient was definably at high risk and therefore received a non-ionic agent, his risk level, on average, was lower than that of a patient with no definable risk factors who received a conventional ionic agent. In short, it is safer to have a risk factor (assuming you get the non-ionic)! It seems clear that IVUs should be performed with a non-ionic agent since they are better tolerated by patients and because they are safer. However, they are substantially more expensive (5-6 times the cost of the equivalent conventional agent), a fact which has led to their being rationed in most centres, where they are reserved for the definably at risk patients only, in spite of the paradox inherent in this. The medico-legal as opposed to ethical position in the UK appears to be that the use of a
BRITISH JOURNAL OF UROLOGY
conventional agent for the IVU is defensible if no significant risk factors are definable in the patient. If such risk factors are definable, a non-ionic agent should be used. There is no question but that in practice the threshold at which radiologists define ‘increased’or ‘definable’ risk tends to slip and more and more patients are ‘given the benefit of the doubt’. Despite financial restraints, some 40% by volume of all intravascular contrast agent used is now in the form of non-ionic agents. This represents more than 75% of the total expenditure. Although figures are not available, it appears that in intravenous urography the conversion rate to non-ionics has been less than the overall figure. Nephro toxicity
An association between impaired renal function and administration of contrast has long been noted, but the mechanism remains obscure. This is an important issue in all centres where intravascular contrast is administered, but it is of special interest in intravenous urography where, by definition, many patients already have abnormal renal function. It is difficult to obtain hard data in this area and the literature is often confusing and contradictory. A recent editorial has attempted to distinguish between fact and assumption (Dawson and Trewhella 1990). The following can be stated as fact: many patients who receive intravascular contrast agents exhibit a transient rise in creatinine and fall in creatinine clearance ;occasionally a patient may suffer acute-on-chronic clinical renal failure following a contrast examination; in animals and man, proteinuria (indicating renal injury) is seen following contrast injection, particularly after selective renal arteriography. No link has been established between the proteinuria and clinical events and no great significance seems to be attached to minor and short-lived changes in creatinine clearance. It appears that the risk of a significant clinical event is increased if the patient is dehydrated and/or receives a high contrast dose. Other alleged “risk” factors such as diabetes, pre-existing renal failure and old age have not been definitively established (Dawson and Trewhella, 1990). Vasopressin release, stimulated by contrast administration, has been reported (Trewhella et d., 1989). This is an osmolality-related phenomenon and is less marked with the ‘low osmolality’ agent. It is dramatically enhanced in the presence of dehydration. Since vasopressin is a potent vasoconstrictor, it reduces renal perfusion. It has been
567
INTRAVENOUS UROGRAPHY REVISITED
postulated that this may be one of the pathophysiological mechanisms of contrast agent-associated nephrotoxicity, an attractive hypothesis. It would suggest that the low osmolality agents should be safer in this regard, but it must be stressed that this has not been established. Some studies have found no clearcut difference between older and newer agents (Gomes et al., 1989; Schwab et al., 1989), but these are open to criticism and it must be concluded that the question remains open. Whether or not vasopressin is involved in these important events, a consensus is emerging that dehydration should never be actively promoted and, if suspected, an attempt should be made to correct it before any contrast procedure. This is certainly the most important modification of established technique which needs to be reviewed.
References Ansell, G. (1970). Adverse reactions to contrast agents: scope of problem. Invest. Radiol., 5, 374384. Dawson, P. (1985). Contrast agent nephrotoxicity. An appraisal. Br. J . Radiol.,58, 121-124. Dawson, P. (1985). Chemotoxicity of contrast media and clinical adverse effects: a review. Investig. Radiol., 20,52-59. Dawson, P. and Trewhella, M. (1990). Intravascular contrast agents and renal failure. Clin. Radiol. (In press). Dawson, P., Britton, J. and Pitfield, J. (1983a). Contrast media and bronchospasm. A study with iopamidol. Clin. Radiol., 34, 227-230. Dawson, P., Grainger, R. G. and Pitfield, J. (1983b). The low osmolality contrast agents. A simple guide. Clin. Radiol., 34, 221-226. Dawson, P., Heron, C. W. and Marshall, J. (1984). Intravenous urography with low osmolality contrast agents; theoretical considerations and clinical findings. Clin. Radiol., 35, 137-
Grainger, R. G. (1984). The clinical and financial implications of low osmolar radiological contrast media. Clin. Radiol., 35, 251-252. Hattery, R. R., Williamson, B., Hartman, G. W. et al. (1988). Intravenous urography technique. Radiology, 167,593-600. Heron, C . W., Underwood, S. R. and Dawson, P. (1984). Electrocardiographic changes during intravenous urography : a study with iothalamate and iohexol. Clin. Radiol., 35, 137141. Kay, B., Howard, J., Foord, K. D. er al. (1988). Comparison of the image quality of intravenous urograms using low osmolar contrast media. Br. J. Radiol., 61, 589-591. Manhire, A., Dawson, P. and Dennett, R. (1984). Contrast agent induced emesis. Clin. Radiol., 35, 369-370. Marshall, V. F. (1977). The controversial history of excretory urography. In Clinical Urography, ed. Emmett, J. Volume 1, pp. 2-5. Philadelphia: Saunders. Osborse, E. D., Sutherland, C. G., Scholl, A. F. et al. (1923). Roentgenography of the urinary tract during excretion of sodium iodide. J . A . M . A . ,80,368-373. Palmer, F. J. (1988). The RACR survey of intravenous contrast media reactions: final report. Aust. Radiol., 32,426-428. Rawlinrion, J., Hyde, I. and Williams, J. (1988). Quality of urograms in infants: a comparison of sodium diatrizoate, metnizamide and iohexol. Br. J . Radiol., 61, 592-595. Saxton.,H. M. (1969). Urography. Br. J . Radiol., 42, 321-346. Schwab, S. J., Hlatky, M. A., Pieper, K. S. etal. (1989). Contrast nephrotoxicity: a randomised controlled trial of a non-ionic and an ionic radiographic contrast agent. N . Engl. J . Med., 320, 149-153. Strautnian, P. R., Fajardo, L. L., Hillman, B. J. et al. (1989). Evaluation of contrast dose reduction for excretory urography using computed radiography. Eur. J . Radiol., 9,60-63. Swick, IM.(1978). Radiographic media in urology. The discovery of excretion urography. Surg. Clin.North Am., 58, 197771994, Trewhella,M., Dawson, P., Forsling, M. etal. (1989). Vasopressin release in response to intravenously injected contrast media. Br. J. Radiol., 63, 97-100. Trewhella, M., Dawson, P., Rickards, D. et al. (1987). Dehydration, antidiuretic hormone and the IVU. Br. J . Radiol., 60, 445-147.
141.
Gomes, A. S., Lois, J. F., Baker, J. D. et al. (1989). Acute renal dysfunction in high risk patients after angiography : comparison of ionic and non-ionic contrast media. Radiology, 170, 65-68. Grainger, R. G. (1982). Intravascular contrast media-the past, the present and the future. Br. J . Radiol., 55, 1-18.
The Author P. Dawson, MRCP, FRCR, Senior Lecturer and Honorary Conmltant Radiologist, Department of Diagnostic Radiology, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W 12 OHS.
0007-1 331/90/006&0561 /$IO.OO
01990 British Journal of Urology
REVIEW
Intravenous Urography Revisited P. DAWSON Department of Diagnostic Radiology, Royal Postgraduate Medical School, Hammersmith Hospital, London
Intravenous urography remains the most frequently Historical Background performed, contrast agent-enhanced procedure in diagnostic radiology. Newer contrast agents have The first intravenous urogram was performed in made the procedure more comfortable and safer for 1923 at the Mayo Clinic by Osborne et al. (1923). patients, though at a significantly higher cost and These workers noted that the urine in the bladder with changes in the quality and pace of the was opaque to X-rays in some patients with syphilis examination. The historical development of this who had been treated with large intravenous doses important technique is reviewed and the physiology of sodium iodide. However, they had little success of contrast agent handling, essential for understand- in obtaining good visualisation of the renal pelvis ing of image formation, is outlined. The problems and sodium iodide was much too toxic to be of anaphylactoid reactions and contrast agent- administered in enormous doses. It was some 5 years later that the first really associated nephrotoxicity are discussed and the successful IVU was performed using an agent of a place of the newer agents in this picture is indicated. not too dissimilar to the agents of today (Fig. type Despite some dramatic developments in recent years of new technology and techniques of diagnos- 1A). These were mono-iodinated pyridine comtic imaging, such as magnetic resonance imaging pounds which had been synthesised, along with a (MRI), computed tomography (CT), ultrasound large number of others, by Binz and Rath in Berlin and isotope studies, the intravenous urogram (IVU) in their search for an anti-syphilitic agent (Grainremains an important and simple means of visual- ger, 1982). Some of the compounds were found to king the renal tract. It has been performed for more be not exclusively, but rather selectively, excreted than 60 years, during which time the chemistry of in the urine (‘Uroselectans’) and in 1928/9 were the essential contrast agents has changed and the used by a young American, Moses Swick, working sophistication and reliability of radiological and in the Berlin department of the urologist, von film technology have markedly improved but during Lichtenberg, to perform IVUs in animals and man which time the basic technique of the examination (Marshall, 1977; Swick, 1978; Grainger, 1982). Within 2 or 3 years these mono-iodinated has remained unchanged. When carried out with pyridine compounds were replaced by more soluble the most modern of the contrast agents it is a safer versions, carrying 2 iodines and therefore offering procedure than ever before but should, of course, a greater contrast punch (Fig. IB). Because these be used appropriately and always with a thought to agents were very effective tWy held sway until the the alternative techniques which may be available. The interpretation of any radiological examina- early 1950s, when the tri-iodinated benzoic acid tion requires a knowledge of anatomy. Where the group of agents (also based on an idea of Swick) IVU is concerned, a full understanding of the (Grainger, 1982) were introduced (Fig. 2). Just how images also requires some knowledge of physiology. good the second generation pyridine compounds were may be judged from Figure 3, which shows an This essential physiology will be discussed below. IVU obtained in 1934 using one of them. When it is noted that this is a print of a copy of a copy of an old original from a time when radiograpic and film Accepted for publication 15 June 1990 561
562
BRITISH JOURNAL OF UROLOGY CH,COO-Na’
I
I
Do
I Selectan neutral
I
Do
Uroselectan
C H 2 C O O - Meg’
CHI +
I
I
0 0 - Na+
N a 00C
I
0
Uroselectan B
XAI 0
Diodone
Fig. 1 (A) Mono-iodinated pyridine compounds used by Swick to perform the first IVU. (B) Diodinated pyridine compound successors of greater water solubility introduced in the early 1930s.
R2
R3
Proper name Commercial name
H
NHCOCH,
Acetrizoate Urokon, Diaginol
CH,CONH
NHCOCH,
Diatrizoate
CH,CONH
CONHCH,
lothalamate Conray
CH,CONH
NCOCH,
~-
Metrizoate
I
Urografin, Hypaque
Isopaque, Triosil
CH, ~
Fig. 2 The tri-iodinated benzoic acid derivative salts introduced in the 1950s. Still in use today, they are now known as the ‘conventional ionic agents’.
Fig. 3 An IVU performed in England in the 1930s using a second generation pyridine compound (‘Uroselectan B’). Right renal carcinoma. (The author is grateful to Dr L. S. Carstairs for a copy of this film from the R.C.R. Museum).
technology were not what they are now, it will be realised how effective they were. The benzene ring based agents introduced in the 1950s were a further distinct improvement both in terms of contrast density and tolerance, but these ionic agents were all of high osmolality-up to 7 times plasma osmolality-a fact responsible for some of their toxic effects. In recent years they have been superseded but not entirely replaced by a new generation of ‘low osmolality’ agents (Dawson et al., 1983b). These are of 2 kinds, non-ionic and mono acid dimeric. The former are much better tolerated intravenously than either the earlier agents or the latter monoacid dimeric agents (Manhire et al., 1984). Some non-ionic compounds are illustrated in Figure 4. These are not only associated with a reduced incidence and severity of subjective side effects than any other intravenous agents but are also significantly safer in terms of
being associated with a reduced incidence of major idiosyncratic adverse reactions.
Technique As indicated already, the basic technique of the
IVU has changed very little since the subject was put on a rigorous scientific basis in the 1960s (Saxton, 1969). A bolus of an iodinated contrast agent is administered rapidly intravenously (typically 300 mg iodine/kg body weight over min) and an ‘immediate’ film of the renal areas obtained (nephrogram phase). (In the past some radiologists preferred to give a slow infusion but this is now rarely done in Europe). More films are obtained of the renal areas at about 5 min to demonstrate the contrast-filled pelvicaliceal system (pyelogram phase). At about 10min a full length abdominal film is obtained to demonstrate ureters and bladder
-
-+
563
INTRAVENOUS UROGRAPHY REVISITED
OH
CH,OH
I
I CONHCHCH~OH
CONHCHl-
CH - CHZOH
I
CH,CO, CONH - CH - CHZOH
CH,CHCOHN
I
OH
I
CONHCH,CHCH,OH
N
I
CH,OH
H c c H,cA
I
c H,
I
I
OH
OH
~ M O L
IOPAMIDOL CH,
I
OH
I
CONHCH,CHCH,OH I
CH3-O-CH;-C-N II
I
II
I
O
H
I
CONHCHZCHCH,OH II OH
IOPROMIDE Fig. 4 The non-ionic 'low osmolality' contrast agents in use in the UE:. Iopamidol (Niopam) (Merck), iohexol (Omnipaque) (Nycomed), iopromide (Ultravist) (Schering Health Care).
and finally, when appropriate, a post-micturition film of the bladder may be taken. Variations on the theme include tomograms when appropriate, administration of a diuretic to precipitate and demonstrate a pelviureteric junction obstruction, prone films and delayed films to try to demonstrate the level of an obstruction. The review of Saxton (1969), though 20 years old and having nothing to say about low osmolality contrast agents, remains a key source of basic information on all aspects of the procedure. More recently, Hattery et al. (1988) have provided a technique update and Strautman et al. (1989) have investigated the possibility of performing digital intravenous urography, taking advantage of the high contrast sensitivity of such systems to use lower doses of contrast. Unfortunately, the latter authors found that no amount of post-acquisition image manipulation could compensate for the diminished image quality obtained using a low dose rather than a conventional dose of contrast agent. They did not use any low osmolality contrast agents in their investigation, leaving unanswered the question of whether some aspects of low dose digital IVUs might be adequate with low osmolality agents in view of the higher urinary concentrations these achieve (see below). Traditionally, patients have been dehydrated
prior 'to the examination in order to increase urinary contrast concentrations and pyelographic density. This is still widely practised but should be abandoned in view of its importance as a factor increasing the risk of nephrotoxic events associated with contrast agents (Dawson, 1985; Trewhella et al., 1987; Dawson and Trewhella, 1990). In summary, other than a greater range of choice of contrast media the technique remains essentially unchanged since the 1960s, and very little changed for half a century.
Physi'ologyand Contrast Handling Following rapid bolus injection, iodinated contrast agents are rapidly diluted in the circulating blood volume and begin immediately to diffuse across the blood vessel walls into the extravascular extracelM a r space. The agents do not significantly enter the iritracellular space. Within about 2 min some 70% of the administered dose has disappeared from the plasma. Strictly speaking, an equilibrium is never reached, for although distribution throughout the extracellular fluid space is very rapid, the plasma levels begin to fall immediately because of renal excretion. Contrast molecules are excreted by the kidneys entirely by passive glomerular filtration with no significant tubular secretion or reabsorp-
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tion. The plasma half-life of contrast agents is of the order of 2 h.
The Nephrogram The nephrogram is an essentially simple phenomenon. It represents X-ray absorbing iodinated contrast agent in the renal vasculature, in the extravascular extracellular space and in the proximal tubules. Radiographic density obtained in an ‘immediate’ nephrogram is a function of the total dose injected and the size of the patient. The Pyelograrn The pyelogram is based on a more complex series of physiological events. If there is normal renal tubular function, 85% of water in the glomerular filtrate is reabsorbed from the proximal tubules. In the distal and collecting tubules more water is reabsorbed with further concentration of the urine, but this process is active and under the control of
vasopressin. It is, of course, in order to increase the amount of absorption here that vasopressin levels have been traditionally raised in patients attending for IVU by dehydration. This should now be abandoned, as will be discussed below. The presence in the glomerular filtrate of nonreabsorbable foreign molecules such as urea or contrast agent will engender an osmotic diuretic effect opposing the urine concentrating mechanisms. The osmotic effect will increase in accordance with the total dose of contrast agent (Fig. 5). As this dose increases, so does the amount of contrast material delivered into the urine. The osmotic diuresis increases and the urine concentration and pyelographic density therefore increase. However, at a certain dose level, the urine concentration reaches a plateau as the osmotic diuretic effect begins to dominate. After this point, pyelographic density cannot be enhanced further by any increase in contrast dose. With conventional ionic
Diuresis
A
Iodine concentration
A
i I
B
300 mg I/kg
600 mg I/kg
Fig. 5 (A) The osmotic diuresis increases with increasing contrast load. (B) With increasing dose of contrast agent the urinary concentration and pyelographic density increase up to a point beyond which the osmotic diuresis dominates and a urinary iodine concentrationplateau is reached. Concentrationsare always higher for the low osmolality agents and the dose to achieve maximum is approximatelytwice as high because of their lower osmolality.
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contrast agents the maximum pyelographic density is achieved with a dose of approximately 300 mg iodine/kg body weight (Saxton, 1969; Dawson et al., 1984), this being the sort of dose which is given clinically in the UK for urography. However, with the low osmolality agents the diuretic effect, which is based on osmolality, is less marked and larger doses of contrast continue, to a higher level, to increase the urinary iodine concentration and therefore the pyelographic density. It is not until approximately 600 mg iodine/kg body weight that the plateau is reached (Dawson et al., 1984). Thus, for any given iodine dose administered, the low osmolality agents will produce higher urinary concentrations and pyelographic densities ; they are also capable, in principle, for basic physiological reasons, of producing higher urinary concentrations and pyelographic densities than could be achieved by the conventional high osmolality agents at any dose. A strong osmotic effect with a large osmotic diuresis will assist in the distension of the collecting system of the kidney, a desirable feature in an IVU. In the early days it was predicted that the low osmolality agents might produce a dense but rather poorly distended pelvicaliceal system with consequent loss of diagnostic information. However, at the iodine doses used in the UK and certainly with the use of abdominal compression, this anxiety has not been borne out in practice. However, it may be that there is a dose-dependent factor to be considered and if a low dose IVU is performed with a low osmolality agent there might, even with abdominal compression, be poor distension of the pelvicaliceal system. Another consideration, predictable on simple physiological grounds, is that there will be slow filling of the bladder when the low osmolality agents are used, the reduced osmotic diuresis being responsible. Clinical Experience The non-ionic agents have been in use in the UK for about 8 years. It was clear from the outset that they were better tolerated by patients and it was also realised that the IVU they produced was different in its details and in its style and pace, facts which are explicable on the basis of the analysis outlined above. Nephrograms appeared to be comparable, allowing for any difference in total iodine dose administered, but pyelograms seemed to be denser. At least when abdominal compression was used, there was no significant loss of pyelo-
graphic distension. These observations were first p1ace:d on a sound basis in a double-blind study by Dawson et al. (1984). The change of pace of the examination, arising from the lesser diuretic effect of the low osmolality agents, is seen in the relatively slow filling of the bladder. To the extent that the cystogram is an important part of the examination, it is a. slower examination. Other authors have made similar observations but with differences in detail and emphasis. Kay et al. (1988) found a difference in the pyelographic quality and density between 2 non-ionic agents but no simple explanation for this is readily to hand. Rawllinson et al. (1988) studied a large number of infants with a conventional agent and with 2 nonionic agents. It was found that conventional ionic agenit yielded slightly better nephrograms and pyelograms but the authors thought the differences had no significant effect on the information obtained. The explanation for this deviation from both theory and other clinical practice was not obvious but may be related to the lower dose used in children. It may be that there is a dose threshold which must be passed if good pyelographic density and distension are to be achieved. Safely of New Agents Other than the general question of exposure to radiation, there are 2 significant problems associated with the IVU or, indeed, with any administration of an intravascular contrast agent. These are the severe (and occasionally fatal) iodiosyncratic adverse reactions to the agents (Ansell, 1970) and the nephrotoxic potential associated with them (Dawson, 1985; Dawson and Trewhella, 1990). Anaphylactoid Reactions The mechanisms of these severe adverse reactions remain obscure, though a number have been postulated (Dawson, 1985). Perhaps the only thing which is clear is that most of them are not truly anaphylactic. There are some established risk factors, which will significantly increase the likelihood of such a major adverse reaction. These include previous reactions to contrast material, allergy to other materials, asthma, atopy and cardiac disease (Ansell, 1970; Grainger, 1984). Apart from the interesting matter of pathophysiology, however, a crucially important question is : are the non-ionic agents safer in this regard? Certainly the nlon-ionics are biologically more inert (Dawson, 1985), as is reflected in their greater tolerance, and so greater safety would not be too surprising.
566 Early evidence of their greater safety as compared to the conventional agents, in terms of a reduced degree of subclinical bronchospasm and a reduced number of electrocardiographic changes associated with their administration, was observed by Dawson et al. (1983a) and Heron et al. (1984). The general impression in Europe was that the incidence of severe reactions was reduced with their use but it was felt that formal studies to establish this firmly would be difficult, if not impossible, to organise. This was because of the difficulty of controlling the very large scale multicentre trial which would be necessary and because a policy had been widely implemented of using non-ionic agents in all patients with definable risk factors on the working assumption that they were safer (Grainger, 1984). This would skew the data against the non-ionic agents; in addition, many radiologists would have misgivings from the ethical and medico-legal standpoint about giving conventional agents to any (control) patients who had definable risk factors. In spite of such considerations, large scale studies have been performed in Australia (Palmer, 1988) and in Japan (Katayama et al., unpublished observations). Both of these studies confined themselves entirely to intravenous injections of their conventional or non-ionic agents and so the results are directly relevant to the IVU. The Japanese data on 330,000 patients revealed an approximately 6fold reduction in the incidence of severe and very severe reactions when non-ionics rather than conventional agents were used. The Australian data on 169,000patients indicated a similar finding. In the groups definably at high risk there was a 12fold reduction in the likelihood of a severe reaction in the Australian series. In both studies an interesting paradox emerged. If a patient was definably at high risk and therefore received a non-ionic agent, his risk level, on average, was lower than that of a patient with no definable risk factors who received a conventional ionic agent. In short, it is safer to have a risk factor (assuming you get the non-ionic)! It seems clear that IVUs should be performed with a non-ionic agent since they are better tolerated by patients and because they are safer. However, they are substantially more expensive (5-6 times the cost of the equivalent conventional agent), a fact which has led to their being rationed in most centres, where they are reserved for the definably at risk patients only, in spite of the paradox inherent in this. The medico-legal as opposed to ethical position in the UK appears to be that the use of a
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conventional agent for the IVU is defensible if no significant risk factors are definable in the patient. If such risk factors are definable, a non-ionic agent should be used. There is no question but that in practice the threshold at which radiologists define ‘increased’or ‘definable’ risk tends to slip and more and more patients are ‘given the benefit of the doubt’. Despite financial restraints, some 40% by volume of all intravascular contrast agent used is now in the form of non-ionic agents. This represents more than 75% of the total expenditure. Although figures are not available, it appears that in intravenous urography the conversion rate to non-ionics has been less than the overall figure. Nephro toxicity
An association between impaired renal function and administration of contrast has long been noted, but the mechanism remains obscure. This is an important issue in all centres where intravascular contrast is administered, but it is of special interest in intravenous urography where, by definition, many patients already have abnormal renal function. It is difficult to obtain hard data in this area and the literature is often confusing and contradictory. A recent editorial has attempted to distinguish between fact and assumption (Dawson and Trewhella 1990). The following can be stated as fact: many patients who receive intravascular contrast agents exhibit a transient rise in creatinine and fall in creatinine clearance ;occasionally a patient may suffer acute-on-chronic clinical renal failure following a contrast examination; in animals and man, proteinuria (indicating renal injury) is seen following contrast injection, particularly after selective renal arteriography. No link has been established between the proteinuria and clinical events and no great significance seems to be attached to minor and short-lived changes in creatinine clearance. It appears that the risk of a significant clinical event is increased if the patient is dehydrated and/or receives a high contrast dose. Other alleged “risk” factors such as diabetes, pre-existing renal failure and old age have not been definitively established (Dawson and Trewhella, 1990). Vasopressin release, stimulated by contrast administration, has been reported (Trewhella et d., 1989). This is an osmolality-related phenomenon and is less marked with the ‘low osmolality’ agent. It is dramatically enhanced in the presence of dehydration. Since vasopressin is a potent vasoconstrictor, it reduces renal perfusion. It has been
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postulated that this may be one of the pathophysiological mechanisms of contrast agent-associated nephrotoxicity, an attractive hypothesis. It would suggest that the low osmolality agents should be safer in this regard, but it must be stressed that this has not been established. Some studies have found no clearcut difference between older and newer agents (Gomes et al., 1989; Schwab et al., 1989), but these are open to criticism and it must be concluded that the question remains open. Whether or not vasopressin is involved in these important events, a consensus is emerging that dehydration should never be actively promoted and, if suspected, an attempt should be made to correct it before any contrast procedure. This is certainly the most important modification of established technique which needs to be reviewed.
References Ansell, G. (1970). Adverse reactions to contrast agents: scope of problem. Invest. Radiol., 5, 374384. Dawson, P. (1985). Contrast agent nephrotoxicity. An appraisal. Br. J . Radiol.,58, 121-124. Dawson, P. (1985). Chemotoxicity of contrast media and clinical adverse effects: a review. Investig. Radiol., 20,52-59. Dawson, P. and Trewhella, M. (1990). Intravascular contrast agents and renal failure. Clin. Radiol. (In press). Dawson, P., Britton, J. and Pitfield, J. (1983a). Contrast media and bronchospasm. A study with iopamidol. Clin. Radiol., 34, 227-230. Dawson, P., Grainger, R. G. and Pitfield, J. (1983b). The low osmolality contrast agents. A simple guide. Clin. Radiol., 34, 221-226. Dawson, P., Heron, C. W. and Marshall, J. (1984). Intravenous urography with low osmolality contrast agents; theoretical considerations and clinical findings. Clin. Radiol., 35, 137-
Grainger, R. G. (1984). The clinical and financial implications of low osmolar radiological contrast media. Clin. Radiol., 35, 251-252. Hattery, R. R., Williamson, B., Hartman, G. W. et al. (1988). Intravenous urography technique. Radiology, 167,593-600. Heron, C . W., Underwood, S. R. and Dawson, P. (1984). Electrocardiographic changes during intravenous urography : a study with iothalamate and iohexol. Clin. Radiol., 35, 137141. Kay, B., Howard, J., Foord, K. D. er al. (1988). Comparison of the image quality of intravenous urograms using low osmolar contrast media. Br. J. Radiol., 61, 589-591. Manhire, A., Dawson, P. and Dennett, R. (1984). Contrast agent induced emesis. Clin. Radiol., 35, 369-370. Marshall, V. F. (1977). The controversial history of excretory urography. In Clinical Urography, ed. Emmett, J. Volume 1, pp. 2-5. Philadelphia: Saunders. Osborse, E. D., Sutherland, C. G., Scholl, A. F. et al. (1923). Roentgenography of the urinary tract during excretion of sodium iodide. J . A . M . A . ,80,368-373. Palmer, F. J. (1988). The RACR survey of intravenous contrast media reactions: final report. Aust. Radiol., 32,426-428. Rawlinrion, J., Hyde, I. and Williams, J. (1988). Quality of urograms in infants: a comparison of sodium diatrizoate, metnizamide and iohexol. Br. J . Radiol., 61, 592-595. Saxton.,H. M. (1969). Urography. Br. J . Radiol., 42, 321-346. Schwab, S. J., Hlatky, M. A., Pieper, K. S. etal. (1989). Contrast nephrotoxicity: a randomised controlled trial of a non-ionic and an ionic radiographic contrast agent. N . Engl. J . Med., 320, 149-153. Strautnian, P. R., Fajardo, L. L., Hillman, B. J. et al. (1989). Evaluation of contrast dose reduction for excretory urography using computed radiography. Eur. J . Radiol., 9,60-63. Swick, IM.(1978). Radiographic media in urology. The discovery of excretion urography. Surg. Clin.North Am., 58, 197771994, Trewhella,M., Dawson, P., Forsling, M. etal. (1989). Vasopressin release in response to intravenously injected contrast media. Br. J. Radiol., 63, 97-100. Trewhella, M., Dawson, P., Rickards, D. et al. (1987). Dehydration, antidiuretic hormone and the IVU. Br. J . Radiol., 60, 445-147.
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Gomes, A. S., Lois, J. F., Baker, J. D. et al. (1989). Acute renal dysfunction in high risk patients after angiography : comparison of ionic and non-ionic contrast media. Radiology, 170, 65-68. Grainger, R. G. (1982). Intravascular contrast media-the past, the present and the future. Br. J . Radiol., 55, 1-18.
The Author P. Dawson, MRCP, FRCR, Senior Lecturer and Honorary Conmltant Radiologist, Department of Diagnostic Radiology, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W 12 OHS.
