Urol Radiol 9:30-35 (1987)

Urologic Radiology

© Springer-Vedag New York Inc. 1987

Comparison of Two Strengths of Iohexol and Iothalamate in Urography

Peter Davies, 1 Jeffrey Glaves, I* Philip Panto, ~ and Rosalyn E. Richardson 2 Departments of tRadiology and 2Medical Physics, City Hospital, Nottingham, Great Britain

Abstract. Iohexol and iothalamate were studied in 2 strengths and compared with results f rom a pre- vious trial o f Iopamidol and 4 ionic agents. Scoring was consistent f rom trial to trial.

No worthwhile increase in density was achieved at high doses using nonionics and pyelographic dis- tention was less than for ionic media. The t iming o f the nephrogram was the same for ionics and non- ionics. There is no need to adopt a different film sequence for nonionic media.

Urticarial reactions were identical for all 4 me- dia studied in this trial.

Nonionic media perform as well as other media; at lower doses they are much better than meglumine salts o f ionic media.

Key words: Urography -- Media, nonionic con- trast.

A previous trial at the City Hospital, Not t ingham, compared the use o f various ionic contrast media with iopamidol in a strength o f 370 mg I /ml (Nio- pam 370 [1]. It was found that N iopam did not distend the calices as well as the ionic media. Non- ionic contrast media carry less water with them when excreted than ionic media and therefore produce a

* Present address: Department of Radiology, Chesterfield and North Derbyshire Royal Hospital, Chesterfield, Derbyshire, Great Britain. Address reprint requests to: Dr. Peter Davies, Department of Ra- diology, City Hospital, Hucknall Road, Nottingham, Great Brit- ain.

denser, less well-distended pyelogram. Thus, one would expect density to be greater for nonionics at equal doses o f iodine. This leads one to suppose that adequate density might be attained with lower doses o f nonionics. This should be reflected in the scores.

The present study was set up to test this hy- pothesis. The 2 control contrast media were meg- lumine iothalamate 280 mg I /ml (Conray 280) and sodium iothalamate 420 mg I /ml (Conray 420), which in a 50-ml dosage defined the bo t tom and top o f a urographic rating scale [ 1 ]. The 2 strengths of iohexol (Omnipaque) were 240 mg I /ml and 350 mg I/ml, chosen as being closest to the strengths o f the 2 iothalamates.

Materials and Methods

After a 50-ml bolus of 1 of the 4 contrast media selected was given based on preprepared random number charts, films were taken at 1, 2, 3, 5, and 8 minutes. Compression was applied after the 3-rain film and released after the 8-minute film, with a postre- lease film taken at 10 minutes. Tomography was used if required and a second injection (always of Conray 420) was given if the films were not diagnostic. The tomograms were not scored.

The film was Kodak XSI in X-o-matic cassettes fitted with AGFA SE 400 blue-emitting rare earth screens. The examination couches used were Phillips floating top tables with Potter-Bucky grid, and tomographs were taken on a Siemens Multi-Planigraph table. All tubes were energized from a Phillips DR 3T 3-phase generator and usually a 1.0-mm focal spot was used.

All patients were over the age of 18. A blood sample was taken for serum urea and creatinine estimation; if these levels were elevated the films were excluded from analysis. Patients examined on an emergency basis, with urinary diversion or bi- lateral obstruction, were excluded from the trial.

The patients were carefully observed during the examination for any side effects and were interviewed at the end of the ex- amination to record any subjective sensations. They were also

P. Davies et al.: Urography with Iohexol and Iothalamate

Table 1. Patients and examinations

Contrast medium C280 O240 O350 C420

Number of patients 85 86 85 86 Number of males 52 49 47 56 Number of females 33 37 38 30 Average age (yrs) 53.2 51.2 51.1 52.4 Average weight (kg) 69.9 69.4 71.2 73.7 Average injection time (sees) 23.1 22.5 39.3 28.5

Table 2. Reactions at the time of examination

Reactions

Contrast medium

C280 0240 0350 C420

Uncomfortable examination 7 3 5 3 Discomfort at injection site 3 4 5 5 Discomfort in injected limb 4 11 6 13 Warmth or heat 74 51 43 80 Flushing 43 25 19 45 Perineal sensation 18 13 8 28 Other sensation 7 5 6 12 Taste 25 15 11 32 Cough or sneeze 6 1 1 6 Nausea 16 2 7 13 Vomit 2 0 0 5 Faintness 5 3 5 11 Vasovagal reaction 0 1 1 2 Urticaria 2 1 2 2 Swelling of lips, eyes, or tongue 0 1 0 0 Severe reactions 0 0 0 0

Number of patients having a re- action" 54 33 28 63

Total number of patients 85 86 85 86

a The first four reactions were omitted when this total was cal- culated.

31

given a questionnaire to fill in later to record delayed reactions [21.

For each agent, 125 patients were admitted to the trial, giving a total of 500. However, after exclusions (patients who had raised blood urea levels or incomplete film series) the films of 342 patients were available for the study. The films were scored blind independently by 2 scorers. One scorer (PD) was the same as for the previous trial but 1 was different (JG).

The scoring system was a 4-point scale recording the quality of radiography, the nephrographic density on the I-, 2-, 3-, and 5-minute film, the pyelographic density, and the distention on the 3-, 5-, and 8-minute films, ureteric filling, and overall diag- nostic quality.

The data were entered into a custom-built microcomputer using a Zg0B microprocessor running CP/M. The software was Infostar (MicroPro) and statistical analysis was performed using Microstat (Ecosoft Inc). The main statistical test used was Stu- dent 's t-test and statistical significance was attained at the 95% level.

Results

Numbers of patients, their age, sex, weight, and any reactions occurring in the department are summa- rized in Tables 1 and 2.

Nephrogram

The scores for nephrogram density are set out in the first column of Table 3. All differences except that between Conray 280 and Omnipaque 350 are sig- nificant. The highest nephrogram score was on film 1 for all contrast media and declined on subsequent films (Fig. 1).

Pyelographic Density

The scores for the 2 Omnipaques were very similar to that for Conray 420. The score for Conray 280

Table 3. Average scores (2 scorers)

Nephrogram density

Pyelographic density

Overall quality Pyelographic (assessed distention Total score independently)

C280 6.8 9.6 9.7 26.1 2.5 0240 5.9 11.3 9.3 26.5 2.6 0350 6.8 11.8 9.8 28.5 3.0 C420 7.8 11.5 10.8 30.1 3.1

P values for paired comparisons using Student's t-test (%)

C280/O240 1 0.1 NS NS NS C280/O350 NS 0.1 NS 1 0.1 C280/C420 1 0.1 1 0.1 0.1 0 2 4 0 / 0 3 5 0 1 NS NS 0.1 1 O240/C420 0.1 NS 0.1 0.1 0.1 O350/C420 1 NS 1 5 NS

NS, not significant.

32 P. Davies et al.: Urography with Iohexol and Iothalamate

4.'

4O

e a. 3

g 2¢

z

i

SO

PRESENT TRIAL - - 5 Minutes

tl /I,'b-

Conray 420

[l] Omn;Deque 350

~ Omnlpaque 240

I ents), 280

71 Niopam 370

Urom,ro 300

E] Utogralin 370

3 PREVIOUS TRIAL

5

Fig. 1. The percentage of patients having a nephrogram score of 3 or 4 on each of the first four films, taken 1, 2, 3, and 5 minutes after the start of the injection for the present trial and that of Davies et al. [1]. The difference between Niopam and Conray on the 3-minute film is not statistically significant.

Table 4. Calices opacified on 2- or 3-minute films

% Calyces opacified

Medium 2-min 3-min

C280 23 99 0240 15 96 0350 17 92 C420 43 96

was significantly less (Table 3). Pyelographic density was good on the 3-minute film and improved stead- ily for both concentrations of Omnipaque and Con- ray 420 but was worse on the 5-minute film for Conray 280. The scores on the 8-minute film for Conray 420 and Omnipaque 350 were very similar.

Pyelographic Distention

There is a significant difference between the scores for Conray 420 and the other 3 media but not be- tween Conray 280, Omnipaque 240, or Omnipaque

350. The pyelographic distention was worse on the 3-minute film, improved on the 5-minute, and was best on the 8-minute film for all media. The scores for Omnipaque were slightly worse than for the cor- responding concentrations of Conray, but the score for Omnipaque 350 was very similar to that for Conray 280.

Total Score

The total score (i.e., the sum of scores for nephro- gram density, pyelogram density, and distension and ureteric filling) was significantly different for all con- trast medium pairs except Omnipaque 240 and Conray 280. Conray 420 was best, followed by the 2 Omnipaques with Conray 280 being worst. This is similar to the assessment of overall quality which was performed independently.

The proportions of patients whose calices were opacified on the 2- and 3- minute film are shown in Table 4.

Poor and undiagnostic examinations (scores 1 and 2) were 43.75% for Conray 280, 32.6% for Om- nipaque 240, 24.7% for Omnipaque 350, and 16.2%

P. Davies et al.: Urography with Iohexol and Iothalamate

Table 5. Comparison of the 2 trials of nonionic media (both scorers)

33

Previous trial N370

Present trial

0350 0240

Nephrogram density 7.1 6.8 5.9 Pyelogram density 11.1 11.8 11.3 Pyelogram distension 9.8 9.8 9.3 Average score 28.0 28.5 26.5 Overall quality 2.8 3.0 2.6

P values for paired comparison using Student's t-test (%)

N370/O350 N370/O240 0 2 4 0 / 0 3 5 0

Nephrogram density NS 0.1 1 Pyelogram density NS NS NS Pyelogram distension NS NS NS Averge score NS 5 0.1 Overall quality NS NS 1

NS, not significant.

Table 6. Comparison of doses

Medium

Average dose (mg I/kg) (+standard deviation)

Dose for a 70-kg man (gI)

C280 (first trial) 206.4 + 48.8 14.5 C280 (present trial) 207.4 + 39.5 14.5 C420 (first trial) 304.2 + 64.5 21.3 C420 (present trial) 299.0 + 66.3 21.0 0240 178.2 _+ 30.7 12.5 0350 252.5 + 44.5 17.6 U300 221.4 + 43.3 15.5 U370 272.6 + 55.9 19.0 N370 271.1 + 57.4 19.0

Table 7. Average scores and proportions of poor scores on the 8-minute film (with compression)

Density Distention

% % Number Poor Poor of

Score scores Score scores patients

C280 (first trial) 2.7 36.4 3.1 20.8 103 C280 (present thai) 2.7 32.4 3.0 26.5 85 C420 (first trial) 3.1 15.0 3.3 12.2 90 C420 (present trial) 3.2 11.6 3.2 13.4 86 0240 3.2 19.8 3.0 22.6 86 0350 3.3 12.3 3.1 25.8 85 U300 3.2 7.8 3.1 19.2 96 U370 2.8 30.0 3.2 19.5 90 N370 3.2 12.6 3.0 23.0 103

of the total for Conray 420. The need for a second injection (of Conray 420) defined an undiagnostic examination, which scored 1 on overall quality. The rates for undiagnostic examinations were 27.1% for Conray 280, 16.3% for Omnipaque 240, 9.4% for Omnipaque 350, and 7% for Conray 420.

Comparison with Previous Trial [1]

The top and bottom of the scoring scale is deter- mined by Conray 420 and 280. The scores of scorer 1 for these 2 media indicated consistency of scoring between trials, as do the proportions of poor and undiagnostic examinations (table 5 in ref. 1).

The averaged scores for both sets of scorers, and both men and women, were compared for Niopam 370 and Omnipaque 350 and 240 (Table 5).

None of the differences between Niopam 370 and Omnipaque 350 reach significance, but there is a significant difference between the results for Om- nipaque 350 and 240. The difference in scores, how- ever, is less than that between Conray 420 and Con- ray 280.

The nephrographic appearances are shown for the two trials in Fig. 1.

The dose rate in milligrams of iodine per kilo- gram body weight is given in Table 6, together with the equivalent average dose in grams for a man weighing 70 kg.

The scores for density and distension on the 8-minute film were averaged and are shown in Table 7, together with the proportions of films classified into the 2 lower categories 1 and 2 (poor) and the higher 3 and 4 (good).

34

Discussion

The method used has been previously described [ 1 ] but the present trial shows the following points.

Scor/ng

Scoring is consistent from trial to trial and Conray 420 and 280 are satisfactory media for defining the top and bottom of a urographic quality scale. One is the best and the other is the worst of the media tested. The method is easy to use for studying large numbers of patients in a busy department.

The method of scoring is to compare the films with the highest standard and to deduct marks if this is not reached; this tends to make the standard of urography appear worse than it is. All the ex- aminations rated poor were in fact diagnostic. In some of the patients given second injections, the effect was to confirm a diagnosis that could have been made on the original films but was much more obvious after the second injection.

This constancy of the rating scale allows com- parison of the two nonionic media from the 2 trials: Niopam 370 and Omnipaque 350 and 240. There is little difference between the results from Niopam 370 and Omnipaque 350 but Omnipaque 240 is slightly worse, although still better than Conray 280. The scores for pyelogam distention and density are little different for the 3 nonionics. The difference in total scores is chiefly due to the difference in nephrogram score. Thus, differing concentrations and doses of nonionic medium have less effect on urographic quality.

Average scores can be most easily understood when compared on a single film. We chose to look at the scores of the 8-minute film, which was taken at the time of maximum diuresis (and, in our series, maximum opacification) with compression applied. All agents scored an average of 3 or more for dis- tention and both sodium salts and nonionics scored 3 or more for density. Omnipaque 240 had slightly more poor and undiagnostic films scored for density. This shows that for both sodium salts and nonionic media it is not necessary to use the higher dose routinely. For example, a sodium salt with 300 mg iodine/ml is nearly as good as Conray 420, as are the nonionics at 350 and 370 strengths. Omnipaque 240 in a dose of 12.5 g for the 70-kg standard man (Table 6) performed very well and much better than Conray 280 (Tables 3 and 7). This may be because the effect of increasing the dose is to increase the proportions of good and excellent examinations from 80% (0240) to 88% (0350). Alternatively, it may be that nonionics perform better at lower dose ranges.

P. Davies et al.: Urography with Iohexol and Iothalamate

The rate of second injections was similar for Conray 420 and Omnipaque 350, as was the density of the 8-minute film (Table 7), despite Omnipaque 350 having 20% less iodine. We think that this confirms our original hypothesis and indicates that lower dos- es and concentrations of nonionics may be as effec- tive as higher ones.

Since all agents scored an average of 3 for dis- tention we must conclude that in routine urography the lesser diuretic effect of nonionics is barely no- ticeable.

Effect of Cations on Urography

It has been shown that sodium salts of ionic agents produce better urograms than meglumine salts be- cause of a smaller diuresis [3]. Other authors have shown that Omnipaque produces better urograms than meglumine-containing agents [4, 5]. We think that the density and diuresis of sodium salts are most appropriate for urography. This accounts for the fact that sodium iodamide (Uromiro 300) pro- duces better examinations than meglumine diatri- zoate (Urografin 370) and that the former produced better urograms than the nonionics [1].

Nephrogram

The pattern of development of the nephrogram was carefully studied. We have been unable to confirm Dawson's [6] observation of a delay in the time of the best nephrogram density in about one-third of patients. The nephrogram density was highest on the first film for all media and declined steadily thereafter. Figure 1 shows the percentages of pa- tients having a score of 3 or 4 for the nephrogram for the first 4 films in each trial. In particular contrast to the view of Levorstad et al. [7], there was no evidence of a better nephrogram at 3 or 5 minutes. Our results are similar to those of Rankin and Eng [5]. We can think of no reason for a delay in the appearance of the nephrogram or an increase in its density when the plasma level of contrast medium is falling.

Time of Pyelogram Appearance

There is slight delay for some media but Conray 420 reliably produces a pyelogram at 3 minutes [8] in all cases. If the first film was taken at 5 minutes, no difference could be observed. We see no reason to alter standard timing of a urographic examination to compensate for this very slight delay in a small proportion of patients. Nor do we see any reason,

P. Davies et al.: Urography with Iohexol and Iothalamate 35

con t ra ry to the v iew o f Cuef f a nd P ine t [3], to al ter ou r pract ice o f hav ing pat ients water - res t r ic ted and wi th an e m p t y s t o m a c h (ach ieved by omi t t ing the prev ious meal) when undergoing urography. W e have f o u n d (as a separate obse rva t ion) tha t n o n i o n i c agents are washed ou t o f the calices as easily as ionic agents by a diuret ic in jec t ion o r a water load.

Subject ive side effects were less for the pat ients g iven O m n i p a q u e . H o w e v e r , the n u m b e r o f cases o f ur t icar ia and mucosa l swelling was ident ical for all 4 m e d i a [2].

N o n i o n i c m e d i a are expensive . The i r use for u r o g r a p h y gives bet ter results t han m e g l u m i n e salts bu t slightly poore r results than wi th use o f the so- d i u m salt o f an ion ic agent. Whi le t r ivial side effects are reduced, this does no t ou tweigh this d i s advan - tage and is no t sufficient jus t i f ica t ion for their rou- t ine use.

Acknowledgments. We are grateful to the radiographers and ra- diologists who completed the forms, Nyegaard (now Nycomed) for providing us with supplies of Omnipaque and assistance with finance, Miss Karen Kelly for typing the manuscript, Mrs. Celia Richards for Figure 1, Dr. Alan Chrispin and Dr. Jill Minford for advice and encouragement.

References

1. Davies P, Panto PN, Bucldey J, Richardson RE: The old and the new: a study of five contrast media for urography. Br J Radiol 58:593-597, 1985

2. Panto PN, Davies P: Delayed reactions to urographic contrast media. Br J Radiol 59:41-44, 1986

3. Cueff J, Pinet A: Clinical trial of a new non-ionic contrast medium (Iopamidol) in intravenous urography. Thesis, Uni- versity Claude Bernard, Lyon, France, 1979

4. Benness GT: Urographic contrast agents: a comparison of sodium and methyl glucamine salts. Clin Radio121:150-156, 1970

5. Taenzer V, Heep M, Clauss W: Urography with non-ionic contrast media. In Taenzer V, Seither E (eds): Contrast Media. Stuttgart: George Thiene Verlag, 1983, pp 148-I 52

6. Rankin RN, Eng FWHT: Iohexol vs diatrizoate. A compar- ative study in intravenous urography. Invest Radiot 20 (Suppl): S112-S114, 1985

7. Dawson P, Herm L, Marshall J: Intravenous urography with low osmolality contrast agents: theoretical considerations and clinical findings. Clin Radiol 35:1973-1975, 1984

8. Levorstad K, Kolbenstreet A, Sommerfelt SC, Zackinssen BE, Jagenburge R, Egebhad M, Thrane-Neilsen W, Sjoberg S, Oldbring J, Sveen K: Tolerability and diagnostic usefulness of iohexol in urography. An open multi-centre clinical trial. Acta Radiol Diagn 23:491-496, 1982

9. Addess R: The normal kidneys reaction to intravenous py- elography. Am J Roentgenol 107:746-749, 1969