Vol. 11:J, May
THE JOURNAL OF UROLOGY
Copyright © 1975 by The Williams & Wilkins Co.
Printed in U.SA.
DIRECT AND INDIRECT RADIONUCLIDE CYSTOGRAPHY JAMES J. CONWAY,* A. BARRY BELMAN, LOWELL R. KING
AND
R. BRUCE FILMERt
From the Department of Radiology and the Division of Urology, The Children's Memorial Hospital, McGaw-Aiedical Center of Northwestern University, Chicago, Illinois
ABSTRACT
Direct radionuclide cystography, using short half-life radiopharmaceuticals, is considered to be more reliable for detecting vesicoureteral reflux than conventional roentgenographic techniques. In addition to the detection of vesicoureteral reflux, other parameters determined include the bladder volume when reflux occurs, calculation of volume of fluid that has refluxed, accurate calculation of residual urine volume, estimation of reflux drainage time, and the visualization and diagnosis of gross anatomic abnormalities. Currently, a major disadvantage is poor resolution, prohibiting analysis of small bladder defects and urethral abnormalities. The major advantage of nuclear cystography is the small radiation dose delivered with its use. It is estimated that at least 100 radionuclide studies can be performed for the same radiation expense as a single roentgenographic study. In 1959 Winter reported on the detection of vesicoureteral reflux following instillation of 131 I diodrast into the bladder and recording radioactivity over the kidneys with scintillation probes. 1 An indirect radionuclide technique was reported in 1963 by Dodge. 2 He used an injection of 1311 hippuran intravenously. After sufficient time was allowed for excretion into the bladder, detector probes were placed over the kidneys. An increase in radioactivity during voiding indicated reflux. Little interest in radionuclide cystography was stimulated by these initial reports. However, there is renewed interest in the use of radionuclide techniques with the advent of shorter half-life radiopharmaceuticals, primarily 99 mtechnetium compounds (Tc), which are well suited for gamma camera imaging. Findings other than the presence or absence of reflux that can now be determined by direct radionuclide cystography include 1) the bladder volume when reflux occurs, 2) a calculation of fluid volume that has refluxed, 3) an accurate calculation of residual urine volume, 4) the estimation of reflux drainage time and 5) the visualization and diagnosis of gross anatomic abnormalities such as duplication with ureteral obstruction, hydronephrosis or ectopic kidney. Techniques and the current developmental status of radionuclide cystography are briefly discussed herein. A comparison of the advantages and disadvantages of direct versus indirect radionuclide cystography, and direct radionuclide cystogAccepted for publication July 5, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. * Requests for reprints: The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Illinois 60614. t Current address: The Children's Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, Pennsylvania 19104.
raphy versus spot film roentgenographic cystography is presented. MATERIALS AND METHODS
Indirect radionuclide cystography. The indirect method of radionuclide cystography relies upon the rapid and complete renal clearance of an intravenously injected radiopharmaceutical. 2 • 3 131I ran was tried initially 2 and 99 mTc-Sn-diethylene-triaminepentaacetic acid has been recommended more recently. 3 When the radionuclide is adequately accumulated in the bladder and residuai activity in the kidneys is low enough to visualization of any reflux the patient is then seated with his back to the gamma camera. As the patient voids any significant increase in radioactivity over the upper urinary tracts indicates reflux. The indirect method has 2 advantages: 1) the bladder is not catheterized, eliminating the bility of introducing infection in susceptible pa tients, and 2) renal function and anatomy can be assessed to a certain degree during the post-injection stages of the study. However, the indirect method suffers from sev era! drawbacks. 1) The patient must cooperate to a considerable degree by retaining bladder urine until nearly complete renal clearance is achieved and then must be able to void on command in unusual surroundings. Many children can do neither. 2) Vesicoureteral reflux is a dynamic process. With direct radionuclide cystography, which volves gradual instillation of the radionuclide into the bladder by catheter, reflux into the upper tracts has been observed during filling to disappear during and after voiding. Such transient but possibly significant reflux may thus be completely missed by the indirect method. 3) The patients selected for renal studies often have an 689
690
CONWAY AND ASSOCIATES
impaired renal function and/or hydronephrosis. Considerable radioactivity may be retained in the kidneys for long periods after intravenous administration of radiopharmaceutical compounds. Small amounts of reflux are obscured by such retained activity. Presently, it would seem that the indirect method is suitable for cooperative older children who have good renal function and little or no hydronephrosis. A comparison study of indirect radionuclide cystography versus roentgenographic cystography and/or direct radionuclide cystography will be required to determine if this technique is better for evaluating vesicoureteral reflux. However, direct radionuclide cystography seems certain to be accepted as the more reliable technique. Direct radionuclide cystography. Direct radionuclide cystography implies the direct instillation of the radionuclide into the bladder via catheter. •- 1 • The catheter is connected to a solution of normal saline via regular intravenous infusion tubing. As flow is established and there is confirmation of a correct catheter placement, 1 mCi. ••mTc pertechnetate is injected into the catheter which is then flushed with normal saline. The patient assumes a supine position upon the inverted gamma camera. Bladder filling is readily visualized on the oscilloscope of the gamma camera but is better viewed with the aid of a persistence scope (fig. 1). The persistence scope enables the bladder and kidneys to be monitored at all times without increasing radiation dosage. The patient is so positioned that the bladder is bisected by the lower edge of the imaging area. A high intensity is set on the gamma camera so that small amounts of radionuclide which reflux may be easily detected (fig. 2). Consequently, the bladder image is overexposed and appears larger than one would expect. Imaging of the upper tracts on Polaroid film is started in the direct posterior projection. For each
image production 300,000 counts have been arbitrarily selected. With 1 mCi. ••mTc pertechnetate in the bladder, this usually requires 3 to 5 minutes per exposure. Both posterior oblique projections are also recorded. The persistence scope is continuously monitored for evidence of reflux, thus the saline infusion volume at which time reflux occurs can be noted. The actual bladder volume when reflux occurs is then easily calculated. This has been noted to be a rather constant feature of the reflux occurring in some patients who have been studied repeatedly. Complete bladder filling is difficult to define. Protestations by children often represent attempts to get the procedure over with and escape. There are no rules to help determine individual bladder tolerance unless intravesical pressure is monitored simultaneously. Factors such as bladder irritability from infection, voiding habits, neurogenic blad-
FIG. 1. Reflux is readily visualized on persistence scope. When reflux is visualized saline volume is noted. Bladder volume when reflux occurs can then be easily calculated. Persistence scope is continuously monitored during examination. By this means dynamism of reflux becomes evident.
FIG. 2. Proper intensity setting allows minimum amounts of radioactivity to be visualized. Relatively large amount of activity in bladder overexposes image and makes bladder appear larger than one would expect.
DIRECT AND INDIRECT RADIONUCLIDE CYSTOGRAPHY
der disorders and even apprehension or orneriness are involved. An increased tempo of protestation, leakage of urine around the catheter, backup or cessation of urine flow through the infusion apparatus generally signals the limit of bladder tolerance. A 2-minute posterior image is then recorded. An is made to include all of the abdominal radioactivity in the image area. The intensity is set low for this image to better visualize the contour and content of the bladder. An abnormality of the bladder contour, for following ureteral reimplantation, large diverticula and so forth, is readily recognized. Defects within the bladder can be further clarified with magnification techniques using a pinhole collimator. The total counts for the 2-minute image are recorded since they will be required later for the calculation of residual urine volume. The patient then assumes a sitting position and the gamma camera is rotated 90 degrees to obtain a posterior image during voiding. The data from the kidney areas are recorded into a video tape data storage device so that reflux which occurs with the increased bladder pressure during voiding can be detected. The urine is collected and the volume is measured. If reflux has occurred during examination the video tape recording is continued in order to evaluate the drainage time following voiding. Finally, a 2-minute quantification of radioactivity within the abdomen is recorded after voiding for the calculation of residual urine volume. The residual urine volume calculation requires measurement of the voided urine volume, and pre-voiding and timed determinations of total abdominal radioactivity. 16 - 19 These numbers are then inserted into a dilution formula which can be simply stated: Residual volume (cc)
~
voided volume (cc) x residual count ------·--initial count - residual count
Technique artifacts. On occasion, particularly in children less than 2 years old and uncooperative children, voiding or urine leakage may occur around the catheter during examination. The artifacts produced are recognizable their bizarre appearance. No harm is done unless the activity in the bladder is completely lost, in which case filling must be repeated. If the camera or patient becomes contaminated, this radioactivity can be easily removed washing with soap and water. Another uncommon artifact is the visualization of from absorbed radiopharmaceutical that is secreted into the stomach. Stomach radioactivity Can be n«,rn,,•c,C if it is not recognized as such. derived from absorption through the mucosa of the tract. Our initial report showed that 20 per cent of children without reflux had detectable levels of through the tract. 7 Of the with reflux 40
per cent also showed such an occurrence. The most significant levels of absorption occurred in who were instrumented just prior to the nude,Jr cystogram. Catheterization alone may traumatize the mucosa of the urethra and bladder sufficiently to allow such resorption to occur. The theoretical objection that subsequent excretion of the radionuclide through the kidneys will simulate reflux ha:, not proved to be a problem since the prime target organ for ••mTc pertechnetate is the stomach. H any question arises regarding the location of activity a simple lateral view will readily the problem. Finally, an artifact that we have encountered only once was caused by catheterization of the vagina. The catheter entered a vaginal through the penis in a hermaphrodite. The smaller volume of the vagina and leakage around tlw catheter allowed it to be distinguished from bladder. A lateral view would be of further when confusion persists. One should also be alert to such an occurrence if urine does not drain following catheterization. For this reason, the tients are not asked to void before catheterization. Drainage time of the upper tracts. Various radionuclide techniques for accurately deterrnin· ing the drainage time of refluxed fluid are available with gamma camera systems. Since a video tape data storage recording device has been available us, the post-voiding reflux activity has been recorded onto the video tape. Regions of interest can then be located electronically over the upper nary tracts. By this means an accurate determination of drainage time is achieved. The data are even simpler to obtain with the aid of a small hard wired on-line computer, which graphically records the regions of interest during the actual time of study. If access to such equipment is not available one can still estimate drainage time as roentgenographic cystography by obtaining serial images over a period of time and comparing for the visual degree of radioactivity Calculated residual volume. This information is reliable only if there is complete bladder The significance of retained urine after ization is always questionable. The child fo2quently will not void completely because of uria. Incomplete emptying is a common older children who are embarrassed about in company or in a bustling open nuclear medicine facility. If reflux occurs additional information can obtained by quantifying the actual volume of urine which refluxes. This is accomplished regions of interest over the reflux site and the bladder. The calculated residual volume is determined the dilution formula. The ratio of radioactivity in each kidney and the bladder will indicate the volume which has refluxed. Dosimetry. It is estimated that because of the variety of techniques used, radiation dose roentgenographic cystourethrography ranges from several hundred mrads in spot film to
692
CONWAY AND ASSOCIATES
several rads when fluoroscopy or cine is used. 20 The calculated radiation dose to the bladder during an average 30-minute exposure to 1 mCi. ••mTc pertechnetate is approximately 30 mrads. 7 The estimated gonadal radiation dose is only 4 to 5 mrads. It is evident from these figures that there is a considerable reduction in radiatio.µ dose when one uses radionuclide techniques for detecting vesicoureteral reflux. It is safe to estimate that at least 100 radionuclide studies can be performed for the same radiation expense as a single roentgenographic study. With the ever increasing use of roentgenographic techniques, particularly in that population being screened for urinary tract disease, use of a radionuclide screening method for the detection of reflux will undoubtedly result in a reduction of the over-all radiation exposure of the general population. In those patients with known reflux the use of radionuclides for followup seems particularly appropriate. Vesicoureteral reflux dynamism. The persistence scope attachment to the gamma camera enables instantaneous visualization of reflux into the upper urinary tracts. The intermittent dynamic nature of vesicoureteral reflux is striking when viewed in this way. Reflux may appear and completely disappear within seconds (fig. 3). Roentgenographic cystography, which uses static films and perhaps some fluoroscopy, will visualize the urinary tracts only for a few seconds to perhaps a few minutes during the examination. Direct radionuclide cystography imaging is continuous for indefinite periods. It becomes evident that techniques that intermittently visualize or image the urinary tracts, such as indirect radionuclide cystography or roentgenographic cystography, miss many examples of reflux completely. The increased resolution obtained in newer imaging devices promises that smaller and smaller variations in the bladder itself may be detected in this way also. The rare urethral abnormality such as a posterior urethral valve or stricture cannot yet be adequately delineated with the radionuclide technique. Disadvantages. Currently, a major disadvantage
of nuclear cystography is a poorer resolution than roentgenographic techniques. Image detail is not comparable to that available from roentgenographic cystography. Aside from reflux only major anomalies such as large bladder diverticula or large ureteroceles can be detected with certainty. CURRENT USE OF DIRECT RADIONUCLIDE CYSTOGRAPHY
The most common indication for roentgenographic evaluation of the urinary tract in children is urinary infection. The first study performed is usually a roentgenographic cystogram, followed often by excretory urography (IVP). If vesicoureteral reflux is noted the ureterovesical junction is studied at cystoscopy. When reflux is caused by a short intravesical ureter, as is commonly the case, and if infection can be eradicated, these patients are treated medically. Prophylactic treatment with sulfa, nitrofurantoin, nalidixic acid or mandelamine may be instituted in an attempt to prevent further urinary tract infection. 21 In general, sterile vesicoureteral reflux does not cause renal damage 2 2-2 3 and vesicoureteral reflux will ultimately stop with growth in at least half the children. 24 Therefore, the prime responsibility is to prevent further infections and subsequent renal damage. 25 In most children without obstruction this can be accomplished successfully with or without medication. Although the prognosis is excellent in this group the abatement period for reflux may be several years. Periodic re-evaluation is necessary to be certain that renal damage does not progress and to ascertain whether reflux has indeed stopped. Therefore, nuclear cystograms are principally used in an effort to reduce the total amount of radiation that these children receive. In general, a radionuclide cystogram is obtained 6 months after the initial roentgenographic evaluation to determine if the reflux persists. In those cases in which mild reflux is associated and probably caused by cystitis, long-term medication is seldom required after the reflux disappears. 22 In the face of persistent reflux without infection, an IVP is required every 2 years. Recurrent pyelonephritis or increasing
FIG. 3. This series of images demonstrates dynamism of reflux. Techniques that intermittently image urinary tract, such as indirect radionuclide cystography and roentgenographic cystography, will miss such reflux.
DIRECT AND INDIRECT RADIONUCLIDE CYSTOGRAPHY
ureterectasis suggests progressive disease which should be surgically treated by ureteroneocystostomy. Continued recurrence of infection is much more often an indication for surgical correction than increasing hydronephrosis, which is rare unless an obstruction is overlooked at the time of the initial evaluation. If the urinary tracts remain stable despite persistent reflux then yearly re-evaluation is performed, alternating radionuclide cystography with IVP and roentgenographic cystography. After puberty vesicoureteral reflux should be treated surgically since the chance for further growth of the intravesical ureter or maturation of the ureterovesical junction is slight. Only about a quarter of the patients followed this way ultimately will require an operation. However, patience is required. Significant renal damage is prevented careful followup, with urinalysis and culture at regular 2 to 3-month intervals and use of periodic roentgenographic and radionuclide evaluation of the urinary tracts. Radiation exposure is reduced more by using the nuclear cystogram, which is more reliable than the spot film technique in detecting persistent reflux. Ms. Mildred Early, Roxann Stawicki and Sue Weiss provided technological assistance and Mrs. Louise Khalilian provided editorial assistance. REFERENCES
1. Winter, C. C.: A new test for vesicoureteral reflux: an
2.
3.
4.
5.
6.
7.
external technique using radioisotopes. J. Urol., 81: 105, 1959. Dodge, E. A.: Vesicoureteric reflux. Diagnosis with iodine-131 rndium ortho-iodohippurate. Lancet, 1: 303, 1963. Handmaker, H., McRae, J. and Buck, E.G.: Intravenous radionuclide voiding cystography (IRVC). An atraumatic method of demonstrating vesicoureteral reflux. Radiology, Hl8: 703, 1973. Berne, E. and Ekman, H.: Method for clinical studies of vesicoureteral reflux using colloidal 198Au. Urol. Int., 18: 335, 1964. Blaufox, M. D., Gruskin, A. B., Sandler, P., Ogwo, J. E., Goldman, H. S. and Edelmann, C. M., Jr.: Detection of ureteral-vesical reflux in children with Tc-pertechnetate. J. Nucl. Med., abstracts, work in progress, H: 622. 1970. Blaufox, M. D., Gruskin, A., Sandler, P., Goldman, H., Ogwo, J. E. and Edelmann, C. M., Jr.: Radionuclide scintigraphy for detection of vesicoureteral reflux in children. J. Pediat .. 79: 239, 1971. Conway, J. J., King, L. R., Belman, A. B. and Thorson, T., Jr.: Detection of vesicoureteral reflux with radionuclide cystography. A comparison study with roentgenographic cystography. Amer.
J. Roentgen., l.15: 720, 1972. 8. Corriere, J. N., Jr., Kuhl, D. E. and Murphy, The use of 99mTc labeled sulfur colloid to study particle dynamics in the urinary tract. Vesicoureteral reflux. Invest. Urol., 4: 570, 1967. 9. Corriere, J. N., Jr., Sanders, T. P., Kuhl, Schoenberg, H. W. and Murphy, J. J.: Urinary particle dynamics and vesicoureteral reflux human. J. Urol., l03: 599, 1970. 10. Corriere, J. N., Jr., Sanders, T. P., Cohen, T Lipschultz, L. I. and Kuhl, D. E.: Urinary particle scan: a tracer technique for the study of renal infection in patients with ureterovesical reflux. Nucl. Med. (abstract), H: 311, 1970. 11. Dec kart, H.: Nuklearmedizinische nephrologische Untersuchungsverfahren in der Padiatrie. Kin deraerztl. Prax., 34: 197, 1966. 12. Goldman, H. S. and Freeman, L. M.: Radiographic and radioisotopic methods of evaluation of the kidneys and urinary tract. Pediat. Clin. N. Amer.. 18: 409, 1971. 13. Timmermans, L. and Merchie, G.: Etude des reflux vesico-ureteraux par !es techniques radioisotopiques; premiers essais d'association de ia camera a scintillations a la cystosphincteromanometrie. J. Urol. Nephrol., 74: 267, 1968. 14. Timmermans, L. and Merchie, G.: Une nouvelle methode d'exploration des reflux vesico-uretercrenaus. Acta Urol. Belg., 37: 105, 1969. 15. Winter, C. C.: Pediatric urological tests using radio isotopes. J. Urol., 95: 584, 1966. 16. Mulrow, P. J., Huvos, A. and Buchanan, D. L.: Measurement of residual urine I-131-labeled dio drast. J. Lab. Clin. Med., 57: 109, 1961. 17. Rosenthall, L.: Residual urine determination by roentgenographic and isotope means. Radiolog~,,, 80: 454, 1963. 18. Shand, D. G., MacKenzie, J. C., Cattell, W.R. and Cato, J.: Estimation of residual urine volume with 131I-hippuran. Brit. J. Urol., 40: 196, 1968. 19. Strauss, B. S. and Blaufox, M. D.: Estimation residual urine and urine flow rates without methral catheterization. J. Nucl. Med., H: 81, 1970. 20. Fendell, H.: Radiation exposure due to urinary disease. Prog. Pediat. Radio!., 3: 116, 1970. 21. King, L. R., Kazmi, S. 0., Campbell, J. A. and Belman, A. B.: The case for non-surgical management in vesicoureteral reflux. In: Current Controversies in Urologic Management. Edited by R. Scott. Philadelphia: W. B. Saunders Co., 1972. 22. King, L. R. and Sellards, H. G.: The effect of vesicoureteral reflux on renal growth and development in puppies. Invest. Urol., !I: 95, 1971. 23. Hutch, J. A. and Amar, A. D.: Vesicoureteral Reflux and Pyelonephritis. New York: Appleton-Century. Crofts, 1972. 24. King, L. R., Kazmi, S. 0. and Belman, A. Unpublished data. 25. Hodson, C. J. and Edwards, D.: Chronic pyelonephritis and vesico-ureteric reflux. Clin. Radiol.. H: 219, 1960.
THE JOURNAL OF UROLOGY
Copyright © 1975 by The Williams & Wilkins Co.
Printed in U.SA.
DIRECT AND INDIRECT RADIONUCLIDE CYSTOGRAPHY JAMES J. CONWAY,* A. BARRY BELMAN, LOWELL R. KING
AND
R. BRUCE FILMERt
From the Department of Radiology and the Division of Urology, The Children's Memorial Hospital, McGaw-Aiedical Center of Northwestern University, Chicago, Illinois
ABSTRACT
Direct radionuclide cystography, using short half-life radiopharmaceuticals, is considered to be more reliable for detecting vesicoureteral reflux than conventional roentgenographic techniques. In addition to the detection of vesicoureteral reflux, other parameters determined include the bladder volume when reflux occurs, calculation of volume of fluid that has refluxed, accurate calculation of residual urine volume, estimation of reflux drainage time, and the visualization and diagnosis of gross anatomic abnormalities. Currently, a major disadvantage is poor resolution, prohibiting analysis of small bladder defects and urethral abnormalities. The major advantage of nuclear cystography is the small radiation dose delivered with its use. It is estimated that at least 100 radionuclide studies can be performed for the same radiation expense as a single roentgenographic study. In 1959 Winter reported on the detection of vesicoureteral reflux following instillation of 131 I diodrast into the bladder and recording radioactivity over the kidneys with scintillation probes. 1 An indirect radionuclide technique was reported in 1963 by Dodge. 2 He used an injection of 1311 hippuran intravenously. After sufficient time was allowed for excretion into the bladder, detector probes were placed over the kidneys. An increase in radioactivity during voiding indicated reflux. Little interest in radionuclide cystography was stimulated by these initial reports. However, there is renewed interest in the use of radionuclide techniques with the advent of shorter half-life radiopharmaceuticals, primarily 99 mtechnetium compounds (Tc), which are well suited for gamma camera imaging. Findings other than the presence or absence of reflux that can now be determined by direct radionuclide cystography include 1) the bladder volume when reflux occurs, 2) a calculation of fluid volume that has refluxed, 3) an accurate calculation of residual urine volume, 4) the estimation of reflux drainage time and 5) the visualization and diagnosis of gross anatomic abnormalities such as duplication with ureteral obstruction, hydronephrosis or ectopic kidney. Techniques and the current developmental status of radionuclide cystography are briefly discussed herein. A comparison of the advantages and disadvantages of direct versus indirect radionuclide cystography, and direct radionuclide cystogAccepted for publication July 5, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. * Requests for reprints: The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Illinois 60614. t Current address: The Children's Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, Pennsylvania 19104.
raphy versus spot film roentgenographic cystography is presented. MATERIALS AND METHODS
Indirect radionuclide cystography. The indirect method of radionuclide cystography relies upon the rapid and complete renal clearance of an intravenously injected radiopharmaceutical. 2 • 3 131I ran was tried initially 2 and 99 mTc-Sn-diethylene-triaminepentaacetic acid has been recommended more recently. 3 When the radionuclide is adequately accumulated in the bladder and residuai activity in the kidneys is low enough to visualization of any reflux the patient is then seated with his back to the gamma camera. As the patient voids any significant increase in radioactivity over the upper urinary tracts indicates reflux. The indirect method has 2 advantages: 1) the bladder is not catheterized, eliminating the bility of introducing infection in susceptible pa tients, and 2) renal function and anatomy can be assessed to a certain degree during the post-injection stages of the study. However, the indirect method suffers from sev era! drawbacks. 1) The patient must cooperate to a considerable degree by retaining bladder urine until nearly complete renal clearance is achieved and then must be able to void on command in unusual surroundings. Many children can do neither. 2) Vesicoureteral reflux is a dynamic process. With direct radionuclide cystography, which volves gradual instillation of the radionuclide into the bladder by catheter, reflux into the upper tracts has been observed during filling to disappear during and after voiding. Such transient but possibly significant reflux may thus be completely missed by the indirect method. 3) The patients selected for renal studies often have an 689
690
CONWAY AND ASSOCIATES
impaired renal function and/or hydronephrosis. Considerable radioactivity may be retained in the kidneys for long periods after intravenous administration of radiopharmaceutical compounds. Small amounts of reflux are obscured by such retained activity. Presently, it would seem that the indirect method is suitable for cooperative older children who have good renal function and little or no hydronephrosis. A comparison study of indirect radionuclide cystography versus roentgenographic cystography and/or direct radionuclide cystography will be required to determine if this technique is better for evaluating vesicoureteral reflux. However, direct radionuclide cystography seems certain to be accepted as the more reliable technique. Direct radionuclide cystography. Direct radionuclide cystography implies the direct instillation of the radionuclide into the bladder via catheter. •- 1 • The catheter is connected to a solution of normal saline via regular intravenous infusion tubing. As flow is established and there is confirmation of a correct catheter placement, 1 mCi. ••mTc pertechnetate is injected into the catheter which is then flushed with normal saline. The patient assumes a supine position upon the inverted gamma camera. Bladder filling is readily visualized on the oscilloscope of the gamma camera but is better viewed with the aid of a persistence scope (fig. 1). The persistence scope enables the bladder and kidneys to be monitored at all times without increasing radiation dosage. The patient is so positioned that the bladder is bisected by the lower edge of the imaging area. A high intensity is set on the gamma camera so that small amounts of radionuclide which reflux may be easily detected (fig. 2). Consequently, the bladder image is overexposed and appears larger than one would expect. Imaging of the upper tracts on Polaroid film is started in the direct posterior projection. For each
image production 300,000 counts have been arbitrarily selected. With 1 mCi. ••mTc pertechnetate in the bladder, this usually requires 3 to 5 minutes per exposure. Both posterior oblique projections are also recorded. The persistence scope is continuously monitored for evidence of reflux, thus the saline infusion volume at which time reflux occurs can be noted. The actual bladder volume when reflux occurs is then easily calculated. This has been noted to be a rather constant feature of the reflux occurring in some patients who have been studied repeatedly. Complete bladder filling is difficult to define. Protestations by children often represent attempts to get the procedure over with and escape. There are no rules to help determine individual bladder tolerance unless intravesical pressure is monitored simultaneously. Factors such as bladder irritability from infection, voiding habits, neurogenic blad-
FIG. 1. Reflux is readily visualized on persistence scope. When reflux is visualized saline volume is noted. Bladder volume when reflux occurs can then be easily calculated. Persistence scope is continuously monitored during examination. By this means dynamism of reflux becomes evident.
FIG. 2. Proper intensity setting allows minimum amounts of radioactivity to be visualized. Relatively large amount of activity in bladder overexposes image and makes bladder appear larger than one would expect.
DIRECT AND INDIRECT RADIONUCLIDE CYSTOGRAPHY
der disorders and even apprehension or orneriness are involved. An increased tempo of protestation, leakage of urine around the catheter, backup or cessation of urine flow through the infusion apparatus generally signals the limit of bladder tolerance. A 2-minute posterior image is then recorded. An is made to include all of the abdominal radioactivity in the image area. The intensity is set low for this image to better visualize the contour and content of the bladder. An abnormality of the bladder contour, for following ureteral reimplantation, large diverticula and so forth, is readily recognized. Defects within the bladder can be further clarified with magnification techniques using a pinhole collimator. The total counts for the 2-minute image are recorded since they will be required later for the calculation of residual urine volume. The patient then assumes a sitting position and the gamma camera is rotated 90 degrees to obtain a posterior image during voiding. The data from the kidney areas are recorded into a video tape data storage device so that reflux which occurs with the increased bladder pressure during voiding can be detected. The urine is collected and the volume is measured. If reflux has occurred during examination the video tape recording is continued in order to evaluate the drainage time following voiding. Finally, a 2-minute quantification of radioactivity within the abdomen is recorded after voiding for the calculation of residual urine volume. The residual urine volume calculation requires measurement of the voided urine volume, and pre-voiding and timed determinations of total abdominal radioactivity. 16 - 19 These numbers are then inserted into a dilution formula which can be simply stated: Residual volume (cc)
~
voided volume (cc) x residual count ------·--initial count - residual count
Technique artifacts. On occasion, particularly in children less than 2 years old and uncooperative children, voiding or urine leakage may occur around the catheter during examination. The artifacts produced are recognizable their bizarre appearance. No harm is done unless the activity in the bladder is completely lost, in which case filling must be repeated. If the camera or patient becomes contaminated, this radioactivity can be easily removed washing with soap and water. Another uncommon artifact is the visualization of from absorbed radiopharmaceutical that is secreted into the stomach. Stomach radioactivity Can be n«,rn,,•c,C if it is not recognized as such. derived from absorption through the mucosa of the tract. Our initial report showed that 20 per cent of children without reflux had detectable levels of through the tract. 7 Of the with reflux 40
per cent also showed such an occurrence. The most significant levels of absorption occurred in who were instrumented just prior to the nude,Jr cystogram. Catheterization alone may traumatize the mucosa of the urethra and bladder sufficiently to allow such resorption to occur. The theoretical objection that subsequent excretion of the radionuclide through the kidneys will simulate reflux ha:, not proved to be a problem since the prime target organ for ••mTc pertechnetate is the stomach. H any question arises regarding the location of activity a simple lateral view will readily the problem. Finally, an artifact that we have encountered only once was caused by catheterization of the vagina. The catheter entered a vaginal through the penis in a hermaphrodite. The smaller volume of the vagina and leakage around tlw catheter allowed it to be distinguished from bladder. A lateral view would be of further when confusion persists. One should also be alert to such an occurrence if urine does not drain following catheterization. For this reason, the tients are not asked to void before catheterization. Drainage time of the upper tracts. Various radionuclide techniques for accurately deterrnin· ing the drainage time of refluxed fluid are available with gamma camera systems. Since a video tape data storage recording device has been available us, the post-voiding reflux activity has been recorded onto the video tape. Regions of interest can then be located electronically over the upper nary tracts. By this means an accurate determination of drainage time is achieved. The data are even simpler to obtain with the aid of a small hard wired on-line computer, which graphically records the regions of interest during the actual time of study. If access to such equipment is not available one can still estimate drainage time as roentgenographic cystography by obtaining serial images over a period of time and comparing for the visual degree of radioactivity Calculated residual volume. This information is reliable only if there is complete bladder The significance of retained urine after ization is always questionable. The child fo2quently will not void completely because of uria. Incomplete emptying is a common older children who are embarrassed about in company or in a bustling open nuclear medicine facility. If reflux occurs additional information can obtained by quantifying the actual volume of urine which refluxes. This is accomplished regions of interest over the reflux site and the bladder. The calculated residual volume is determined the dilution formula. The ratio of radioactivity in each kidney and the bladder will indicate the volume which has refluxed. Dosimetry. It is estimated that because of the variety of techniques used, radiation dose roentgenographic cystourethrography ranges from several hundred mrads in spot film to
692
CONWAY AND ASSOCIATES
several rads when fluoroscopy or cine is used. 20 The calculated radiation dose to the bladder during an average 30-minute exposure to 1 mCi. ••mTc pertechnetate is approximately 30 mrads. 7 The estimated gonadal radiation dose is only 4 to 5 mrads. It is evident from these figures that there is a considerable reduction in radiatio.µ dose when one uses radionuclide techniques for detecting vesicoureteral reflux. It is safe to estimate that at least 100 radionuclide studies can be performed for the same radiation expense as a single roentgenographic study. With the ever increasing use of roentgenographic techniques, particularly in that population being screened for urinary tract disease, use of a radionuclide screening method for the detection of reflux will undoubtedly result in a reduction of the over-all radiation exposure of the general population. In those patients with known reflux the use of radionuclides for followup seems particularly appropriate. Vesicoureteral reflux dynamism. The persistence scope attachment to the gamma camera enables instantaneous visualization of reflux into the upper urinary tracts. The intermittent dynamic nature of vesicoureteral reflux is striking when viewed in this way. Reflux may appear and completely disappear within seconds (fig. 3). Roentgenographic cystography, which uses static films and perhaps some fluoroscopy, will visualize the urinary tracts only for a few seconds to perhaps a few minutes during the examination. Direct radionuclide cystography imaging is continuous for indefinite periods. It becomes evident that techniques that intermittently visualize or image the urinary tracts, such as indirect radionuclide cystography or roentgenographic cystography, miss many examples of reflux completely. The increased resolution obtained in newer imaging devices promises that smaller and smaller variations in the bladder itself may be detected in this way also. The rare urethral abnormality such as a posterior urethral valve or stricture cannot yet be adequately delineated with the radionuclide technique. Disadvantages. Currently, a major disadvantage
of nuclear cystography is a poorer resolution than roentgenographic techniques. Image detail is not comparable to that available from roentgenographic cystography. Aside from reflux only major anomalies such as large bladder diverticula or large ureteroceles can be detected with certainty. CURRENT USE OF DIRECT RADIONUCLIDE CYSTOGRAPHY
The most common indication for roentgenographic evaluation of the urinary tract in children is urinary infection. The first study performed is usually a roentgenographic cystogram, followed often by excretory urography (IVP). If vesicoureteral reflux is noted the ureterovesical junction is studied at cystoscopy. When reflux is caused by a short intravesical ureter, as is commonly the case, and if infection can be eradicated, these patients are treated medically. Prophylactic treatment with sulfa, nitrofurantoin, nalidixic acid or mandelamine may be instituted in an attempt to prevent further urinary tract infection. 21 In general, sterile vesicoureteral reflux does not cause renal damage 2 2-2 3 and vesicoureteral reflux will ultimately stop with growth in at least half the children. 24 Therefore, the prime responsibility is to prevent further infections and subsequent renal damage. 25 In most children without obstruction this can be accomplished successfully with or without medication. Although the prognosis is excellent in this group the abatement period for reflux may be several years. Periodic re-evaluation is necessary to be certain that renal damage does not progress and to ascertain whether reflux has indeed stopped. Therefore, nuclear cystograms are principally used in an effort to reduce the total amount of radiation that these children receive. In general, a radionuclide cystogram is obtained 6 months after the initial roentgenographic evaluation to determine if the reflux persists. In those cases in which mild reflux is associated and probably caused by cystitis, long-term medication is seldom required after the reflux disappears. 22 In the face of persistent reflux without infection, an IVP is required every 2 years. Recurrent pyelonephritis or increasing
FIG. 3. This series of images demonstrates dynamism of reflux. Techniques that intermittently image urinary tract, such as indirect radionuclide cystography and roentgenographic cystography, will miss such reflux.
DIRECT AND INDIRECT RADIONUCLIDE CYSTOGRAPHY
ureterectasis suggests progressive disease which should be surgically treated by ureteroneocystostomy. Continued recurrence of infection is much more often an indication for surgical correction than increasing hydronephrosis, which is rare unless an obstruction is overlooked at the time of the initial evaluation. If the urinary tracts remain stable despite persistent reflux then yearly re-evaluation is performed, alternating radionuclide cystography with IVP and roentgenographic cystography. After puberty vesicoureteral reflux should be treated surgically since the chance for further growth of the intravesical ureter or maturation of the ureterovesical junction is slight. Only about a quarter of the patients followed this way ultimately will require an operation. However, patience is required. Significant renal damage is prevented careful followup, with urinalysis and culture at regular 2 to 3-month intervals and use of periodic roentgenographic and radionuclide evaluation of the urinary tracts. Radiation exposure is reduced more by using the nuclear cystogram, which is more reliable than the spot film technique in detecting persistent reflux. Ms. Mildred Early, Roxann Stawicki and Sue Weiss provided technological assistance and Mrs. Louise Khalilian provided editorial assistance. REFERENCES
1. Winter, C. C.: A new test for vesicoureteral reflux: an
2.
3.
4.
5.
6.
7.
external technique using radioisotopes. J. Urol., 81: 105, 1959. Dodge, E. A.: Vesicoureteric reflux. Diagnosis with iodine-131 rndium ortho-iodohippurate. Lancet, 1: 303, 1963. Handmaker, H., McRae, J. and Buck, E.G.: Intravenous radionuclide voiding cystography (IRVC). An atraumatic method of demonstrating vesicoureteral reflux. Radiology, Hl8: 703, 1973. Berne, E. and Ekman, H.: Method for clinical studies of vesicoureteral reflux using colloidal 198Au. Urol. Int., 18: 335, 1964. Blaufox, M. D., Gruskin, A. B., Sandler, P., Ogwo, J. E., Goldman, H. S. and Edelmann, C. M., Jr.: Detection of ureteral-vesical reflux in children with Tc-pertechnetate. J. Nucl. Med., abstracts, work in progress, H: 622. 1970. Blaufox, M. D., Gruskin, A., Sandler, P., Goldman, H., Ogwo, J. E. and Edelmann, C. M., Jr.: Radionuclide scintigraphy for detection of vesicoureteral reflux in children. J. Pediat .. 79: 239, 1971. Conway, J. J., King, L. R., Belman, A. B. and Thorson, T., Jr.: Detection of vesicoureteral reflux with radionuclide cystography. A comparison study with roentgenographic cystography. Amer.
J. Roentgen., l.15: 720, 1972. 8. Corriere, J. N., Jr., Kuhl, D. E. and Murphy, The use of 99mTc labeled sulfur colloid to study particle dynamics in the urinary tract. Vesicoureteral reflux. Invest. Urol., 4: 570, 1967. 9. Corriere, J. N., Jr., Sanders, T. P., Kuhl, Schoenberg, H. W. and Murphy, J. J.: Urinary particle dynamics and vesicoureteral reflux human. J. Urol., l03: 599, 1970. 10. Corriere, J. N., Jr., Sanders, T. P., Cohen, T Lipschultz, L. I. and Kuhl, D. E.: Urinary particle scan: a tracer technique for the study of renal infection in patients with ureterovesical reflux. Nucl. Med. (abstract), H: 311, 1970. 11. Dec kart, H.: Nuklearmedizinische nephrologische Untersuchungsverfahren in der Padiatrie. Kin deraerztl. Prax., 34: 197, 1966. 12. Goldman, H. S. and Freeman, L. M.: Radiographic and radioisotopic methods of evaluation of the kidneys and urinary tract. Pediat. Clin. N. Amer.. 18: 409, 1971. 13. Timmermans, L. and Merchie, G.: Etude des reflux vesico-ureteraux par !es techniques radioisotopiques; premiers essais d'association de ia camera a scintillations a la cystosphincteromanometrie. J. Urol. Nephrol., 74: 267, 1968. 14. Timmermans, L. and Merchie, G.: Une nouvelle methode d'exploration des reflux vesico-uretercrenaus. Acta Urol. Belg., 37: 105, 1969. 15. Winter, C. C.: Pediatric urological tests using radio isotopes. J. Urol., 95: 584, 1966. 16. Mulrow, P. J., Huvos, A. and Buchanan, D. L.: Measurement of residual urine I-131-labeled dio drast. J. Lab. Clin. Med., 57: 109, 1961. 17. Rosenthall, L.: Residual urine determination by roentgenographic and isotope means. Radiolog~,,, 80: 454, 1963. 18. Shand, D. G., MacKenzie, J. C., Cattell, W.R. and Cato, J.: Estimation of residual urine volume with 131I-hippuran. Brit. J. Urol., 40: 196, 1968. 19. Strauss, B. S. and Blaufox, M. D.: Estimation residual urine and urine flow rates without methral catheterization. J. Nucl. Med., H: 81, 1970. 20. Fendell, H.: Radiation exposure due to urinary disease. Prog. Pediat. Radio!., 3: 116, 1970. 21. King, L. R., Kazmi, S. 0., Campbell, J. A. and Belman, A. B.: The case for non-surgical management in vesicoureteral reflux. In: Current Controversies in Urologic Management. Edited by R. Scott. Philadelphia: W. B. Saunders Co., 1972. 22. King, L. R. and Sellards, H. G.: The effect of vesicoureteral reflux on renal growth and development in puppies. Invest. Urol., !I: 95, 1971. 23. Hutch, J. A. and Amar, A. D.: Vesicoureteral Reflux and Pyelonephritis. New York: Appleton-Century. Crofts, 1972. 24. King, L. R., Kazmi, S. 0. and Belman, A. Unpublished data. 25. Hodson, C. J. and Edwards, D.: Chronic pyelonephritis and vesico-ureteric reflux. Clin. Radiol.. H: 219, 1960.
