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Pediatric Imaging |
1 Departments of Pediatric Radiology (K.D., J.T., T.D., B.Z., W.R.)
2 Urology (K.M., C.W.)
3 Division of Pediatric Nephrology (B.T.), Heidelberg University Hospital, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany.
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Abstract |
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MATERIALS AND METHODS: One hundred eighty-eight patients (aged 5 days to 20 years) referred for investigation of VUR underwent voiding US with echo enhancement, which was followed by VCUG in 110 patients (226 kidney-ureter units). After US of the renal tract, the bladder was filled with normal saline solution. Then SH U 508 A, a galactose-based, microbubble-containing echo-enhancing agent, was administered. Reflux was diagnosed when microbubbles appeared in the ureter or pelvicalyceal system.
RESULTS: VUR was detected in 80 of the units with one (n = 18) or both (n = 62) methods. All grades of reflux were identified. In 15 units, reflux diagnosed at voiding US was not observed at VCUG; the reverse was true in three units. In 208 (92%) of the 226 kidney-ureter units, there was concordance between the two methods regarding the diagnosis or exclusion of VUR. The echo-enhancing agent was well tolerated.
CONCLUSION: SH U 508 A enhanced voiding US is as good as VCUG in the detection or exclusion of VUR and thus will make it possible to reduce the number of children having to be exposed to ionizing radiation.
Index terms: Bladder, US, 83.12988, 83.12989 • Ultrasound (US), contrast media, 82.12988, 83.12988 • Ureter, reflux, 82.85, 83.85 • Ureter, US, 82.12988, 82.12989 • Voiding cystourethrography, 82.123, 83.123
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The primary diagnostic procedure for evaluation of VUR is fluoroscopic voiding cystourethrography (VCUG). The recent introduction of digital fluoroscopy has permitted a reduction in the radiation dose (2). Radionuclide cystography, which involves the use of substantially less radiation, has been shown to be an alternative sensitive method for detecting VUR, but it lacks spatial resolution (3).
Attempts to detect VUR with ultrasonography (US) have been made to eliminate the radiation exposure intrinsic in nuclear or fluoroscopic cystography (4–6). These attempts have also involved the use of specially produced echo enhancers (ie, US contrast media) that act as strong acoustic scatter media (7). Sonicated albumin (Albunex; Molecular Biosystems, San Diego, Calif) was shown to be useful in the detection of VUR in a porcine model (8). There is one case report (9) of its use in the diagnosis of reflux in a child. As early as 1992, the galactose-based microbubble-containing echo enhancers, gadoxetate disodium and SH U 508 A (Echovist and Levovist, respectively; Schering, Berlin, Germany), were shown in animal experiments to be potentially useful for the US-based diagnosis of VUR (10). Von Rohden et al (11) compared VCUG with US by using gadoxetate disodium and found high diagnostic concordance in children. The short imaging window of gadoxetate disodium (approximately 5 minutes) resulted in static images that were insufficiently convincing of VUR and therefore limited the widespread use of this agent.
We administered SH U 508 A intravesically for the US examination of VUR. Unlike its predecessor gadoxetate disodium, SH U 508 A is a more stable echo enhancer; the echo-enhancing properties of this agent remain potent even as it passes through the lungs after intravenous injection (7). The aim of this study was to evaluate the feasibility of the use of US with SH U 508 A in the diagnosis of VUR by comparing its diagnostic usefulness with that of VCUG. The safety and tolerability of intravesical SH U 508 A administration was also assessed.
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MATERIALS AND METHODS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Combining all of the patients from parts 1 (n = 36) and 2 (n = 78) of the study who underwent both examinations yielded a total of 114 patients. For proper comparison, only those patients who either had micturated during both examinations or had not micturated during both examinations were included. Four patients who did not fulfill this criteria were excluded. Consequently, 110 of the 188 patients who had undergone both voiding US of the bladder and retrovesical space with echo enhancement and VCUG were included in the comparison of diagnostic usefulness in the evaluation of reflux.
To make a comparative calculation in these 110 patients, it was essential to assess the presence of reflux in terms of kidney-ureter units rather than in terms of patients. A kidney-ureter unit was considered a renal pelvis with its own ureter inserting into the bladder. Thus, a normal kidney was regarded as one kidney-ureter unit. Consequently, a complete renal duplication was counted as two kidney-ureter units, and a transplanted kidney was counted as one unit. Among the 110 patients, 10 had unilateral and one had bilateral complete renal duplications. In eight of the 12 renal duplications, reflux was detected ultrasonographically or radiographically in one or both poles of the kidneys. The remaining four renal duplications without VUR had obstructed upper poles of the kidneys; two of these were associated with ureteroceles. Thus, these were complete renal duplications, which justified counting each as two kidney-ureter units. Two patients each had a single nontransplanted kidney, and four patients each had a transplanted kidney. Accordingly, there were a total of 226 kidney-ureter units in the 110 patients.
The indications for the reflux examinations were as follows: urinary tract infection (n = 121); follow-up of VUR after conservative or surgical management (n = 37); pyelectasis, megaureter, or both (n = 16); and miscellaneous indications (eg, nocturnal enuresis) (n = 14). Those patients in whom one or both kidneys could not be adequately visualized at US (eg, those with severe scoliosis) were excluded.
The studies were approved by the ethical committees of the Berlin Medical Board and the University of Heidelberg. Before each investigation began, written informed consent was obtained from the parents or guardians and, whenever applicable, from the child after the nature of the procedure had been fully explained.
Part 1
Preparation and setup.—Both voiding US of the bladder and retrovesical space with echo enhancement and VCUG were performed in the fluoroscopy room. The US scanner was equipped with 3.5–5.0-MHz convex and 5.0-MHz linear transducers (model 128XP/4; Acuson, Mountain View, Calif). The power setting was turned to the lowest level of -9 dB to minimize the possible disruption of the microbubbles. VCUG was performed with digital fluoroscopy (DSI Diagnost 66; Philips, Holland, the Netherlands) according to our routine procedure. The examination findings were documented by using a laser camera (Scopix LR 5200; Agfa-Gevaret N.V., Mortsel, Belgium); US findings were videotaped on S-VHS (SVO-9500 MDP; Sony, Tokyo, Japan). The duration of each examination step was recorded.
US.—The initial examination was standard US of the urinary tract performed with the patient in the supine and prone positions. Particular attention was paid to subtle findings in the retrovesical region, vesicoureteral junction, and any dilated ureter. In addition, the renal pelvises were scanned with maximum magnification. The US examination was followed by transurethral catheterization of the bladder with a 5-F infant feeding tube (Luer; B Braun, Melsungen, Germany). The bladder was emptied and filled with prewarmed normal saline solution by using direct injection. The saline solution was slowly administered into the bladder until the patient had the urge to micturate or the operator felt the slightest back pressure from the injection. This volume of bladder filling was used as the basis for calculating the amount of SH U 508 A to be administered.
The SH U 508 A suspension (300 mg/mL) was prepared just before it was administered. The volume administered was approximately 10% of that of the bladder filling. US monitoring of the bladder and retrovesical space was performed during the very slow injection of SH U 508 A into the normal saline solution to detect any regurgitation of microbubbles into the ureters. To ensure that none of the Levovist remained in the catheter, it was rinsed with 5 mL saline after the administration. Initially, when microbubbles are still attached to galactose microparticles, the SH U 508 A suspension has a higher specific gravity than that of the bladder contents. Therefore, it fills in the bladder from the dorsal region to the ventral region when the patient is in the supine position and gradually achieves homogeneous distribution. A fast injection results in the settling of the entire suspension at the bottom of the bladder, which causes the retrovesical region to be obscured on the image. In this case, it takes a few minutes for the suspension to achieve the homogeneous bladder distribution needed for the assessment of the ureters.
A second examination in which all of the parameters were parallel to those used in the first examination was performed. The patient voided while lying prone with the catheter still in the bladder. Both kidneys were scanned alternately during the micturition. Scanning of the kidneys in the dorsal region permitted the best view of the pelvicalyceal system and consequently of the microbubbles. Then the patient was turned back into the supine position to check for any residual volume. In cases where, despite long waiting, no voiding occurred, the bladder was emptied by means of the catheter.
The diagnosis of reflux was made when microbubbles appeared in a ureter or renal pelvis. In cases in which a ureter was distinctly visible behind the bladder, the microbubbles turned the echofree lumen into an echogenic one (Fig 1). When the ureter was not clearly visible as a round echofree structure, reflux could be demonstrated by the finding of microbubbles entering the vesicoureteral junction. Also, just behind this junction, a round echogenic spot, which could be differentiated from its surroundings by its strong echogenicity and the constant movement of the microbubbles, could be seen on a transverse section (Fig 2). When reflux occurs in the kidneys, one can observe different patterns and quantities of echogenic microbubbles floating in the pelvicalyceal system (Figs 3, 4). At the end of voiding US, the presence or absence of VUR was recorded to avoid bias from the outcome of the VCUG that followed.
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Adverse event monitoring.—The vital signs were documented before and at the end of the examination session. Any symptoms spontaneously mentioned by the patients were recorded during the entire examination and up to 24 hours thereafter. In addition, an active 24-hour follow-up was conducted by contacting the patients or their parents or guardians.
Part 2
The main differences between parts 1 and 2 of the study were the inclusion of all age groups and the definition of criteria for VCUG after voiding US with echo enhancement in part 2. A few other small procedural changes were introduced also.
US Fluoroscopy.—Owing to the frequent micturition of newborns and small children, 5 mL of SH U 508 A was injected into the empty bladder first; immediately afterward, normal saline solution was injected during the scanning of the bladder and kidneys. Furthermore, the administration of the same dose of SH U 508 A was changed from one to two equal boluses, with the patient in the supine and prone positions, because the echo enhancement was too strong in the bladder. Fluoroscopy was performed as in part 1 but in selected patients.
Adverse event monitoring.—Only those symptoms experienced before, during, and directly after the examination were documented. The patients or their parents or guardians were instructed to contact the department to report any symptoms experienced in the subsequent 24 hours.
Study analysis.—After each examination session, the records were reviewed with regard to the presence or absence of reflux by at least two experienced pediatric radiologists who had not been present during the procedures (J.T., B.Z.). At the end of each part of the study, all of the film and video records (without patient names) were reviewed again by one of the radiologists who had conducted the examinations (K.D.), without reference to the written results. The statistical analyses were performed by using the SPSS 7.5 program (Statistical Package for the Social Sciences; SPSS, Chicago, Ill).
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RESULTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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2 value (2 = 65.7) and the correlation coefficient (
= 0.9) both were highly significant (P < .001). Because this calculation was based on kidney-ureter units, the possibility of dependent observations cannot be ignored. To adjust for any such bias, the sensitivity and specificity were also calculated for the right and left kidneys separately. The results were comparable to the combined results of analyses of kidneys on both sides (right, 100% and 100%; left, 100% and 95%, for sensitivity and specificity, respectively). This implies that one can reliably predict the outcome of VCUG on the basis of the findings of voiding US of the bladder and retrovesical space with echo enhancement, particularly with respect to the absence of reflux.
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The mean bladder volume (± SD) during voiding US with echo enhancement was 175 mL ± 53 in part 1 of the study and 128 mL ± 57 in part 2. The mean bladder filling volumes during the VCUG performed afterward were 188 ± 52 mL and 137 ± 73 mL in parts 1 and 2, respectively. While lying prone, 169 (90%) of the 188 patients were able to micturate on the examination table at the end of voiding US with echo enhancement; 106 (93%) of the 114 patients micturated at the end of VCUG.
The mean times (± SDs) of each examination step were as follows: initial US, 10.0 minutes ± 5; catheterization, 9.0 minutes ± 4; voiding US with echo enhancement, 14.0 minutes ± 7; VCUG fluoroscopy, 1.8 minutes ± 1.4; and overall VCUG examination, 7.0 minutes ± 4. The overall mean duration for performing voiding US with echo enhancement was 32.0 minutes ± 10. The comparable mean time for VCUG, with the time for catheterization added, was 16.0 minutes ± 4. Diagnostically usable echo enhancement with SH U 508 A was visible in the bladder until the time of micturition or until the bladder was emptied by means of the catheter. Thus, the average imaging window of SH U 508 A exceeded the mean duration of 14.0 minutes ± 7 needed to perform voiding US with echo enhancement. The longest observation time was 47 minutes. In all of the US examinations, there was ample time after the administration of SH U 508 A to scan the bladder and kidneys in the ventral and dorsal regions and during voiding.
It was beyond the objective of the study to attempt to grade reflux at voiding US with echo enhancement by using a grading system similar to that used for VCUG. Furthermore, when the total number of kidney-ureter units with reflux was divided into groups according to the five radiologic reflux grades, the number of cases in each group was relatively few for a statistically significant comparison for grading purposes.
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The direct means used to diagnose VUR involve instilling various substances intravesically. Hofmann (18) and Schneider et al (19) compared VCUG with US after filling the bladder with normal saline solution and an x-ray contrast medium, respectively. VUR was diagnosed on the basis of dilatation of the renal pelvis or visibility of the ureter in the retrovesical space during bladder filling, bladder emptying, or both. These methods were sensitive for high grades of reflux but were limited in the diagnosis of the lower grades.
Contrast medium–enhanced US for the detection of VUR has been performed by creating air bubbles from normal saline solution or an iodinated contrast medium by either rapidly flushing the material in and out of a syringe or shaking it within the container immediately before administration into the bladder (4,20). Direct addition of room air or carbon dioxide has been tried as well (6,21). Although filling the empty bladder with air only is not physiologic, others (22,23) have used this method and found it to be very sensitive, particularly for high grades of reflux. The disadvantages of these contrast-enhanced methods, which include the fast dissolution of the air bubbles, the inhomogeneity of the echo enhancement, and the strong acoustic shadow, make it difficult to produce convincing documentation of the findings. When properly used, the properties of SH U 508 A allow the detection of all grades of reflux.
The experimental design was created to minimize differences between the VCUG and voiding US with echo enhancement examinations. During voiding US, the patients micturated while lying prone, whereas during VCUG, they were supine or on their side. It is unlikely that the changes in positions were important (24). Similarly, the order in which the studies were performed should not change the results (25).
Recognizing that about half of the children who are referred for examination for possible reflux will have a negative diagnosis, we placed emphasis on screening these cases to obviate VCUG. The high negative predictive value of voiding US with echo enhancement confirms the reliability of this method. The difference in the reflux detection rate between the two methods was in favor of voiding US with echo enhancement. Several authors (19,20) have made similar observations by using US reflux examinations. The duration of the examination as well as the intermittent nature of VUR may play a role in this discrepancy (24,26). Furthermore, in this study, in seven kidney-ureter units with grade 1 reflux at VCUG, microbubbles were detected in the renal pelvises at voiding US with echo enhancement. The possibility to visualize even single microbubbles at US differentiates this method from that in which an x-ray contrast medium is used, where a certain concentration at a given time is needed to be able to see the contrast.
The pediatric vesicoureteral reflux guidelines panel of the American Urological Association made an appeal for the development of "techniques of voiding cystourethrography that result in less radiation exposure" (27). The capability of voiding US of the bladder and retrovesical space with echo enhancement extends further in that the method enables complete elimination of radiation exposure in selected patients. This may justify the longer examination time compared with that of VCUG. A shortcoming of voiding US, similar to radionuclide voiding cystography, is the lack of diagnostic coverage of the urethra.
At the end of the study, we changed the algorithm of diagnostic imaging for VUR in our department. Voiding US of the bladder and retrovesical space with echo enhancement is performed primarily in girls and at follow-up. Only those patients who have reflux and have not undergone VCUG previously subsequently undergo VCUG. Boys undergo VCUG when they present for the first time. Undoubtedly, it will be necessary to adapt the diagnostic algorithm to local practices (28). The largest group of children who are referred for reflux examination is that of children with urinary tract infections. The American College of Radiology (29) published Appropriateness Criteria for Imaging and Treatment Decisions regarding urinary tract infections. Here, the list of recommendations for radionuclide voiding cystography can easily be replaced by those for voiding US with echo enhancement. Voiding US of the bladder and retrovesical space with echo enhancement will facilitate the screening of groups at high risk for reflux—for example, siblings of children with VUR and patients with kidney transplants (1). Cyclic filling of the bladder to increase the reflux detection rate in selected cases may be easily performed (24,26).
The ideal method for reflux examination would be one that is accurate, safe, without radiation, and noninvasive. The first three criteria are met by using voiding US with echo enhancement. A future technique in which all of the criteria might be fulfilled is US with exogenous bubble generation (30). Meanwhile, voiding US of the bladder and retrovesical space with echo enhancement, which has high sensitivity and specificity compared with VCUG, is a safe and reliable complement to VCUG. It will make it possible to substantially reduce the number of VCUG examinations performed in a large proportion of cases and thus reduce the number of children having to be exposed to ionizing radiation.
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Acknowledgments |
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Footnotes |
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Address reprint requests to K.D.
From the 1997 RSNA scientific assembly.
Abbreviations: VCUG = voiding cystourethrography VUR = vesicoureteral reflux
Author contributions: Guarantor of integrity of entire study, K.D.; study concepts, K.D., J.T.; study design, K.D., J.T., K.M.; definition of intellectual content, K.D., J.T., C.W., B.T.; literature research, K.D., J.T., T.D.; clinical studies, K.D., T.D., J.T., B.Z., W.R.; data acquisition, K.D., J.T., T.D.; statistical analysis, K.D.; manuscript preparation, K.D.; manuscript editing, K.D., J.T., T.D., W.R.; manuscript review, J.T., B.Z., K.M., C.W., B.T.
Received December 22, 1997;
revision requested March 17, 1998; revision received June 16, 1998;
accepted August 10, 1998.
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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