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An assessment of sodium acetrizoate and an experimental basis for its use in intravenous pyelography
CARCINOMA
OF
THE
VOCAL
CORD
~37
active needles being held in a separate piece of material which then fits into the fenestration as a single, rigid unit. A piece of polythene sheet, one-eighth of an inch thick, cut to size slightly larger than the active area required for the radon sources, was drilled parallel to the flat faces of the sheet to take
Fig. i i 8 . - - R a d i o g r a p h s of applicators in p o s i t i o n - - C a s e
I is on the left, C a s e ~ is on the right.
pieces of 0. 5 ram. wall gold capillary tube in which the radon is sealed (Fig. i i 7 ) . I n the smaller unit illustrated, the drill holes break through the surface of the p01ythene so that the radon sources are in contact with the exposed tissue, as in the established radium technique. This is unnecessary and there appears to be some advantage in keeping the holes completely within the polythene. T h e usual six to eight radium needles of the F i n z i - H a r m e r technique may be loaded in this way. T h e sources are then inserted into the exposed window in one operation instead of needle by needle. Bevelled edges on the polythene fit under the surrounding cartilage and small holes permit more positive fixation by stitching. All sources are held immobile both with respect to the larynx and to each other. As a point of technical interest it was found essential to provide an unloaded piece of polythene of identical dimensions to enable accurate cutting of the window in the thyroid cartilage. T h e use of radon brings further advantages. T h e sources are active right to the ends so that the extent of the fenestration need only be slightly larger than the area to be treated. Unsymmetrical distributions of activity are commonly desirable since the malignant tissue does not always run parallel to the plane of the polythene. A n y desirable distribution of activity can be realized with radon, in contrast to the restrictions placed by radium needles of fixed strength. Spare holes drilled in the polythene provide for a last minute change in the treated area should this be found necessary. T h e softness of gold and polythene is such that the sources can be pushed easily in and out of the holes without being so loose as to fall out.
CASE REPORTS Case I.--R. S., a retired civil servant, aged 57 years, had noticed hoarseness for three months. On examination on July 3o, 1954, a nodular lesion, covering the anterior two-thirds of the right vocal cord, was found. A biopsy was taken and reported to show a moderately well differentiated squamous cell carcinoma. On Aug. 6, I954, a window was made in the right lamina of the thyroid cartilage and a polythene-radon applicator was
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inserted for 4 days and 4 hours (Fig. 118). This was designed to deliver 45oo r to the right vocal cord (Fig. 119). One month later, the view of the cord was found to be obscured by oedema of the right false cord. On Oct. 15, 1954, two months after treatment, laryngoscopy revealed an apparently normal larynx. He was last seen in April, 1955, and again the appearance of the larynx was completely normal.
~
ocal folds
u T 500r I-0 crn. )¢
~L
9000!,5cm ~1 F
I 1,000 r
|
22,000 r
XlD .v. . . . ~ . " P l a n e of Radon Sources (Perpendicular to paper) ( , 2 . 0 era., ) Fig. z i9.--Distribntion of g a m m a - r a y dose in r units in plane bisecting
plane of radon sources at right angles, T h e radon is more strongly concentrated at the end of the plane, nearest to point F.
Case 2.--L. N., a mental hospital inmate, aged 44 years, was first seen on Oct. 18, 1954. Hoarseness had been noticed for six weeks. Fie was found to have a carcinoma of the right vocal cord, anterior commissure, and the anterior end of the left vocal cord. A biopsy of the lesion was reported to show an anaplastic carcinoma. On Nov. 4, I954, a large fenestration was made in the thyroid cartilage, and the larger radon applicator illustrated in Fig. 117 inserted ; 5500 r was delivered to the right and left cords in 4½ days. Convalescence was uneventful. He was seen again in February, 1955, when it was considered that some periochondritis was present. This has subsided and he remains well and apparently free of disease seven months after treatment. S i n c e this r e p o r t was first p r e p a r e d , several p a t i e n t s w i t h s i m i l a r lesions h a v e b e e n t r e a t e d b y t h e t y p e of a p p l i c a t o r d e s c r i b e d . T h e g e n e r a l o p i n i o n of t h o s e c o n c e r n e d i n its use r e m a i n s favourable. SUMMARY
A n a p p l i a n c e for t r e a t i n g c a r c i n o m a of t h e vocal c o r d is d e s c r i b e d , a n d two cases t r e a t e d b y it are r e p o r t e d . W e w i s h to t h a n k t h e D i r e c t o r of t h e Q u e e n s l a n d R a d i u m I n s t i t u t e for p e r m i s s i o n to p u b l i s h this report. REFERENCES SIR STANFORD (I949), Malignant Disease and its Treatment by Radium, 2nd ed., 2, 33 o. Bristol : John Wright & Sons. FINZI, N. S., and HARMER, W. D. (I928), Brit. reed. J., 2, 886. GREEN, A., and JENNINGS, W. A, (I95I), ft. Fac. Radiol., Lond., 2, 206. MORTON, J . , GRAY, L. H., and NEARY, G. J. (i944) , B r i t . ff. Radiol., 17, 204. NEOUS, V. E. (I947), Proc. R. Soe. Med., 40, 515. PATERSON, RALSTON (I948), Treatment of Malignant Disease by Radium and X-rays. London : Edward Arnold & Co. CADE,
sODIUM
ACETRIZOATE
IN
INTRAVENOUS
PYELOGRAPHY
~39
AN ASSESSMENT OF S O D I U M A C E T R I Z O A T E A N D A N E X P E R I M E N T A L B A S I S F O R I T S U S E IN I N T R A V E N O U S PYELOGRAPHY* BY P. G. KEATES, M.D., M,R.C.P., D.M.R.D. THE DIAGNOSTIC X-RAy DEPARTMENT, THE GENERAL INFIRMARY, LEEDS
SODIUM acetrizoate is a m e d i u m for i n t r a v e n o u s pyelography which differs from the more familiar diodone and iodoxyl in having three iodine atoms o n each molecule instead of two (Fig. 12o). I n America it has been marketed u n d e r the trade n a m e U r o k o n and more recently in this country as Diaginol. Reports on its use in A m e r i c a have all b e e n favourable. W h e n 2 5 c.c. of 3 ° per cent CHz. COOH. N H
<
CH2. CH~ OH CH2. CH~ OH
I
CH3
L
NaOOC--~//N~{~COONa I--
\(
I
I
O B.P. name :
O
B.P. name : Iodoxyl. Chemical name: Disodium salt of 3-5-di-iodoN-methyi-4-pyridone-2 : 6-dicarboxylic acid.
Diodone.
Chemical name: Diethanolamine salt of 3-5-diiodopyridone-N-acetic acid. COONa I
I NHCOCHa
I
I
Short chemical name : Sodium acetrizoate. Trade names : Diaginol ; Urokon. Chemical name : Sodium salt of 3-acetylamino-e : 4 : 6-triiodobenzoic acid. Fig.
~2o.--The
f o r m u l a e of t h e c o m m o n
intravenous pyelographic media.
solution were used the pyelograms were described as b e i n g equal or superior to those with diodone or iodoxyl (Nesbit and Lapides, 195o ; Richardson a n d Rose, 195o ; Robbins, Colby, Sosman, and Eyler, 1951 ). T h o s e following injection of 25 c.c. of 7 ° per cent solution were better still (Barry and Rose, 1953 ; Bohne a n d Christeson, 1953 ; N e s b i t and Nesbitt, 1953 ; Porporis, Zink, Wilson, Barry, Royce, and Rose, 1953 ; Wall and Rose, 1951 ). T h e first report p u b l i s h e d in this c o u n t r y on the use of 20 c.c. of the 3 ° per cent solution described the degree of contrast and rate of appearance of shadows as n o t significantly different from those with diodone or iodoxyl (Cave, Burfield, a n d Rankin, 1953). * This paper is part of one which was read to the Radiological Section of the Royal Society of Medicine on February 18, 1955.
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T h e author (Keates, i954) published an account of a comparison of 20 c.c. of 35 per cent diodone and 2o c.c. of 3 ° per cent sodium acetrizoate in which each m e m b e r of a group of normal patients was examined with both media under controlled conditions which included deprivation of Table I . - - D A T A ON AN INVESTIGATION INTO URINE CONCENTRATIONS OF SODIUM ACETRIZOATE U r e t e r i c c a t h e t e r s p e c i m e n s w e r e o b t a i n e d e v e r y few m i n u t e s a f t e r i n j e c t i o n a n d t h e c o n c e n t r a t i o n o f m e d i u m w a s e s t i m a t e d b y t h e m e t h o d of N e u h a u s , C h r i s t m a n , a n d L e w i s (195o). D o s e : z o c.c. of 7o p e r c e n t s o l u t i o n of s o d i u m a c e t r i z o a t e . N u m b e r of C a s e s : F i v e . Age : 21-62 years. W e i g h t : 8 - 1 i st. L a s t fluid t a k e n : i 5 - i 9 h o u r s b e f o r e i n j e c t i o n . A v e r a g e m a x i m u m u r i n e c o n c e n t r a t i o n : = 13"4 p e r c e n t ± 0"7.
fluid for fourteen hours and ureteric compression by pads and abdominal binder. T h e t w o sets of pyelograms in each case were compared by three observers who were not told the order in which the media had been used. I n two-thirds of the cases the diodone pyelograms were p r e f e r r e d ; the density of the sodium acetrizoate pyelograms was somewhat greater than with diodone, but the ' filling ' of the calices was often incomplete, the pyelograms were described as ' spastic ' and it was frequently possible to decide which m e d i u m had been used by this characteristic appearance. In discussing these findings it was suggested that poor ' filling ' of the pyelograms might be due to the low rate of urine flow following injection of sodium acetrizoate. T h e present paper includes an investigation of the concentrations of sodium acetrizoate reached in the urine ; a report on the use of a high dose of sodium acetrizoate compared with diodone and a discussion of the place of sodium acetrizoate in intravenous pyelography.
THE
EXCRETION
OF
SODIUM
ACETRIZOATE
In arriving at the best method of use of any pyelographic m e d i u m certain fundamental principles must be taken into account. Firstly, immediately following intravenous injection the blood level of a substance is at a m a x i m u m and therefore its rate of extraction from the blood by the kidneys is maximal. As the blood level falls the renal clearance of the m e d i u m is progressively reduced, and though excretion of the injected dose may take 24 hours the final clearance is very 10w. On the other hand the collecting system of the kidney, which includes the calices, pelvis, and ureter, initially contains urine which is free from medium and therefore non-opaque to X-rays. As excretion of the m e d i u m proceeds the calices, pelvis, and ureter become increasingly radio-opaque as the original urine is washed out. T h e rise in urine concentration of the medium due to the ' washing through ' effect is to some extent countered by the failing renal clearance and there is a point in time at which the concentration is at a maximum. If a single radiograph were to be taken without any attempt to obstruct the ureters then this would be the time at which the film should be exposed. If obstruction of the ureters is to be carried out then this should be applied some minutes before the time of m a x i m u m concentration and the fihn exposed some minutes after, so that the urine d a m m e d up shall have as high a content of m e d i u m as possible. A curve showing the concentrations reached at various times after injection of diodone has been previously published (Keates, 1953) and this work has now been repeated using sodium acetrizoate. Five out-patients attending a cystoscopy clinic were investigated, each of whom was shown to have normal renal tracts. Ureteric catheters were inserted to within 3 in. of the renal pelves, 2o c.c. of a 7 ° per cent solution of sodium acetrizoate was injected intravenously and specimens of urine were collected at intervals of a few minutes for chemical analysis by the method of Neuhaus, Christman, and Lewis (195o). Table I shows data for these patients and it will be seen that the average maximum
sODIUM
ACETRIZOATE
IN
INTRAVENOUS
PYELOGRAPHY
~41
concentration
reached was 13"4 per cent of medium in urine. This is about one fifth of the concentration of the solution injected and represents a very high iodine level in the urine. A curve (Fig. 121), drawn to show the rate of rise and fall in concentration of sodium acetrizoate in the urine after injection of this dose, shows a peak about io minutes after injection but has narrow shoulders so that it is at or above 9 ° per cent for only five minutes. The same figure shows a curve L00
80 70 -.o so
Sod,,,m
I
I
s
ho
I
I
I
I
hs
20
2S
30
MINUTES AFTS~ IN~ECTLO~
I
Fig. l Z i . - - C u r v e s showing the rise in concentration of diodone and sodium acetrizoate in the urine. T i m e is measured from the completion of the injection. M a x i m u m concentration was expressed as ioo pe r cent in each case and the other values adjusted accordingly (mean m a x i m u m concentration after injection of ao c.c. 35 per cent diodone was 8.0 q- o. 5 g. pe r cent ; mean m a x i m u m concentration after 20 c.c. 70 per cent sodium acetrizoate was I 3 ' 4 + 0"7 g. per cent) T h e curve for diodone was based on 28 cases, and that for s o d i u m acetrizoate on 5.
/ l
/ I I I
i/
for diodone and it will be seen that there are striking differences in the shapes of the curves for the / two media. Firstly, the peak concentration of sodium acetrizoate is five minutes earlier than with ~0 diodone and, secondly, the concentration of sodium acetrizoate falls off much more rapidly. Because Fig. i a z . - - F i g , i2 1 r e d r a w n so t h a t the curves show the of this the best t i m e s t o apply ureteric compression ofappr°ximatediodone andC°ncentrati°nSsodium acetrizoate.°f iodine in the u r in e after injection and to take films are different with the two media, and it is suggested that when using sodium acetrizoate ureteric compression be started seven minutes after injection, and films be taken fifteen or twenty minutes after injection. Because the fall in diodone concentration is relatively slow the exact timing of compression and radiography is not critical, though the period between 11 minutes and 25 minutes after injection is optimum. With sodium acetrizoate, on the other hand, if comPression is applied too early the concentration of medium in the urine will be low, while if compression is much delayed the most highly radio-opaque urine will have escaped and the urine trapped will be relatively poor in medium. Several previous papers on this medium have commented on the rapid appearance of good pyelograms and have concluded that excretion is more rapid than with other media. Now though the highest concentration is reached several minutes earlier than with diodone, in the first five minutes, when early pyetograms are causing comment, these curves seem to show that the slopes are similar so that after five minutes each medium has reached about half the concentration to which it will eventually rise. T h e explanation of the early pyelograms is that in terms of iodine concentration sodium acetrizoate will in the end reach a level about twice as high as diodone, so that when /
is
~JNOrfs
gFTfN t~eC~c,re
IO
i4z
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each medium is halfway to its own peak in fact the iodine concentration in sodium acetrizoate urine is twice that in diodone urine (Fig. I22). The same figure makes apparent two other features. Firstly, the advantage in increased radio-opacity to be gained from the new medium must be seized during the 6- to i6-minute period, for after that the difference in urinary iodine content between the two media is less. On the other
A
B
Fig. I23.--Case M. P. A, 20 c.c. of 35 per cent diodone injected and compression applied at 7 minutes. T h e illustration
shows the appearance of the right kidney 25 minutes after injection. S, 2o c.c. of 70 per cent sodium acetrizoate injected and compression applied I5 minutes later. T h e illustration shows the appearance of the right kidney 30 minutes after injection. T h e radio-opacity of the shadows is similar showing that pyelograms persist after 15 minutes with sodium aeetrizoate, contrary to some published statements.
hand even thirty minutes after injection the iodine level in sodium acetrizoate urine is reasonably high, and though it has sometimes been suggested that after about 15 minutes the pyelograms are ' gone ' in fact this curve shows that this should not be so. To illustrate the point a few patients were examined in the usual routine manner with diodone. On a second visit no compression was applied until 15 minutes after injection with sodium acetrizoate, by which time the urine with the greatest concentration of medium had been lost, and yet the pyelograms obtained on the first and second visits were comparable. Fig. i23 shows the right kidney of a patient examined first with diodone with routine compression-and then with sodium acetrizoate with compression delayed for 15 minutes. The pyelograms are similar in appearance.
C O M P A R I S O N OF S O D I U M A C E T R I Z O A T E A N D D I O D O N E P Y E L O G R A M S The method of comparing sodium acetrizoate and diodone has again been to obtain pyelograms with both media in a series of normal adolescent and adult out-patients ; excluding those over the age of 55 because one's experience is that in older patients excretory pyelograms are less often satisfactory than in younger individuals. Some of the many variable factors which control the quality of a pyelogram can be eliminated by this plan of selecting a homogeneous group of patients, and one can thus obtain a clearer indication of the part that choice of medium is playing in deciding the result. The routine procedure was for patients to attend the X-ray department having had an ounce of castor oil the preceding night and having taken no fluids for an average period of 13 hours. Abdominal compression by the method of Lundstr/Sm (1946) was applied 7 minutes after completion
SODIUM
ACETRIZOATE
IN
INTRAVENOUS
PYELOGRAPHY
~43
of the injection and films taken 5 and x8 m i n u t e s later. T h e dose of diodone used was 20 c.c. of 35 per cent solution, and of s o d i u m acetrizoate 20 c.c. of 70 per cent solution. T h e panel of two consultant radiologists and one consultant genito-urinary surgeon w h o had assessed the films in the previous investigation p e r f o r m e d the same service in this one T h e right and left kidneys were treated separately in eacla case and the observers stated a preference for one or other e x a m i n a t i o n w i t h o u t knowing w h i c h m e d i u m had b e e n used first.
Table (zo
- / / , - - P A N E L MEMBERS' PREFERENCE FOR PYELOGRAMS IN
33
CASES RECEIVING BOTH DIODONE
c . c . , 35 PER CENT SOLUTION) AND SODIUM ACETRIZOATE ( 2 0 C.C., 7 ° PER CENT SOLUTION) i
NO. OF CASES PREFERRED
PANEL MEMBER
D1ODONE
SODIUM ACETRIZOATE
Z2
P
A B C M~ority opinion
IZ'5 Iz'5 IO ii
20"5 2o'5 23 22
3"88 3'88 lO"24 7'33
<0"05 <0"05
7 ° PER CENT
SIGNIFICANCE OF DIFFERENCE
Significant Significant Highly significant Highly significant
Mean weight of patients : 135 lb. Age of patients : 14 to 52 years (mean 35 years). Mean period without fluid : 13"1 hours. Note : Where a panel member preferred different media for the right and left kidneys 0"5 was scored to each medium. In 4 cases there was no clear majority opinion for either medium and 0"5 was scored to each. T h e findings, s u m m a r i z e d in Table Ii, show that in about 2 out of 3 cases the s o d i u m acetrizoate results were better t h a n those w i t h diodone. D i r e c t comparison of pyelograms in this fashion is p r o b a b l y the m o s t accurate and least subjective m e t h o d available for assessing m e d i a but c o m p a r i s o n
Table IlL--QUALITY OF t)YELOGRAMSIN 33 CASESRECEIVINGBOTH DIODONE AND 70 PER CENT SODIUM ACETRIZOATE EACH KIDNEY ASSESSEDSEPARATELY PANEL MEMBER
'A
B
C
MEDIUM
NO, OF KIDNEYS ASSESSED AS MODERATE POOR
GOOD
Diodone 70 per cent sodium acetrizoate Diodone 7° per cent sodium acetrizoate Diodone 70 per cent sodium aeetrizoate
53
io
3
64
2
o
51
io
5
6z
2
2
43
17
6
57
7
z
SIGNIFICANCE OF D IFFERENCE
Zz
FOR DIFFERENCE BETWEEN MEDIA
9"37
Highly significant
7'69
<0"05
Significant
8"I3
Significant
of the n u m b e r of examinations classed as good, moderate, and poor, m a y also be used. Table 111, which shows such a survey, confirms the superiority of the n e w e r m e d i u m . So m u c h for the statistical evidence. H o w did the films appear to the observers ? Firstly, each of t h e m had learnt f r o m the previous series to recognize s o d i u m acetrizoate pyelograms by the appearance of p o o r filling, but n o w that a large dose was being used this difference was no longer seen, and after c o m p a r i n g the first i o sets of films each observer i n d e p e n d e n t l y and
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I should like to thank Professor A. S. Johnstone, Dr. G. H. Illingworth, and Mr. F. Raper for judging the films, and Professor A. Hemingway for allowing me to carry out the chemical estimations in his department. Messrs. M a y and Baker gave generous supplies of sodium acetrizoate (Diaginol). REFERENCES BARRY, C. N., and ROSE, D. K. (I953), ft. Urol., 69, 849. BOHNE, A. W., and CHRISTESON,W. W. (I953), Radiology, 6o, 4Ol. CAVE, P., BURFIELD, G. A., and RANKIN, J. A. (I953) , Brit. ft. Radiol., 26, 548. KEATES, P. G. (I953), Brit. ft. Urol., 25, 366. - - - - (I954), Brit. 7. Radiol., 27, 236. LUNDSTROM, E. (I946), Acta radiol., Stockh., 27, 385. NESBIT, R. M., and LAPIDES,J. (I95o), ft. Urol., 63, 11o9. - - - - NESBITT, T. E. (I953) , Ibid., 70, 332. NEUHAUS, D. R., CHRISTMAN,A. A., and LEWIS, H. B. (I95O), J. Lab. clin. Med., 35, 43. PORPORIS, A. A., ZINK, O. C., WILSON, H. M., BARRY, C. N., ROYCE, R., and RosE, D. K. (I953), Radiology, 60, 675. RICHARDSON,J. F., and ROSE, D. K. (I95O), J. Urol., 63, III3. RmLER, L. (I953), Radiology, 60, 686. ROBBINS, L. L., COLBY, F. H., SOSMAN,J. L., and EYLER, W. R. (I95I), Ibid., 56, 684. WALL, B., and RosE, D. K. (I95I), `7. Urol., 66, 3o5.
FOURTH SYMPOSIUM NEURORADIOLOGICUM, LONDON, 1955 THE F o u r t h International Symposium of Neuroradiology held in the University of London, September 12-17, 1955, under the Presidency of Dr. James Bull, of the National Hospital, Queen Square, was attended b y o v e r 3oo members from twenty-nine different countries. Some Sixty papers were presented, covering all aspects of neuroradiology from the commoner contrast methods to stereotaxis and isotope localization of brain lesions. T h e r e were also scientific and technical exhibitions and a combined session, which was held with the Second International Congress of Neuropathology. T h e Conference emphasized the increasingly important part played by radiology in neurological conditions and did much to enhance the prestige of British radiology. Its unqualified success was a tribute to the work of the President, the Treasurer, Dr. H u g h Davies, the Honorary Secretary, Dr. R. D. Hoare, and their numerous helpers.
OF
THE
VOCAL
CORD
~37
active needles being held in a separate piece of material which then fits into the fenestration as a single, rigid unit. A piece of polythene sheet, one-eighth of an inch thick, cut to size slightly larger than the active area required for the radon sources, was drilled parallel to the flat faces of the sheet to take
Fig. i i 8 . - - R a d i o g r a p h s of applicators in p o s i t i o n - - C a s e
I is on the left, C a s e ~ is on the right.
pieces of 0. 5 ram. wall gold capillary tube in which the radon is sealed (Fig. i i 7 ) . I n the smaller unit illustrated, the drill holes break through the surface of the p01ythene so that the radon sources are in contact with the exposed tissue, as in the established radium technique. This is unnecessary and there appears to be some advantage in keeping the holes completely within the polythene. T h e usual six to eight radium needles of the F i n z i - H a r m e r technique may be loaded in this way. T h e sources are then inserted into the exposed window in one operation instead of needle by needle. Bevelled edges on the polythene fit under the surrounding cartilage and small holes permit more positive fixation by stitching. All sources are held immobile both with respect to the larynx and to each other. As a point of technical interest it was found essential to provide an unloaded piece of polythene of identical dimensions to enable accurate cutting of the window in the thyroid cartilage. T h e use of radon brings further advantages. T h e sources are active right to the ends so that the extent of the fenestration need only be slightly larger than the area to be treated. Unsymmetrical distributions of activity are commonly desirable since the malignant tissue does not always run parallel to the plane of the polythene. A n y desirable distribution of activity can be realized with radon, in contrast to the restrictions placed by radium needles of fixed strength. Spare holes drilled in the polythene provide for a last minute change in the treated area should this be found necessary. T h e softness of gold and polythene is such that the sources can be pushed easily in and out of the holes without being so loose as to fall out.
CASE REPORTS Case I.--R. S., a retired civil servant, aged 57 years, had noticed hoarseness for three months. On examination on July 3o, 1954, a nodular lesion, covering the anterior two-thirds of the right vocal cord, was found. A biopsy was taken and reported to show a moderately well differentiated squamous cell carcinoma. On Aug. 6, I954, a window was made in the right lamina of the thyroid cartilage and a polythene-radon applicator was
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inserted for 4 days and 4 hours (Fig. 118). This was designed to deliver 45oo r to the right vocal cord (Fig. 119). One month later, the view of the cord was found to be obscured by oedema of the right false cord. On Oct. 15, 1954, two months after treatment, laryngoscopy revealed an apparently normal larynx. He was last seen in April, 1955, and again the appearance of the larynx was completely normal.
~
ocal folds
u T 500r I-0 crn. )¢
~L
9000!,5cm ~1 F
I 1,000 r
|
22,000 r
XlD .v. . . . ~ . " P l a n e of Radon Sources (Perpendicular to paper) ( , 2 . 0 era., ) Fig. z i9.--Distribntion of g a m m a - r a y dose in r units in plane bisecting
plane of radon sources at right angles, T h e radon is more strongly concentrated at the end of the plane, nearest to point F.
Case 2.--L. N., a mental hospital inmate, aged 44 years, was first seen on Oct. 18, 1954. Hoarseness had been noticed for six weeks. Fie was found to have a carcinoma of the right vocal cord, anterior commissure, and the anterior end of the left vocal cord. A biopsy of the lesion was reported to show an anaplastic carcinoma. On Nov. 4, I954, a large fenestration was made in the thyroid cartilage, and the larger radon applicator illustrated in Fig. 117 inserted ; 5500 r was delivered to the right and left cords in 4½ days. Convalescence was uneventful. He was seen again in February, 1955, when it was considered that some periochondritis was present. This has subsided and he remains well and apparently free of disease seven months after treatment. S i n c e this r e p o r t was first p r e p a r e d , several p a t i e n t s w i t h s i m i l a r lesions h a v e b e e n t r e a t e d b y t h e t y p e of a p p l i c a t o r d e s c r i b e d . T h e g e n e r a l o p i n i o n of t h o s e c o n c e r n e d i n its use r e m a i n s favourable. SUMMARY
A n a p p l i a n c e for t r e a t i n g c a r c i n o m a of t h e vocal c o r d is d e s c r i b e d , a n d two cases t r e a t e d b y it are r e p o r t e d . W e w i s h to t h a n k t h e D i r e c t o r of t h e Q u e e n s l a n d R a d i u m I n s t i t u t e for p e r m i s s i o n to p u b l i s h this report. REFERENCES SIR STANFORD (I949), Malignant Disease and its Treatment by Radium, 2nd ed., 2, 33 o. Bristol : John Wright & Sons. FINZI, N. S., and HARMER, W. D. (I928), Brit. reed. J., 2, 886. GREEN, A., and JENNINGS, W. A, (I95I), ft. Fac. Radiol., Lond., 2, 206. MORTON, J . , GRAY, L. H., and NEARY, G. J. (i944) , B r i t . ff. Radiol., 17, 204. NEOUS, V. E. (I947), Proc. R. Soe. Med., 40, 515. PATERSON, RALSTON (I948), Treatment of Malignant Disease by Radium and X-rays. London : Edward Arnold & Co. CADE,
sODIUM
ACETRIZOATE
IN
INTRAVENOUS
PYELOGRAPHY
~39
AN ASSESSMENT OF S O D I U M A C E T R I Z O A T E A N D A N E X P E R I M E N T A L B A S I S F O R I T S U S E IN I N T R A V E N O U S PYELOGRAPHY* BY P. G. KEATES, M.D., M,R.C.P., D.M.R.D. THE DIAGNOSTIC X-RAy DEPARTMENT, THE GENERAL INFIRMARY, LEEDS
SODIUM acetrizoate is a m e d i u m for i n t r a v e n o u s pyelography which differs from the more familiar diodone and iodoxyl in having three iodine atoms o n each molecule instead of two (Fig. 12o). I n America it has been marketed u n d e r the trade n a m e U r o k o n and more recently in this country as Diaginol. Reports on its use in A m e r i c a have all b e e n favourable. W h e n 2 5 c.c. of 3 ° per cent CHz. COOH. N H
<
CH2. CH~ OH CH2. CH~ OH
I
CH3
L
NaOOC--~//N~{~COONa I--
\(
I
I
O B.P. name :
O
B.P. name : Iodoxyl. Chemical name: Disodium salt of 3-5-di-iodoN-methyi-4-pyridone-2 : 6-dicarboxylic acid.
Diodone.
Chemical name: Diethanolamine salt of 3-5-diiodopyridone-N-acetic acid. COONa I
I NHCOCHa
I
I
Short chemical name : Sodium acetrizoate. Trade names : Diaginol ; Urokon. Chemical name : Sodium salt of 3-acetylamino-e : 4 : 6-triiodobenzoic acid. Fig.
~2o.--The
f o r m u l a e of t h e c o m m o n
intravenous pyelographic media.
solution were used the pyelograms were described as b e i n g equal or superior to those with diodone or iodoxyl (Nesbit and Lapides, 195o ; Richardson a n d Rose, 195o ; Robbins, Colby, Sosman, and Eyler, 1951 ). T h o s e following injection of 25 c.c. of 7 ° per cent solution were better still (Barry and Rose, 1953 ; Bohne a n d Christeson, 1953 ; N e s b i t and Nesbitt, 1953 ; Porporis, Zink, Wilson, Barry, Royce, and Rose, 1953 ; Wall and Rose, 1951 ). T h e first report p u b l i s h e d in this c o u n t r y on the use of 20 c.c. of the 3 ° per cent solution described the degree of contrast and rate of appearance of shadows as n o t significantly different from those with diodone or iodoxyl (Cave, Burfield, a n d Rankin, 1953). * This paper is part of one which was read to the Radiological Section of the Royal Society of Medicine on February 18, 1955.
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T h e author (Keates, i954) published an account of a comparison of 20 c.c. of 35 per cent diodone and 2o c.c. of 3 ° per cent sodium acetrizoate in which each m e m b e r of a group of normal patients was examined with both media under controlled conditions which included deprivation of Table I . - - D A T A ON AN INVESTIGATION INTO URINE CONCENTRATIONS OF SODIUM ACETRIZOATE U r e t e r i c c a t h e t e r s p e c i m e n s w e r e o b t a i n e d e v e r y few m i n u t e s a f t e r i n j e c t i o n a n d t h e c o n c e n t r a t i o n o f m e d i u m w a s e s t i m a t e d b y t h e m e t h o d of N e u h a u s , C h r i s t m a n , a n d L e w i s (195o). D o s e : z o c.c. of 7o p e r c e n t s o l u t i o n of s o d i u m a c e t r i z o a t e . N u m b e r of C a s e s : F i v e . Age : 21-62 years. W e i g h t : 8 - 1 i st. L a s t fluid t a k e n : i 5 - i 9 h o u r s b e f o r e i n j e c t i o n . A v e r a g e m a x i m u m u r i n e c o n c e n t r a t i o n : = 13"4 p e r c e n t ± 0"7.
fluid for fourteen hours and ureteric compression by pads and abdominal binder. T h e t w o sets of pyelograms in each case were compared by three observers who were not told the order in which the media had been used. I n two-thirds of the cases the diodone pyelograms were p r e f e r r e d ; the density of the sodium acetrizoate pyelograms was somewhat greater than with diodone, but the ' filling ' of the calices was often incomplete, the pyelograms were described as ' spastic ' and it was frequently possible to decide which m e d i u m had been used by this characteristic appearance. In discussing these findings it was suggested that poor ' filling ' of the pyelograms might be due to the low rate of urine flow following injection of sodium acetrizoate. T h e present paper includes an investigation of the concentrations of sodium acetrizoate reached in the urine ; a report on the use of a high dose of sodium acetrizoate compared with diodone and a discussion of the place of sodium acetrizoate in intravenous pyelography.
THE
EXCRETION
OF
SODIUM
ACETRIZOATE
In arriving at the best method of use of any pyelographic m e d i u m certain fundamental principles must be taken into account. Firstly, immediately following intravenous injection the blood level of a substance is at a m a x i m u m and therefore its rate of extraction from the blood by the kidneys is maximal. As the blood level falls the renal clearance of the m e d i u m is progressively reduced, and though excretion of the injected dose may take 24 hours the final clearance is very 10w. On the other hand the collecting system of the kidney, which includes the calices, pelvis, and ureter, initially contains urine which is free from medium and therefore non-opaque to X-rays. As excretion of the m e d i u m proceeds the calices, pelvis, and ureter become increasingly radio-opaque as the original urine is washed out. T h e rise in urine concentration of the medium due to the ' washing through ' effect is to some extent countered by the failing renal clearance and there is a point in time at which the concentration is at a maximum. If a single radiograph were to be taken without any attempt to obstruct the ureters then this would be the time at which the film should be exposed. If obstruction of the ureters is to be carried out then this should be applied some minutes before the time of m a x i m u m concentration and the fihn exposed some minutes after, so that the urine d a m m e d up shall have as high a content of m e d i u m as possible. A curve showing the concentrations reached at various times after injection of diodone has been previously published (Keates, 1953) and this work has now been repeated using sodium acetrizoate. Five out-patients attending a cystoscopy clinic were investigated, each of whom was shown to have normal renal tracts. Ureteric catheters were inserted to within 3 in. of the renal pelves, 2o c.c. of a 7 ° per cent solution of sodium acetrizoate was injected intravenously and specimens of urine were collected at intervals of a few minutes for chemical analysis by the method of Neuhaus, Christman, and Lewis (195o). Table I shows data for these patients and it will be seen that the average maximum
sODIUM
ACETRIZOATE
IN
INTRAVENOUS
PYELOGRAPHY
~41
concentration
reached was 13"4 per cent of medium in urine. This is about one fifth of the concentration of the solution injected and represents a very high iodine level in the urine. A curve (Fig. 121), drawn to show the rate of rise and fall in concentration of sodium acetrizoate in the urine after injection of this dose, shows a peak about io minutes after injection but has narrow shoulders so that it is at or above 9 ° per cent for only five minutes. The same figure shows a curve L00
80 70 -.o so
Sod,,,m
I
I
s
ho
I
I
I
I
hs
20
2S
30
MINUTES AFTS~ IN~ECTLO~
I
Fig. l Z i . - - C u r v e s showing the rise in concentration of diodone and sodium acetrizoate in the urine. T i m e is measured from the completion of the injection. M a x i m u m concentration was expressed as ioo pe r cent in each case and the other values adjusted accordingly (mean m a x i m u m concentration after injection of ao c.c. 35 per cent diodone was 8.0 q- o. 5 g. pe r cent ; mean m a x i m u m concentration after 20 c.c. 70 per cent sodium acetrizoate was I 3 ' 4 + 0"7 g. per cent) T h e curve for diodone was based on 28 cases, and that for s o d i u m acetrizoate on 5.
/ l
/ I I I
i/
for diodone and it will be seen that there are striking differences in the shapes of the curves for the / two media. Firstly, the peak concentration of sodium acetrizoate is five minutes earlier than with ~0 diodone and, secondly, the concentration of sodium acetrizoate falls off much more rapidly. Because Fig. i a z . - - F i g , i2 1 r e d r a w n so t h a t the curves show the of this the best t i m e s t o apply ureteric compression ofappr°ximatediodone andC°ncentrati°nSsodium acetrizoate.°f iodine in the u r in e after injection and to take films are different with the two media, and it is suggested that when using sodium acetrizoate ureteric compression be started seven minutes after injection, and films be taken fifteen or twenty minutes after injection. Because the fall in diodone concentration is relatively slow the exact timing of compression and radiography is not critical, though the period between 11 minutes and 25 minutes after injection is optimum. With sodium acetrizoate, on the other hand, if comPression is applied too early the concentration of medium in the urine will be low, while if compression is much delayed the most highly radio-opaque urine will have escaped and the urine trapped will be relatively poor in medium. Several previous papers on this medium have commented on the rapid appearance of good pyelograms and have concluded that excretion is more rapid than with other media. Now though the highest concentration is reached several minutes earlier than with diodone, in the first five minutes, when early pyetograms are causing comment, these curves seem to show that the slopes are similar so that after five minutes each medium has reached about half the concentration to which it will eventually rise. T h e explanation of the early pyelograms is that in terms of iodine concentration sodium acetrizoate will in the end reach a level about twice as high as diodone, so that when /
is
~JNOrfs
gFTfN t~eC~c,re
IO
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each medium is halfway to its own peak in fact the iodine concentration in sodium acetrizoate urine is twice that in diodone urine (Fig. I22). The same figure makes apparent two other features. Firstly, the advantage in increased radio-opacity to be gained from the new medium must be seized during the 6- to i6-minute period, for after that the difference in urinary iodine content between the two media is less. On the other
A
B
Fig. I23.--Case M. P. A, 20 c.c. of 35 per cent diodone injected and compression applied at 7 minutes. T h e illustration
shows the appearance of the right kidney 25 minutes after injection. S, 2o c.c. of 70 per cent sodium acetrizoate injected and compression applied I5 minutes later. T h e illustration shows the appearance of the right kidney 30 minutes after injection. T h e radio-opacity of the shadows is similar showing that pyelograms persist after 15 minutes with sodium aeetrizoate, contrary to some published statements.
hand even thirty minutes after injection the iodine level in sodium acetrizoate urine is reasonably high, and though it has sometimes been suggested that after about 15 minutes the pyelograms are ' gone ' in fact this curve shows that this should not be so. To illustrate the point a few patients were examined in the usual routine manner with diodone. On a second visit no compression was applied until 15 minutes after injection with sodium acetrizoate, by which time the urine with the greatest concentration of medium had been lost, and yet the pyelograms obtained on the first and second visits were comparable. Fig. i23 shows the right kidney of a patient examined first with diodone with routine compression-and then with sodium acetrizoate with compression delayed for 15 minutes. The pyelograms are similar in appearance.
C O M P A R I S O N OF S O D I U M A C E T R I Z O A T E A N D D I O D O N E P Y E L O G R A M S The method of comparing sodium acetrizoate and diodone has again been to obtain pyelograms with both media in a series of normal adolescent and adult out-patients ; excluding those over the age of 55 because one's experience is that in older patients excretory pyelograms are less often satisfactory than in younger individuals. Some of the many variable factors which control the quality of a pyelogram can be eliminated by this plan of selecting a homogeneous group of patients, and one can thus obtain a clearer indication of the part that choice of medium is playing in deciding the result. The routine procedure was for patients to attend the X-ray department having had an ounce of castor oil the preceding night and having taken no fluids for an average period of 13 hours. Abdominal compression by the method of Lundstr/Sm (1946) was applied 7 minutes after completion
SODIUM
ACETRIZOATE
IN
INTRAVENOUS
PYELOGRAPHY
~43
of the injection and films taken 5 and x8 m i n u t e s later. T h e dose of diodone used was 20 c.c. of 35 per cent solution, and of s o d i u m acetrizoate 20 c.c. of 70 per cent solution. T h e panel of two consultant radiologists and one consultant genito-urinary surgeon w h o had assessed the films in the previous investigation p e r f o r m e d the same service in this one T h e right and left kidneys were treated separately in eacla case and the observers stated a preference for one or other e x a m i n a t i o n w i t h o u t knowing w h i c h m e d i u m had b e e n used first.
Table (zo
- / / , - - P A N E L MEMBERS' PREFERENCE FOR PYELOGRAMS IN
33
CASES RECEIVING BOTH DIODONE
c . c . , 35 PER CENT SOLUTION) AND SODIUM ACETRIZOATE ( 2 0 C.C., 7 ° PER CENT SOLUTION) i
NO. OF CASES PREFERRED
PANEL MEMBER
D1ODONE
SODIUM ACETRIZOATE
Z2
P
A B C M~ority opinion
IZ'5 Iz'5 IO ii
20"5 2o'5 23 22
3"88 3'88 lO"24 7'33
<0"05 <0"05
7 ° PER CENT
SIGNIFICANCE OF DIFFERENCE
Significant Significant Highly significant Highly significant
Mean weight of patients : 135 lb. Age of patients : 14 to 52 years (mean 35 years). Mean period without fluid : 13"1 hours. Note : Where a panel member preferred different media for the right and left kidneys 0"5 was scored to each medium. In 4 cases there was no clear majority opinion for either medium and 0"5 was scored to each. T h e findings, s u m m a r i z e d in Table Ii, show that in about 2 out of 3 cases the s o d i u m acetrizoate results were better t h a n those w i t h diodone. D i r e c t comparison of pyelograms in this fashion is p r o b a b l y the m o s t accurate and least subjective m e t h o d available for assessing m e d i a but c o m p a r i s o n
Table IlL--QUALITY OF t)YELOGRAMSIN 33 CASESRECEIVINGBOTH DIODONE AND 70 PER CENT SODIUM ACETRIZOATE EACH KIDNEY ASSESSEDSEPARATELY PANEL MEMBER
'A
B
C
MEDIUM
NO, OF KIDNEYS ASSESSED AS MODERATE POOR
GOOD
Diodone 70 per cent sodium acetrizoate Diodone 7° per cent sodium acetrizoate Diodone 70 per cent sodium aeetrizoate
53
io
3
64
2
o
51
io
5
6z
2
2
43
17
6
57
7
z
SIGNIFICANCE OF D IFFERENCE
Zz
FOR DIFFERENCE BETWEEN MEDIA
9"37
Highly significant
7'69
<0"05
Significant
8"I3
Significant
of the n u m b e r of examinations classed as good, moderate, and poor, m a y also be used. Table 111, which shows such a survey, confirms the superiority of the n e w e r m e d i u m . So m u c h for the statistical evidence. H o w did the films appear to the observers ? Firstly, each of t h e m had learnt f r o m the previous series to recognize s o d i u m acetrizoate pyelograms by the appearance of p o o r filling, but n o w that a large dose was being used this difference was no longer seen, and after c o m p a r i n g the first i o sets of films each observer i n d e p e n d e n t l y and
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I should like to thank Professor A. S. Johnstone, Dr. G. H. Illingworth, and Mr. F. Raper for judging the films, and Professor A. Hemingway for allowing me to carry out the chemical estimations in his department. Messrs. M a y and Baker gave generous supplies of sodium acetrizoate (Diaginol). REFERENCES BARRY, C. N., and ROSE, D. K. (I953), ft. Urol., 69, 849. BOHNE, A. W., and CHRISTESON,W. W. (I953), Radiology, 6o, 4Ol. CAVE, P., BURFIELD, G. A., and RANKIN, J. A. (I953) , Brit. ft. Radiol., 26, 548. KEATES, P. G. (I953), Brit. ft. Urol., 25, 366. - - - - (I954), Brit. 7. Radiol., 27, 236. LUNDSTROM, E. (I946), Acta radiol., Stockh., 27, 385. NESBIT, R. M., and LAPIDES,J. (I95o), ft. Urol., 63, 11o9. - - - - NESBITT, T. E. (I953) , Ibid., 70, 332. NEUHAUS, D. R., CHRISTMAN,A. A., and LEWIS, H. B. (I95O), J. Lab. clin. Med., 35, 43. PORPORIS, A. A., ZINK, O. C., WILSON, H. M., BARRY, C. N., ROYCE, R., and RosE, D. K. (I953), Radiology, 60, 675. RICHARDSON,J. F., and ROSE, D. K. (I95O), J. Urol., 63, III3. RmLER, L. (I953), Radiology, 60, 686. ROBBINS, L. L., COLBY, F. H., SOSMAN,J. L., and EYLER, W. R. (I95I), Ibid., 56, 684. WALL, B., and RosE, D. K. (I95I), `7. Urol., 66, 3o5.
FOURTH SYMPOSIUM NEURORADIOLOGICUM, LONDON, 1955 THE F o u r t h International Symposium of Neuroradiology held in the University of London, September 12-17, 1955, under the Presidency of Dr. James Bull, of the National Hospital, Queen Square, was attended b y o v e r 3oo members from twenty-nine different countries. Some Sixty papers were presented, covering all aspects of neuroradiology from the commoner contrast methods to stereotaxis and isotope localization of brain lesions. T h e r e were also scientific and technical exhibitions and a combined session, which was held with the Second International Congress of Neuropathology. T h e Conference emphasized the increasingly important part played by radiology in neurological conditions and did much to enhance the prestige of British radiology. Its unqualified success was a tribute to the work of the President, the Treasurer, Dr. H u g h Davies, the Honorary Secretary, Dr. R. D. Hoare, and their numerous helpers.