By Peter Davies, D.M., F.R.C.R., Philip N. Panto, M.A., M.B.B.S., t James Buckley, M.R.C.P.. F.R.C.R., and * Rosalyn E. Richardson, M.Sc, A.R.C.S.. Departments ...
1985, The British Journal of Radiology, 58, 593-597
JULY
1985
The old and the new: a study of five contrast media for urography By Peter Davies, D.M., F.R.C.R., Philip N. Panto, M.A., M.B.B.S., t James Buckley, M.R.C.P. F.R.C.R., and * Rosalyn E. Richardson, M.Sc, A.R.C.S. Departments of Radiology and "Medical Physics, City Hospital, Nottingham (Received July 1984 and in revised form December 1984)
ABSTRACT
Five contrast media, Conray 280 and 420, Urografin 370, Uromiro Sodium 300 and Niopam 370, were compared in a randomised trial involving a total of 482 patients. The best urographic agent was Conray 420 and the worst Conray 280, these control agents defining the ends of the scoring system. Uromiro Sodium 300 was very nearly as good as Conray h1^>. A non-ionic agent, Niopam 370, scored nearly equal with Urografin 370; both were rather better than Conray 280. There was little difference in minor reactions between the media. No reason was found to prefer non-ionic to ionic agents for general use in urography; indeed for a diagnostic examination the sodium salt of an ionic agent is preferable.
A new generation of contrast media which do not dissociate in solution and are therefore known as nonionic have been introduced recently. The characteristics of non-ionic contrast media include a low neurotoxicity and a considerably higher LD 50 in experimental animals than ionic agents. Non-ionic media are said to produce denser pyelograms because of a lower osmotic diuresis but they opacify the collecting system more slowly. Water restriction is thought to be less important for good quality pyelograms (Cueff& Pinet, 1979). There has been considerable interest in the use of non-ionic agents for urography because they are said to cause fewer side effects, to be safer and to produce better urograms. This study was designed to test these hypotheses. The non-ionic contrast medium chosen for this trial was Niopam 370 (iopamidol). Uromiro Sodium 300 (sodium iodamide), an ionic contrast medium, is said to have an additional pathway of excretion by active tubular transport and so to be a better contrast agent (Bonatti et al, 1983; Bollerup et al, 1975). It was therefore included in the trial as an additional test medium. The control media for the study were Conray 420 (sodium iothalamate) and Conray 280 (meglumine iothalamate). These two contrast media have been used for more than a decade at the City Hospital. Conray 420 had displaced Urografin 370 for urography as it was easier to inject, was thought to give better nephrograms, and the urogram could be completed more quickly because it reliably showed a pyelogram on t Present address: Department of Academic Radiology, Queen's Medical Centre, Nottingham.
a 3-minute film (Arkless, 1969). This hypothesis had not been formally tested, so Urografin 370 was included in the trial. The aim of the study was to assess the use of 50 ml of contrast medium injected rapidly as is normal practice «v mo^t d^axtmsnAs, A. second injection of contrast medium was given when the urogram was unsatisfactory and provided an additional method of deciding the adequacy of each contrast medium. The second injection was always Conray 420. The occurrence of minor side effects strongly influences the choice of contrast medium and therefore these were recorded. A postal questionnaire was used to record delayed reactions and these results will be reported separately. MATERIALS AND METHODS
Five agents were studied—Conray 280, Conray 420, Urografin 370, Uromiro Sodium 300 and Niopam 370. Patients were randomly allocated to a contrast medium using pre-prepared tables which ensured that at the end of the trial the same number of patients had been examined using each medium. The aim was to have approximately one hundred patients per medium, after exclusions, with the proportion of men and women reflecting the usual sex ratio attending for urography. The injection consisted of 50 ml of contrast medium given by hand as quickly as possible through a 19G needle, the duration of injection being recorded. This was followed by taking a nephrogram film a few seconds after the end of the injection; further films were taken at 2 and 3 minutes, after which compression was applied, and further films at 5 and 8 minutes and one after release of compression at 10 minutes. Tomography was used if required but the tomograms were not scored. All patients had blood taken for serum urea and creatinine, and those with raised values, bilateral obstructive uropathy, urinary diversion, those being examined as an emergency or being referred for diuretic urography were excluded. Only adults over the age of 18 were admitted to the trial. The patient's weight and urine volume passed after the examination were recorded. The patient was observed during the examination for any side effects and, towards the end of the procedure, 593
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58, NO. 691 P. Davies, P. N. Panto, J. Buckley and R. E. Richardson
was questioned as to whether or not any of the more commonly recognised side effects had been experienced. The urograms were scored independently by two observers (P.D. and J.B.) to assess the following:
TABLE II REACTIONS
1. Viewing conditions, i.e., quality and consistency of radiography, presence or absence of bowel gas or faecal loading. 2. Nephrographic density on the 1-, 2-, 3- and 5-minute films and type (cortical or medullary). 3. Pyelographic density and distension, on the 3-, 5- and 8-minute films. 4. Ureteric filling. 5. Bladder emptying. 6. Overall diagnostic quality. All were scored on a 4-point scale, and the information was entered into a computer for analysis. RESULTS
There were 482 records available for analysis after exclusions. Table I summarises the data giving the number of patients who were given each contrast medium, the average age, weight, injection time and the number of patients who required a second injection (i.e., non-diagnostic examinations). The reactions recorded while the patient was in the department are shown in Table II. When patients were asked if the examination was uncomfortable or if there was discomfort at the injection site there were no significant differences between the media. Significantly more women complained of discomfort in the injected limb with Uromiro 300 (p < 0.05) and Urografin (p < 0.05). There were significant differences in the numbers complaining of a sensation of warmth or heat between contrast media for both men and women. For women the differences between Conray 420 (98%) and both Uromiro 300 (81%) and Niopam (78.3%) were significant (both p < 0.05). Niopam caused significantly fewer sensations of warmth or heat in men than the Other media apart from Uromiro 300. More women than men complained of a perineal sensation and this was statistically significant for Conray 280 (p < 0.05) and Urografin (/? < 0.01) though there were no significant differences between media for each sex. There was no statistical difference between the incidence of nausea for different media among the women. For men there was a significant difference between Conray 280 (7%) and Conray 420 (28%)
Uncomfortable examination 9 Discomfort at injection site 11 Discomfort in injected limb 7 96 Warmth or heat Flushing 21 34 Perineal sensation Other sensation 8 Taste or common chemical 35 7 Cough or sneeze 17 Nausea 1 Vomit Faintness 10 Vasovagal reaction 0 1 Urticaria Swelling of lips, eyes or 0 tongue 0 Severe reactions Number of patients 103
Number of patients Average age (years) Average weight (kg) Average injection time (s) Number of second injections
16 10 4 84 19 16 11 39 7 21 1 15 0 1
14 15 8 80 19 19 12 41 6 17 0 17 0 2
10 10 6 83 16 21 13 31 8 16 0 0 0 0
6 8 9 74 10 24 6 31 4 9 0 13 0 0
0 0 90
0 1 96
0 0 90
0 0 103
Some patients had more than one reaction.
(p < 0.01) and between Niopam (4%) and both Conray 420 (28%) (p < 0.01) and Urografin (18%) (p < 0.05). More women than men experienced nausea and this was significant for Conray 280 (p < 0.01). The number of second injections is shown in Table III. Conray 280 had the greatest proportion and Conray 420 the smallest. The differences between Conray 280 and all the other media apart from Niopam were significant: C280/U370 {p < 0.0); C280/U300 {p < 0.01); C280/C420 (p < 0.001); as was the difference between Conray 420 and Niopam (p < 0.05). Tables IVA and IVB show the number of patients whose calyces could be identified on the 2- and 3minute films. It is interesting to note that the non-ionic contrast medium is not as efficient as the ionic media for opacifying the calyces on early films. Overall quality of the urogram The scorers were asked to judge if the urogram was excellent, adequate, poor or non-diagnostic. The first two categories constitute satisfactory examinations and TABLE III
TABLE I Contrast medium
C280 C420 U300 U370 N370
Contrast medium
SECOND INJECTIONS
C280 C420 U300 U370 N370 103 53.3 71.4 22.9
90 52.3 71.3 30.2
30
6
96 54.5 69.6 19.4
90 55.2 69.8 35.9
103 52.5 68.9 38.0
10
12
19
Total no Contrast medium
Conray 280 103 Niopam 370 103 Urografin 370 90 Uromiro Sodium 300 96 Conray 420 90
594
No of
of patients second injections Percentage 30 19 12 10 6
29.1 18.4 13.3 10.4 6.6
JULY
1985
Five contrast media for urography TABLE IV
TABLE VI
TRANSIT TIMES
C420 U300 U370 N370 C280 A. Appearance of pyelogram on 2-minute film Calyces seen on film Contrast medium No of patients No. % Niopam 370 103 Urografin 370 90 Conray 420 90 Uromiro Na 300 96 103 Conray 280 No differences significant.
15.5 21.1 23.3 27.0 28.1
16 19 21 26 29
B. Appearance of pyelogram on 3-minute film
No Niopam 370 Urografin 370 Conray 280 Uromiro Na 300 Conray 420
103 90 103 96 90
87.4 95.6 96.1 96.9 100.0
90 86 99 93 90
Significant differences between Niopam and all other media apart from Urografin. No other differences significant.
the last two unsatisfactory examinations. There was good agreement between the scorers as to whether or not a urogram was satisfactory or not. The results for men and women together are shown in Table V. The nephrogram
Scorer 2 consistently scored the nephrographic density higher than Scorer 1. The scores were totalled for each examinaton and the averaged scores for all patients are shown in Table VI in rank order. The only differences that were significant were Conray 280 and Conray 420 (p < 0.001), Uromiro 300 and Conray 420 (p < 0.05) and Niopam and Conray 280 (p < 0.01). The pattern of nephrogram density increase and decrease was the same for all media with the densest nephrogram on the 1- or 2-minute film. TABLE V OVERALL QUALITY OF UROGRAM
C420 U300 U370 Non-diagnostic & poor examinations
14
20
26
N370
C280
28
43
Good & excellent examinations
76
76
64
75
60
Total
90
96
90
103
103
Non-diagnostic & poor examinations as % of total
15.6
20.8
28.8
27.2
41.7
Conray 280 significantly different from Conray 420 (p< 0.001), Uromiro 300 (/? < 0.01) and Niopam 370 (p < 0.05). Conray 420 significantly different from Urografin {p < 0.05).
A. Average total scores Density of nephrogram* Density of pyelogram* Distension of pyelogram" Total urographic scoref
7.2 11.3 11.4 30.0
Density of nephrogram Density of pyelogram Distension of pyelogram Total urographic score
> best, 5 is worst) 3 4 1 4 1 1 2 1 3 4 2 1
6.6 11.3 10.3 28.1
6.7 9.7 10.9 27.3
7.1 11.1 9.8 28.0
6.2 9.3 10.0 25.6
2 3 5 3
5 5 4 5
* Maximum possible score = 16. t Maximum possible score = 48.
The pyelogram The pyelogram was scored on the 3-, 5- and 8-minute films for both density and distension on the 4-point scale. The density of the pyelogram was scored highest for Conray 420, Uromiro 300 and Niopam 370 and there was no significant difference in the scores for men or women. Urografin and Conray 280 scored significantly lower (all differences p < 0.001 except for Conray 280 and Niopam where p < 0.01). The distension of the pyelogram was best for Conray 420 and worst for Niopam 370 and this was a significant difference {p < 0.001). The other media occupied intermediate positions with very similar scores. The patterns of scores of density and distension on the 3-, 5- and 8-minute films were the same for all media with both being least on the 3-minute and maximal on the 8-minute film. The urogram The average scores for the pyelogram are shown in Table VIA. The results for the two scorers have been combined as they showed excellent agreement. The rank order is given in Table VIB. The average total score includes nephrogram density, pyelogram density and distension and ureteric filling. DISCUSSION
This trial was set up to study certain long-held assumptions about Conray 280 and 420 and Urografin 370 and to investigate two new agents, Uromiro Sodium 300 and a non-ionic contrast medium Niopam 370. The principal purpose was to compare the urographic quality but the opportunity was taken to record the minor reactions to the media. This study was also designed to see if differences in iodine concentrations of the various media appeared important under working conditions. This approach is justified as we have shown that 595
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58, No. 691 P. Davies, P. N. Panto, J. Buckley and R. E. Richardson
Uromiro Sodium 300 is a better agent than two 370 concentration media and substantially better than Conray 280; it is only a little worse than Conray 420. It has previously been demonstrated that sodium salts of ionic media produce better urograms when used at the same concentration as meglumine salts (Pearson et al, 1971; Dacie & Fry, 1971) but that a 300 medium should be so close in score to a 420 medium and better than a 370 medium is an important and perhaps surprising observation, especially as there is little difference between the performance of the methyl glucamine salts of iodamide and iothalamate (Owen et al, 1981; Dubbins et al, 1981). The various media were tolerated equally well. Direct questioning revealed that fewer of the patients who had received Niopam had sensations of heat and warmth, but these sensations are generally well tolerated. There was no decrease in the incidence of the unpleasant perineal sensations for patients receiving Niopam. Conray 420 caused more nausea than other agents and Niopam least. We think that the use of Niopam is indicated if the patient has had a distressing attack of nausea and vomiting after previous use of an ionic agent. The most sensitive indicator of quality of films produced by a contrast medium is the number of nondiagnostic examinations. In this trial these were picked up by recording that a second injection had been given. This was decided by the radiologist supervising the examination and confirmed by the two scorers as well. On this criterion, Conray 280 was clearly unsatisfactory since nearly 30% of patients required a second injection. From Table III it can be seen that Conray 420 had the lowest number of repeat injections, then, in order, Uromiro Sodium 300, Urografin 370, Niopam 370 and finally Conray 280. This indicates that the non-ionic medium and the meglumine containing media are surpassed for diagnostic purposes by the sodium-containing ionic media. The scoring system used indicates the same conclusion: Conray 420 and Uromiro Sodium 300 scoring high on total scores and pyelographic density and Niopam scoring nearly as high but no higher than Conray 420 on pyelographic density. There is thus no indication of a worthwhile increase in pyelographic density using a non-ionic agent and there is a decrease in pyelographic distension compared with the ionic agents. Adequate pelvicalyceal filling is important and the use of large volumes of ionic contrast media and ureteric compression are used to achieve this. An agent which produces little distension should therefore be rejected as less than adequate for the purposes of the examination. It has been suggested that non-ionic media are excreted more slowly than the ionic media and therefore the films should be taken later. This effect was confirmed in this trial by comparing the number of cases in which the calyces were seen on the 2- and 3minute film. Niopam had a lower proportion of calyces
seen on early films than any other medium while Conray 420 showed a 3-minute pyelogram in all cases. We have come to the conclusion that recording the appearance of the calyces on the 2- and 3-minute film and nephrographic density is of little value in deciding which medium is best for urography. The actual density of the nephrogram may be less important than radiographic factors in outlining the kidney although taking an early film showed the outline much better than the plain or subsequent films for all media. We could discover no reason for using a non-ionic agent routinely for urography and this opinion is shared by Dalla Palma et al (1982). CONCLUSIONS
1. A non-ionic agent, Niopam, has no advantage over conventional media, in urographic quality. It is inferior to Conray 420 and no better than Uromiro Sodium 300 or Urografin 370. 2. Uromiro Sodium 300 is nearly as good as Conray 420 for urography with a much lower iodine content. 3. Contrast media reactions have differing incidences for different media. The reactions cannot be considered to be predictive one for another. 4. Ionic and non-ionic agents were equally well tolerated subjectively by patients, although specific questioning showed that Niopam caused fewer minor sensory disturbances overall. ACKNOWLEDGEMENTS
We are grateful to E. Merck pic for generous supplies of Niopam and the Department of Clinical Chemistry, City Hospital for performing the blood tests. Sue Beadsworth for typing the manuscript, the radiographers and patients for their interest in the work and Dr. J. Minford for advice on the manuscript.
REFERENCES ARKLESS, R.. 1969. The normal kidneys reaction to intravenous pyelography. American Journal of Roentgenology, 107, 146-149. BOLLERUP, A. C ,
HESSE, B. & STEINESS, E.,
1975. Renal
handling of iodamide and diatrizoate, evidence of active tubular secretion of iodamide. European Journal of Clinical Pharmacology, 9, 63-67. BONATTI, F., ROSATTI,G. F. & POLETTO, M. G., 1983. Iodamide, a
new contrast medium, biological properties. ArzneimittelForschung, 15, 222-229. CUEFF, J. & PINET, A., 1979. Clinical trial of a new non-ionic contrast medium (Iopamidol) in intravenous urography. Thesis, University Claude Bernard, Lyon, France. DACIE, J. E. & FRY, I. K., 1971. A comparison of sodium and methylglumine diatrizoate in clinical urography. British Journal of Radiology, 44, 51-54. DALLA PALMA, L., ROSSI, M., STACUL, F. & AGOSTINI, R.,
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1982. Iopamidol in urography. A comparison between ionic and non-ionic contrast media in patients with normal and impaired renal function. Urological Radiology, 4, 1-3.
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Five contrast media for urography methylglucamine salts of iodamide and iothalamate in clinical urography. Clinical Radiology, 32, 341-346.
DUBBINS, P. A., MARSHALL, W., O'RIORDAN, D., O'NEILL, G.,
' RUFFELL, E. & LAWS, J. W., 1981. Comparison between
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PEARSON, M. C , GILKES, R., HALL, J. H., BOULTBEE, J. E. &
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SAXTON, H. M., 1971. Sodium or methylglucamine: a comparison of iothalamates in urography. British Journal of Radiology, 44, 55-57.
WILSDON,
J. B.,
1981.
Comparative
study
of
the
Book review Diagnostic Imaging of the Lower Genitourinary Tract. By M. D. Rifkin, pp. xi + 339, 1985 (Raven Press, New York), $53.50. ISBN 0-88167-045-6 The important role of radiological investigation in the urinary tract has been greatly extended by the introduction of the newer tomographic imaging techniques. High resolution CT scanning with the use of contrast agents allows detailed examination of the pelvis both for the soft tissues and for their bony framework. It has become especially important in assessing the extent of pelvic tumours but is also invaluable for the bladder and prostate. Improved ultrasound technology has made it possible to obtain tomograms of pelvic organs in exquisite detail. Small parts scanners, working at very high frequencies, allow structures as small as 1 mm to be displayed within the testis. The limited penetrating power at these frequencies limits their use to superficial structures, but the development of miniature transducers built into endo-probes that can be inserted into body cavities provide scans of similar detail of the layers of the bladder wall and of the prostate. NMR scanning shows great promise for the pelvis and the already impressive results may be expected to be further improved when magnetic resonance contrast agents are developed. Isotope scanning has also proved useful, especially where functional or dynamic information is critical.
"The focus of this book is the analysis and comparison of the newer imaging techniques" (preface). Essentially it covers the male pelvis, gynaecological problems being dealt with only incidentally. A rather superficial survey of the techniques used is followed by an illustrated review of pelvic anatomy, emphasising the tomographic appearances with due stress on the increasingly important sagittal and coronal projections. The main body of the book covers the bladder, prostate, urethra and scrotum systematically and in some detail. Each is introduced by a survey of the information available from each technique. A description of the major disorders follows with detailed discussion and illustration of the typical appearances as revealed by the various modalities. Catholic rather than critical, these catalogues nevertheless form a valuable reference source. There is more emphasis on completeness than on evaluating the relative merits of the techniques, though where one is pre-eminent, this is clearly stated. Sometimes the text gives the impression of having been hastily thrown together, with irritating and sometimes confusing non-sequiturs and inverse meanings that must make Gowers turn in his grave. But one should not let the expressive defects of this book undermine confidence in its contents, for it is not only up-to-date and excellently illustrated, but also forms a valuable reference work. D . O. COSGROVE
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