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Is routine voiding cystourethrogram necessary following double hit for primary vesicoureteral reflux?
Journal of Pediatric Urology (2015) 11, 40.e1e40.e5
Is routine voiding cystourethrogram necessary following double hit for primary vesicoureteral reflux?
a
Department of Pediatric Urology, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA
b
Department of Biostatistics and Bioinformatics, Rollins School of Public Health and Emory University School of Medicine, Atlanta, GA, USA Correspondence to: A.J. Kirsch, 5445 Meridian Mark Rd, Suite 420, Atlanta, GA, 30342, USA, Tel.: þ1 404 252 5206; fax: þ1 404 252 1268 [email protected] (A.M. Arlen) [email protected] (H.C. Scherz) [email protected] (E. Filimon) [email protected] (T. Leong) [email protected] (A.J. Kirsch) Keywords Vesicoureteral reflux (VUR); Voiding cystourethrogram (VCUG); Double HIT (hydrodistention implantation technique) Received 2 August 2014 Accepted 22 November 2014 Available online 30 January 2015
Angela M. Arlen a, Hal C. Scherz a, Eleonora Filimon a, Traci Leong b, Andrew J. Kirsch a Summary Introduction and objective Current AUA guidelines recommend voiding cystourethrogram (VCUG) following endoscopic treatment of vesicoureteral reflux (VUR). We evaluated the clinical and radiographic outcomes of children undergoing Double HIT (hydrodistention implantation technique) for primary VUR to determine success rates and the necessity of postoperative VCUG. Study design Children with a history of febrile urinary tract infection (fUTI) undergoing Double HIT for primary VUR between 2009 and 2012 were identified. Patients were prospectively classified as high or low clinical and radiographic risk. Children were categorized as high clinical risk if they had 3 fUTIs or documented bladder bowel dysfunction (BBD). High radiographic risk included those <2 years of age or with grade 4e5 VUR. Initially, all children underwent postoperative VCUG (“routine” group), while only those with an indication (high radiographic risk or clinical failure) did so during the latter portion of the study (“indicated” group). Clinical success was defined as no postoperative fUTI and radiographic success as negative postoperative VCUG. Average clinical follow-up was 34.7 17.2 months. Results Two hundred and twenty-two children (198 girls, 24 boys) underwent Double HIT at a mean age of 4.1 2.7 years. Mean maximum VUR grade was 3 0.8. Sixty-eight children (30.6%) had documented BBD. Fourteen children (6.3%) experienced postoperative fUTI, for a clinical success rate of 93.7%. One hundred and fourteen patients (51.4%) underwent postoperative VCUG; 76 were “routine” and 38 were “indicated” [Figure]. Of children classified as low clinical/radiographic risk, 96.6% did not have a postoperative fUTI, compared to 91.1% for high risk patients (P Z 0.771). Odds of clinical success for routine VCUG group were 9.9 times higher than for the indicated VCUG group (95% CI, 2e50). Odds of radiographic success for the routine cohort were 13 times higher than for the indicated group
(95% CI, 4.2e40). Nine children (4.1%) underwent additional procedures. Discussion We found no difference in clinical success among the different risk groups; the number of children with postoperative fUTI was relatively few so there was not statistical power to discern any differences between patients who experienced clinical success versus clinical failure. However, children with an “indicated” VCUG (i.e. those less than 2 years of age, grade 4e5 VUR or those with a fUTI) were 13 times more likely to experience a radiographic failure. This cohort of 38 patients had a 50% radiographic cure rate and a 78.9% clinical cure rate, compared to the overall long-term clinical success rate of 93.7%. Our data demonstrates that we can predict failures with relatively high sensitivity, and it may therefore be prudent to selectively obtain postoperative VCUG rather than recommend it for all children undergoing dextranomer hyaluronic acid co-polymer (Dx/HA) injection. Our study has several limitations that warrant consideration. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. Incidence of fUTI may also be artificially low, as some radiographic failures proceeded directly to another injection or reimplantation. While we were able to demonstrate that children undergoing an “indicated” VCUG were more likely to experience radiographic failure, a larger patient cohort is necessary to determine whether age or VUR grade is more predictive of failure. Finally all patients underwent endoscopic Dx/HA injection, therefore the incidence “spontaneous resolution” is unknown. Conclusion Long-term clinical success following Double HIT for the endoscopic correction of primary VUR is high, and the majority of children avoid additional procedures. Unless indicated by high-grade, young age, clinical failure, or family/surgeon preference, consideration should be given to making postoperative VCUG an option rather than a recommendation in children undergoing endoscopic treatment of primary VUR using the Double HIT method.
http://dx.doi.org/10.1016/j.jpurol.2014.11.011 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Is Routine VCUG Necessary Following Double HIT?
40.e2
Figure Flowchart demonstrating the clinical and radiographic success of patients according to postoperative VCUG status. “Indicated” VCUGs include those for grade 4e5 VUR, those in children less than 2 years of age, and those obtained for a postoperative fUTI.
Introduction The 2010 American Urological Association (AUA) reflux guidelines recommend postoperative VCUG following endoscopic treatment of primary VUR due to highly variable success rates ranging from 50 to 92% [1]. The concept of ureteral hydrodistention and intraluminal submucosal injection (hydrodistention implantation technique, or HIT) was introduced in 2002, and has resulted in improved success rates for endoscopic management of VUR [2]. Further modifications led to the Double HIT method, whereby proximal and distal intraluminal injections coapt both the ureteral tunnel and orifice [3]. The treatment goals of VUR include prevention of recurrent, febrile UTI (fUTI) and renal injury as well as minimizing morbidity of treatment and follow-up [1]. Double HIT has led to improved success rates for endoscopic correction of reflux [4e6]. In the present study, the longterm clinical success of children undergoing Double HIT was evaluated. It was hypothesized that postoperative VCUG could potentially be avoided in a large subset of children following endoscopic injection for VUR due to acceptably high clinical and radiographic success rates.
Materials and methods Institutional review board approval was obtained. Between January 1, 2009 and December 31, 2012, 222 children with a history of fUTI underwent injection of dextranomer hyaluronic acid co-polymer (Dx/HA) for primary VUR using the Double HIT method, as previously described [3,7]. All patients were asked to continue antibiotic prophylaxis and return in 4e6 weeks for a renal-bladder sonogram (RBUS). Routine VCUGs were performed at least 6 weeks (mean 3 1.2 months) after endoscopic injection. Antibiotics were discontinued if RBUS was unchanged and VCUG showed either no VUR or at least a two-grade improvement. The children’s electronic medical records were retrospectively reviewed. Their demographics, VUR grade, presence of bladder bowel dysfunction (BBD), and pre-operative and postoperative fUTIs were assessed. In order to determine the need for postoperative VCUG imaging, the children were prospectively classified as either high or low clinical and radiographic risk. Children were categorized as high clinical risk if they had 3 preoperative fUTIs or documented BBD. Febrile UTI was defined as: > 50,000e100,000 colony forming units (CFU) of
a single organism obtained by catheterization or clean catch, and was associated with a body temperature of 101.5 F. Bladder bowel dysfunction included: urinary frequency and urgency, prolonged voiding intervals, daytime wetting, holding maneuvers, constipation and encopresis in toilet-trained children. All children with BBD were managed with timed voiding, treatment of constipation, anticholinergic medication and/or biofeedback, when indicated by symptomatology. High radiographic risk included those <2 years of age or with grade 4e5 VUR. The children who underwent postoperative VCUG were further categorized as routine or indicated. Initially, all children underwent postoperative VCUG (‘routine’ group) per AUA guidelines [1], while only those with an indication (high radiographic risk or clinical failure) did so during the latter portion of the study (‘indicated’ group). The postoperative imaging protocol was altered during the study period due to an observed low incidence of radiographic failure in children 2 years of age with mild-moderate VUR, regardless of the number of preoperative fUTIs or presence of BBD. Clinical success was defined as no postoperative fUTI and radiographic success was defined as a negative postoperative VCUG. Consecutive children with a history of fUTI and primary VUR undergoing Double HIT by one of two pediatric urologists (HCS or AJK) were included. Children with secondary VUR, prior anti-reflux surgery, aberrant anatomy or without a history of fUTI were excluded from the study. Logistic regression analysis was performed to identify predictors of clinical and radiographic success after a single Double HIT procedure. The Chi-squared test (or Fisher’s exact when necessary) was used to compare the distribution of categorical variables. Two sample t-tests were used to compare the averages by group. Statistical analysis was performed using SAS (SAS Institute Inc, Cary, NC, USA) 9.3, with P < 0.05 representing statistical significance.
Results Two hundred and twenty-two children (198 girls, 24 boys) with primary VUR underwent Double HIT at a mean age of 4.1 2.7 years. Average injected Dx/HA volume was 1.34 0.56 ml per ureter. The mean number of preoperative fUTIs was 2.3 1.3 (range 1e7). The mean maximum VUR grade was 3 0.8, with the following breakdown: grade 1 (n Z 5), grade 2 (n Z 44), grade 3 (n Z 114), grade 4 (n Z 53) and grade 5 (n Z 6). Sixty-eight children (30.6%) had BBD. Fourteen children (6.3%) experienced
40.e3
A.M. Arlen et al.
postoperative fUTI after discontinuing antibiotic prophylaxis; the clinical success rate was 93.7%. Of the clinical failures, five had persistent or recurrent VUR, five had a negative VCUG, and the remaining four did not undergo postoperative cystogram, despite the recommendation to do so. One hundred and fourteen children (51.4%) underwent postoperative VCUG; 76 were ‘routine’ and 38 were ‘indicated’ (i.e. high risk/clinical failures). Three children (1.4%) had postoperative hydronephrosis, and one child (0.5%) had associated nausea/vomiting and flank pain necessitating hospitalization. All three cases resolved spontaneously with no further intervention. The average clinical follow-up was 34.7 17.2 months. Children were categorized as high or low clinical and radiographic risk. One hundred and sixteen children (52.3%) were high clinical risk, i.e. had 3 preoperative fUTIs or documented BBD. Eighty-five children (38.2%) were either younger than 2 years of age at the time of Dx/HA injection or had grade 4e5 VUR, and were classified as high radiographic risk. When evaluating the relationship between clinical success (defined as no postoperative fUTI) and risk status, there was no difference among the risk groups (P Z 0.771) (Table 1). Likewise, there was no difference in radiographic success among the different risk categories (P Z 0.699). In logistic regression, routine VCUG versus indicated VCUG was associated with significant clinical (P < 0.05) and radiographic (P < 0.0001) success when adjusting for age. The odds of achieving clinical success for children having routine VCUG were 9.9 times higher (95% CI 2e50; P < 0.05) than for the indicated VCUG children. Of the 76 children on a routine VCUG protocol, 74 (97.4%) did not experience a postoperative fUTI during clinical follow-up compared to 30 (78.9%) of children in the VCUG-indicated cohort (P < 0.05). The odds of radiographic success for the routine VCUGprotocol children were 13 times higher (95% CI 4.2e40; P < 0.0001) than VCUG-indicated children. Sixty-eight (89.5%) of the 76 children on the routine VCUG protocol achieved radiographic success, compared to just 19 (50%) of the 38 VCUG-indicated children (P < 0.0001). Children with clinical failure (n Z 8) were statistically more likely to have a radiographic failure (P < 0.001) than those who were high radiographic risk (n Z 30) but did not experience a postoperative fUTI. A flowchart demonstrating the outcomes is shown in Figure. The subset of children with BBD (n Z 68, 30.9%) was then compared to those without BBD (n Z 154). Females (33%) were significantly more likely than males (8.3%) to have voiding dysfunction symptoms (P < 0.05). Children
Table 1 Success rates stratified by clinical and radiographic risk groups. No differences were seen between the different risk groups. Risk groups (Clinical/Radiographic)
% Clinical success (N )
% Failure (N )
Low/Low Low/High High/Low High/High
96.6 100.0 94.4 91.1
3.4 0.0 5.6 8.9
(28) (7) (101) (72)
(1) (0) (6) (7)
with BBD (5.8 2.7 years) were significantly older (P < 0.001) than those without voiding dysfunction (3.4 2.4 years). Children with BBD also had statistically significantly more preoperative fUTI (2.7 1.2) than those without BBD (2.1 1.3, P < 0.05). Clinical (P Z 0.134) or radiographic (P Z 0.647) success did not differ by BBD status. Of the 27 radiographic failures, eight (29.6%) experienced a minimum two-grade improvement in VUR. Nine children (4.1%) underwent additional procedures, including repeat Double HIT in six children (2.7%) and robotic or open ureteral reimplantation in three children (1.4%). Of those undergoing a secondary procedure, five had persistent VUR and fUTI, while four had surgery based on postoperative VCUG findings alone. The remaining children with significantly improved VUR were simply observed off antibiotics.
Discussion Diagnosis and management of VUR in children has become increasingly controversial [1,8e10]. The decision to surgically correct reflux in a child is individualized, and dependent upon a host of factors, including: risk of recurrent UTI, risk of developing new renal parenchymal scarring, likelihood of spontaneous resolution, and parental preference. Endoscopic injection with Dx/HA has proven to be an attractive alternative to ureteral reimplantation; it is an outpatient procedure with minimal associated morbidity. Efficacy rates, while up to 94% with Double HIT [4,5], are known to vary widely between surgeons and techniques [11]. Thus, clinical and radiographic outcomes remain a consideration, and the AUA recommends VCUG following endoscopic correction of VUR [1]. In order to determine the necessity of obtaining a postoperative VCUG, the long-term clinical and radiographic success rates of children undergoing Double HIT for primary VUR were evaluated in the present study. Children were grouped into high and low clinical and radiographic risk categories. The presence of BBD has been shown to affect the cure rate of endoscopic procedures, and children with increased preoperative episodes of pyelonephritis are more likely to experience a postoperative fUTI [8,12,13]. Children with a history of BBD and/or 3 fUTIs were therefore classified as high clinical risk. Children younger than 2 years of age, and those with high-grade (4 or 5) VUR, were classified as high radiographic risk. Young children were classified as high radiographic risk as they are most clinically susceptible to the harmful sequelae of untreated VUR [14,15]. There was no difference in the clinical success among the different risk groups; the number of children with postoperative fUTI was relatively few, so there was not statistical power to discern any differences between children who experienced clinical success versus clinical failure. However, children with an ‘indicated’ VCUG (i.e. those younger than 2 years of age, grade 4e5 VUR or those with a fUTI) were 13 times more likely to experience a radiographic failure. This cohort of 38 children had a 50% radiographic cure rate and a 78.9% clinical cure rate, compared to the overall long-term clinical success rate of 93.7%. The findings demonstrate that failures can be
Is Routine VCUG Necessary Following Double HIT? predicted with relatively high sensitivity, and it may therefore be prudent to selectively obtain postoperative VCUG rather than recommend it for all children undergoing Dx/HA injection. Although it is difficult to accurately predict which children will experience recurrent fUTI, the present results may assist with clinical decision-making and parental counseling. Prevention of fUTI is one of the primary goals of surgical management of VUR, and as such clinical success is arguably more important in the long term. While VCUG is paramount in the initial evaluation of children with fUTI, it has proven to be an unpopular test due to radiation exposure as well as child and parent anxiety/discomfort [16,17]. While postoperative VCUG was offered to all children for the duration of the present study, the majority of parents elected to forego postoperative VCUG when quoted a radiographic success rate of 90% [4], unless there was a specific indication such as young age, high-grade reflux or another fUTI. This led to a transition of obtaining VCUGs based on specific indications versus those that were routinely performed based on the AUA guidelines. Parents’ unwillingness to have their children undergo repeated VCUGs is evidenced by the fact that four children in the present study with postoperative fUTI did not undergo a cystogram to assess for recurrent or persistent reflux, despite the strong recommendation to do so. The consistent use of the Double HIT method has provided reproducibly high radiographic and clinical successes [4e6,18,19] and the present study demonstrates long-term follow-up with maintained clinical success. Therefore, it is believed that follow-up after endoscopic injection should include renal-bladder ultrasound and limit further radiographic evaluation (i.e. VCUG) to those children who are younger than 2 years of age, have high-grade VUR or recurrent fUTI, or per surgeon/family request. The later should not be ignored, and all parents are thoroughly counseled regarding postoperative VCUG to assess for radiographic success. Postoperative imaging should also be reflective of the surgeon’s experience. It has been previously reported that twenty cases are required to achieve sufficient proficiency with endoscopic repair of VUR; inexperienced surgeons may therefore consider obtaining postoperative VCUG for a number of cases to ascertain radiographic outcomes [2]. The present study has several limitations that warrant consideration aside from its retrospective nature. Although exhaustive efforts were made to ascertain and confirm the children’s clinical status, some of the data were ultimately dependent upon caregiver report, which is subject to recall bias. While some urine cultures were obtained via catheterization, others were clean-catch specimens, which may have resulted in false positives. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. Moreover, after the initial postoperative VCUG, subsequent imaging was prompted only by clinical pyelonephritis. Therefore, it is feasible that some children with an initial negative VCUG may have recurrent VUR. The incidence of fUTI in the present study may also be artificially low, as some radiographic failures proceeded directly to another injection or to reimplantation before being given a chance to experience another episode of pyelonephritis. While it was demonstrated that children undergoing
40.e4 an ‘indicated’ VCUG were more likely to experience radiographic failure, a larger patient cohort is necessary to determine whether age or VUR grade is more predictive of failure. Renal scarring is a known risk factor for fUTI, however, DMSA (technetium-99 m dimercaptosuccinic acid scans) scans were not routinely obtained; therefore, the incidence of renal scarring/dysplasia in the present cohort is unknown. Finally, all children underwent endoscopic Dx/ HA injection; there was no control group in the study, so the incidence ‘spontaneous resolution’ is unknown. Despite these limitations, the present study demonstrated a strong correlation between ‘indicated’ VCUG and clinical and radiographic failure, implying that postoperative VCUG can be safely avoided in the majority of children undergoing Double HIT for primary VUR. In keeping with the VUR treatment goals, as outlined by the AUA summary guidelines (i.e. prevention of febrile infections while minimizing morbidity of treatment and follow-up), endoscopic correction of reflux via the Double HIT method represents an attractive option for many children, with a high long-term clinical success rate and minimal morbidity [4,5].
Conclusions Long-term clinical success following Double HIT for the endoscopic correction of primary VUR is high, and the vast majority of children avoid additional or more-invasive surgical procedures. Unless indicated by high grade, young age, clinical failure, or family/surgeon preference, consideration should be given to making postoperative VCUG an option rather than a recommendation in children undergoing endoscopic treatment of primary VUR using the Double HIT method.
Funding None declared.
Conflict of interest A.J. Kirsch, MD e Consultant and Speaker’s Bureau e Salix; Consultant e Cook Medical; Royalities. H.C. Scherz, MD e Cook Medical; Royalties.
Ethical approval Approved under Children’s Healthcare of Atlanta IRB 13-106.
References [1] Peters CA, Skoog SJ, Arant Jr BS, Copp HL, Elder JS, Hudson RG, et al. Summary of the AUA guidelines on management of primary vesicoureteral reflux in children. J Urol 2010;184:1134e44. [2] Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004;171:2413e6.
40.e5 [3] Kirsch AJ, Kaye JD, Cerwinka WH, Watson JM, Elmore JM, Lyles RH, et al. Dynamic hydrodistention of the ureteral orifice: a novel grading system with high interobserver concordance and correlation with vesicoureteral reflux grade. J Urol 2009;182:1688e92. [4] Kaye JD, Srinivasan AK, Delaney C, Cerwinka WH, Elmore JM, Scherz HC, et al. Clinical and radiographic results of endoscopic injection for vesicoureteral reflux: defining measures of success. J Pediatr Urol 2012;8:297e303. [5] Kalisvaart JF, Scherz HC, Cuda S, Kaye JD, Kirsch AJ. Intermediate to long-term follow-up indicates low risk of recurrence after double HIT endoscopic treatment for primary vesicoureteral reflux. J Pediatr Urol 2012;8:359e65. [6] Garcia-Aparicio L, Rovira J, Blazquez-Gomez E, GarciaGarcia L, Gimenez-Llort A, Rodo J, et al. Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen’s ureteral reimplantation for vesicoureteral reflux: long-term results. J Pediatr Urol 2013;9:483e7. [7] Cerwinka WH, Scherz HC, Kirsch AJ. Dynamic hydrodistention classification of the ureter and the double HIT method to correct vesicoureteral reflux. Arch Esp Urol 2008; 61:882e7. [8] Austin JC, Cooper CS. Vesicoureteral reflux: who benefits from correction. Urol Clin North Am 2010;37:243e52. [9] Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595e610. [10] Wan J, Skoog SJ, Hulbert WC, Casale AJ, Greenfield SP, Cheng EY, et al., Executive Committee, Section on Urology, American Academy of Pediatrics. Section on urology response to new guidelines for the diagnosis and management of UTI. Pediatrics 2012;129:e1051e3.
A.M. Arlen et al. [11] Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systemic review. Pediatrics 2010;125:1010e9. [12] Sung J, Skoog S. Surgical management of vesicoureteral reflux in children. Pediatr Nephrol 2011;27:551e61. [13] Coletta R, Olivieri C, Briganti V, Perrotta ML, Oriolo L, Fabbri F, et al. Patients with a history of infection and voiding dysfunction are at risk for recurrence after successful endoscopic treatment of vesicoureteral reflux and deserve longterm follow up. Urol Ann 2012;4:19e23. [14] Peters C, Rushton HG. Vesicoureteral reflux associated renal damage: congenital reflux nephropathy and acquired renal scarring. J Urol 2010;184:265e73. [15] Shaikh N, Ewing AL, Bharnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics 2010;126:1084e91. [16] Paradopoulou F, Efremidis SC, Oiconomou A, Badouraki M, Panteleli M, Papchristou F, et al. Cyclic voiding cystourethrography: is vesicoureteral reflux missed with standard voiding cystourethrography? Eur Radiol 2002;12:666e70. [17] Nelson CP, Chow JS, Rosokija I, Ziniel S, Routh JC, Cilento Jr BG. Patient and family impact of pediatric genitourinary diagnostic imaging tests. J Urol 2012;188:1601e7. [18] Stenberg A, Lackgren G. Treatment of vesicoureteral reflux in children using stabilized non-animal hyaluronic acid/dextranomer gel (NASHA/DX): a long-term observational study. J Pedtric Urol 2007;2:80e5. [19] Elder JS, Diaz M, Caldamone AA, Cendron M, Grenfield S, Hurwitz R, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006;175:716e22.
Is routine voiding cystourethrogram necessary following double hit for primary vesicoureteral reflux?
a
Department of Pediatric Urology, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA
b
Department of Biostatistics and Bioinformatics, Rollins School of Public Health and Emory University School of Medicine, Atlanta, GA, USA Correspondence to: A.J. Kirsch, 5445 Meridian Mark Rd, Suite 420, Atlanta, GA, 30342, USA, Tel.: þ1 404 252 5206; fax: þ1 404 252 1268 [email protected] (A.M. Arlen) [email protected] (H.C. Scherz) [email protected] (E. Filimon) [email protected] (T. Leong) [email protected] (A.J. Kirsch) Keywords Vesicoureteral reflux (VUR); Voiding cystourethrogram (VCUG); Double HIT (hydrodistention implantation technique) Received 2 August 2014 Accepted 22 November 2014 Available online 30 January 2015
Angela M. Arlen a, Hal C. Scherz a, Eleonora Filimon a, Traci Leong b, Andrew J. Kirsch a Summary Introduction and objective Current AUA guidelines recommend voiding cystourethrogram (VCUG) following endoscopic treatment of vesicoureteral reflux (VUR). We evaluated the clinical and radiographic outcomes of children undergoing Double HIT (hydrodistention implantation technique) for primary VUR to determine success rates and the necessity of postoperative VCUG. Study design Children with a history of febrile urinary tract infection (fUTI) undergoing Double HIT for primary VUR between 2009 and 2012 were identified. Patients were prospectively classified as high or low clinical and radiographic risk. Children were categorized as high clinical risk if they had 3 fUTIs or documented bladder bowel dysfunction (BBD). High radiographic risk included those <2 years of age or with grade 4e5 VUR. Initially, all children underwent postoperative VCUG (“routine” group), while only those with an indication (high radiographic risk or clinical failure) did so during the latter portion of the study (“indicated” group). Clinical success was defined as no postoperative fUTI and radiographic success as negative postoperative VCUG. Average clinical follow-up was 34.7 17.2 months. Results Two hundred and twenty-two children (198 girls, 24 boys) underwent Double HIT at a mean age of 4.1 2.7 years. Mean maximum VUR grade was 3 0.8. Sixty-eight children (30.6%) had documented BBD. Fourteen children (6.3%) experienced postoperative fUTI, for a clinical success rate of 93.7%. One hundred and fourteen patients (51.4%) underwent postoperative VCUG; 76 were “routine” and 38 were “indicated” [Figure]. Of children classified as low clinical/radiographic risk, 96.6% did not have a postoperative fUTI, compared to 91.1% for high risk patients (P Z 0.771). Odds of clinical success for routine VCUG group were 9.9 times higher than for the indicated VCUG group (95% CI, 2e50). Odds of radiographic success for the routine cohort were 13 times higher than for the indicated group
(95% CI, 4.2e40). Nine children (4.1%) underwent additional procedures. Discussion We found no difference in clinical success among the different risk groups; the number of children with postoperative fUTI was relatively few so there was not statistical power to discern any differences between patients who experienced clinical success versus clinical failure. However, children with an “indicated” VCUG (i.e. those less than 2 years of age, grade 4e5 VUR or those with a fUTI) were 13 times more likely to experience a radiographic failure. This cohort of 38 patients had a 50% radiographic cure rate and a 78.9% clinical cure rate, compared to the overall long-term clinical success rate of 93.7%. Our data demonstrates that we can predict failures with relatively high sensitivity, and it may therefore be prudent to selectively obtain postoperative VCUG rather than recommend it for all children undergoing dextranomer hyaluronic acid co-polymer (Dx/HA) injection. Our study has several limitations that warrant consideration. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. Incidence of fUTI may also be artificially low, as some radiographic failures proceeded directly to another injection or reimplantation. While we were able to demonstrate that children undergoing an “indicated” VCUG were more likely to experience radiographic failure, a larger patient cohort is necessary to determine whether age or VUR grade is more predictive of failure. Finally all patients underwent endoscopic Dx/HA injection, therefore the incidence “spontaneous resolution” is unknown. Conclusion Long-term clinical success following Double HIT for the endoscopic correction of primary VUR is high, and the majority of children avoid additional procedures. Unless indicated by high-grade, young age, clinical failure, or family/surgeon preference, consideration should be given to making postoperative VCUG an option rather than a recommendation in children undergoing endoscopic treatment of primary VUR using the Double HIT method.
http://dx.doi.org/10.1016/j.jpurol.2014.11.011 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Is Routine VCUG Necessary Following Double HIT?
40.e2
Figure Flowchart demonstrating the clinical and radiographic success of patients according to postoperative VCUG status. “Indicated” VCUGs include those for grade 4e5 VUR, those in children less than 2 years of age, and those obtained for a postoperative fUTI.
Introduction The 2010 American Urological Association (AUA) reflux guidelines recommend postoperative VCUG following endoscopic treatment of primary VUR due to highly variable success rates ranging from 50 to 92% [1]. The concept of ureteral hydrodistention and intraluminal submucosal injection (hydrodistention implantation technique, or HIT) was introduced in 2002, and has resulted in improved success rates for endoscopic management of VUR [2]. Further modifications led to the Double HIT method, whereby proximal and distal intraluminal injections coapt both the ureteral tunnel and orifice [3]. The treatment goals of VUR include prevention of recurrent, febrile UTI (fUTI) and renal injury as well as minimizing morbidity of treatment and follow-up [1]. Double HIT has led to improved success rates for endoscopic correction of reflux [4e6]. In the present study, the longterm clinical success of children undergoing Double HIT was evaluated. It was hypothesized that postoperative VCUG could potentially be avoided in a large subset of children following endoscopic injection for VUR due to acceptably high clinical and radiographic success rates.
Materials and methods Institutional review board approval was obtained. Between January 1, 2009 and December 31, 2012, 222 children with a history of fUTI underwent injection of dextranomer hyaluronic acid co-polymer (Dx/HA) for primary VUR using the Double HIT method, as previously described [3,7]. All patients were asked to continue antibiotic prophylaxis and return in 4e6 weeks for a renal-bladder sonogram (RBUS). Routine VCUGs were performed at least 6 weeks (mean 3 1.2 months) after endoscopic injection. Antibiotics were discontinued if RBUS was unchanged and VCUG showed either no VUR or at least a two-grade improvement. The children’s electronic medical records were retrospectively reviewed. Their demographics, VUR grade, presence of bladder bowel dysfunction (BBD), and pre-operative and postoperative fUTIs were assessed. In order to determine the need for postoperative VCUG imaging, the children were prospectively classified as either high or low clinical and radiographic risk. Children were categorized as high clinical risk if they had 3 preoperative fUTIs or documented BBD. Febrile UTI was defined as: > 50,000e100,000 colony forming units (CFU) of
a single organism obtained by catheterization or clean catch, and was associated with a body temperature of 101.5 F. Bladder bowel dysfunction included: urinary frequency and urgency, prolonged voiding intervals, daytime wetting, holding maneuvers, constipation and encopresis in toilet-trained children. All children with BBD were managed with timed voiding, treatment of constipation, anticholinergic medication and/or biofeedback, when indicated by symptomatology. High radiographic risk included those <2 years of age or with grade 4e5 VUR. The children who underwent postoperative VCUG were further categorized as routine or indicated. Initially, all children underwent postoperative VCUG (‘routine’ group) per AUA guidelines [1], while only those with an indication (high radiographic risk or clinical failure) did so during the latter portion of the study (‘indicated’ group). The postoperative imaging protocol was altered during the study period due to an observed low incidence of radiographic failure in children 2 years of age with mild-moderate VUR, regardless of the number of preoperative fUTIs or presence of BBD. Clinical success was defined as no postoperative fUTI and radiographic success was defined as a negative postoperative VCUG. Consecutive children with a history of fUTI and primary VUR undergoing Double HIT by one of two pediatric urologists (HCS or AJK) were included. Children with secondary VUR, prior anti-reflux surgery, aberrant anatomy or without a history of fUTI were excluded from the study. Logistic regression analysis was performed to identify predictors of clinical and radiographic success after a single Double HIT procedure. The Chi-squared test (or Fisher’s exact when necessary) was used to compare the distribution of categorical variables. Two sample t-tests were used to compare the averages by group. Statistical analysis was performed using SAS (SAS Institute Inc, Cary, NC, USA) 9.3, with P < 0.05 representing statistical significance.
Results Two hundred and twenty-two children (198 girls, 24 boys) with primary VUR underwent Double HIT at a mean age of 4.1 2.7 years. Average injected Dx/HA volume was 1.34 0.56 ml per ureter. The mean number of preoperative fUTIs was 2.3 1.3 (range 1e7). The mean maximum VUR grade was 3 0.8, with the following breakdown: grade 1 (n Z 5), grade 2 (n Z 44), grade 3 (n Z 114), grade 4 (n Z 53) and grade 5 (n Z 6). Sixty-eight children (30.6%) had BBD. Fourteen children (6.3%) experienced
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postoperative fUTI after discontinuing antibiotic prophylaxis; the clinical success rate was 93.7%. Of the clinical failures, five had persistent or recurrent VUR, five had a negative VCUG, and the remaining four did not undergo postoperative cystogram, despite the recommendation to do so. One hundred and fourteen children (51.4%) underwent postoperative VCUG; 76 were ‘routine’ and 38 were ‘indicated’ (i.e. high risk/clinical failures). Three children (1.4%) had postoperative hydronephrosis, and one child (0.5%) had associated nausea/vomiting and flank pain necessitating hospitalization. All three cases resolved spontaneously with no further intervention. The average clinical follow-up was 34.7 17.2 months. Children were categorized as high or low clinical and radiographic risk. One hundred and sixteen children (52.3%) were high clinical risk, i.e. had 3 preoperative fUTIs or documented BBD. Eighty-five children (38.2%) were either younger than 2 years of age at the time of Dx/HA injection or had grade 4e5 VUR, and were classified as high radiographic risk. When evaluating the relationship between clinical success (defined as no postoperative fUTI) and risk status, there was no difference among the risk groups (P Z 0.771) (Table 1). Likewise, there was no difference in radiographic success among the different risk categories (P Z 0.699). In logistic regression, routine VCUG versus indicated VCUG was associated with significant clinical (P < 0.05) and radiographic (P < 0.0001) success when adjusting for age. The odds of achieving clinical success for children having routine VCUG were 9.9 times higher (95% CI 2e50; P < 0.05) than for the indicated VCUG children. Of the 76 children on a routine VCUG protocol, 74 (97.4%) did not experience a postoperative fUTI during clinical follow-up compared to 30 (78.9%) of children in the VCUG-indicated cohort (P < 0.05). The odds of radiographic success for the routine VCUGprotocol children were 13 times higher (95% CI 4.2e40; P < 0.0001) than VCUG-indicated children. Sixty-eight (89.5%) of the 76 children on the routine VCUG protocol achieved radiographic success, compared to just 19 (50%) of the 38 VCUG-indicated children (P < 0.0001). Children with clinical failure (n Z 8) were statistically more likely to have a radiographic failure (P < 0.001) than those who were high radiographic risk (n Z 30) but did not experience a postoperative fUTI. A flowchart demonstrating the outcomes is shown in Figure. The subset of children with BBD (n Z 68, 30.9%) was then compared to those without BBD (n Z 154). Females (33%) were significantly more likely than males (8.3%) to have voiding dysfunction symptoms (P < 0.05). Children
Table 1 Success rates stratified by clinical and radiographic risk groups. No differences were seen between the different risk groups. Risk groups (Clinical/Radiographic)
% Clinical success (N )
% Failure (N )
Low/Low Low/High High/Low High/High
96.6 100.0 94.4 91.1
3.4 0.0 5.6 8.9
(28) (7) (101) (72)
(1) (0) (6) (7)
with BBD (5.8 2.7 years) were significantly older (P < 0.001) than those without voiding dysfunction (3.4 2.4 years). Children with BBD also had statistically significantly more preoperative fUTI (2.7 1.2) than those without BBD (2.1 1.3, P < 0.05). Clinical (P Z 0.134) or radiographic (P Z 0.647) success did not differ by BBD status. Of the 27 radiographic failures, eight (29.6%) experienced a minimum two-grade improvement in VUR. Nine children (4.1%) underwent additional procedures, including repeat Double HIT in six children (2.7%) and robotic or open ureteral reimplantation in three children (1.4%). Of those undergoing a secondary procedure, five had persistent VUR and fUTI, while four had surgery based on postoperative VCUG findings alone. The remaining children with significantly improved VUR were simply observed off antibiotics.
Discussion Diagnosis and management of VUR in children has become increasingly controversial [1,8e10]. The decision to surgically correct reflux in a child is individualized, and dependent upon a host of factors, including: risk of recurrent UTI, risk of developing new renal parenchymal scarring, likelihood of spontaneous resolution, and parental preference. Endoscopic injection with Dx/HA has proven to be an attractive alternative to ureteral reimplantation; it is an outpatient procedure with minimal associated morbidity. Efficacy rates, while up to 94% with Double HIT [4,5], are known to vary widely between surgeons and techniques [11]. Thus, clinical and radiographic outcomes remain a consideration, and the AUA recommends VCUG following endoscopic correction of VUR [1]. In order to determine the necessity of obtaining a postoperative VCUG, the long-term clinical and radiographic success rates of children undergoing Double HIT for primary VUR were evaluated in the present study. Children were grouped into high and low clinical and radiographic risk categories. The presence of BBD has been shown to affect the cure rate of endoscopic procedures, and children with increased preoperative episodes of pyelonephritis are more likely to experience a postoperative fUTI [8,12,13]. Children with a history of BBD and/or 3 fUTIs were therefore classified as high clinical risk. Children younger than 2 years of age, and those with high-grade (4 or 5) VUR, were classified as high radiographic risk. Young children were classified as high radiographic risk as they are most clinically susceptible to the harmful sequelae of untreated VUR [14,15]. There was no difference in the clinical success among the different risk groups; the number of children with postoperative fUTI was relatively few, so there was not statistical power to discern any differences between children who experienced clinical success versus clinical failure. However, children with an ‘indicated’ VCUG (i.e. those younger than 2 years of age, grade 4e5 VUR or those with a fUTI) were 13 times more likely to experience a radiographic failure. This cohort of 38 children had a 50% radiographic cure rate and a 78.9% clinical cure rate, compared to the overall long-term clinical success rate of 93.7%. The findings demonstrate that failures can be
Is Routine VCUG Necessary Following Double HIT? predicted with relatively high sensitivity, and it may therefore be prudent to selectively obtain postoperative VCUG rather than recommend it for all children undergoing Dx/HA injection. Although it is difficult to accurately predict which children will experience recurrent fUTI, the present results may assist with clinical decision-making and parental counseling. Prevention of fUTI is one of the primary goals of surgical management of VUR, and as such clinical success is arguably more important in the long term. While VCUG is paramount in the initial evaluation of children with fUTI, it has proven to be an unpopular test due to radiation exposure as well as child and parent anxiety/discomfort [16,17]. While postoperative VCUG was offered to all children for the duration of the present study, the majority of parents elected to forego postoperative VCUG when quoted a radiographic success rate of 90% [4], unless there was a specific indication such as young age, high-grade reflux or another fUTI. This led to a transition of obtaining VCUGs based on specific indications versus those that were routinely performed based on the AUA guidelines. Parents’ unwillingness to have their children undergo repeated VCUGs is evidenced by the fact that four children in the present study with postoperative fUTI did not undergo a cystogram to assess for recurrent or persistent reflux, despite the strong recommendation to do so. The consistent use of the Double HIT method has provided reproducibly high radiographic and clinical successes [4e6,18,19] and the present study demonstrates long-term follow-up with maintained clinical success. Therefore, it is believed that follow-up after endoscopic injection should include renal-bladder ultrasound and limit further radiographic evaluation (i.e. VCUG) to those children who are younger than 2 years of age, have high-grade VUR or recurrent fUTI, or per surgeon/family request. The later should not be ignored, and all parents are thoroughly counseled regarding postoperative VCUG to assess for radiographic success. Postoperative imaging should also be reflective of the surgeon’s experience. It has been previously reported that twenty cases are required to achieve sufficient proficiency with endoscopic repair of VUR; inexperienced surgeons may therefore consider obtaining postoperative VCUG for a number of cases to ascertain radiographic outcomes [2]. The present study has several limitations that warrant consideration aside from its retrospective nature. Although exhaustive efforts were made to ascertain and confirm the children’s clinical status, some of the data were ultimately dependent upon caregiver report, which is subject to recall bias. While some urine cultures were obtained via catheterization, others were clean-catch specimens, which may have resulted in false positives. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. Moreover, after the initial postoperative VCUG, subsequent imaging was prompted only by clinical pyelonephritis. Therefore, it is feasible that some children with an initial negative VCUG may have recurrent VUR. The incidence of fUTI in the present study may also be artificially low, as some radiographic failures proceeded directly to another injection or to reimplantation before being given a chance to experience another episode of pyelonephritis. While it was demonstrated that children undergoing
40.e4 an ‘indicated’ VCUG were more likely to experience radiographic failure, a larger patient cohort is necessary to determine whether age or VUR grade is more predictive of failure. Renal scarring is a known risk factor for fUTI, however, DMSA (technetium-99 m dimercaptosuccinic acid scans) scans were not routinely obtained; therefore, the incidence of renal scarring/dysplasia in the present cohort is unknown. Finally, all children underwent endoscopic Dx/ HA injection; there was no control group in the study, so the incidence ‘spontaneous resolution’ is unknown. Despite these limitations, the present study demonstrated a strong correlation between ‘indicated’ VCUG and clinical and radiographic failure, implying that postoperative VCUG can be safely avoided in the majority of children undergoing Double HIT for primary VUR. In keeping with the VUR treatment goals, as outlined by the AUA summary guidelines (i.e. prevention of febrile infections while minimizing morbidity of treatment and follow-up), endoscopic correction of reflux via the Double HIT method represents an attractive option for many children, with a high long-term clinical success rate and minimal morbidity [4,5].
Conclusions Long-term clinical success following Double HIT for the endoscopic correction of primary VUR is high, and the vast majority of children avoid additional or more-invasive surgical procedures. Unless indicated by high grade, young age, clinical failure, or family/surgeon preference, consideration should be given to making postoperative VCUG an option rather than a recommendation in children undergoing endoscopic treatment of primary VUR using the Double HIT method.
Funding None declared.
Conflict of interest A.J. Kirsch, MD e Consultant and Speaker’s Bureau e Salix; Consultant e Cook Medical; Royalities. H.C. Scherz, MD e Cook Medical; Royalties.
Ethical approval Approved under Children’s Healthcare of Atlanta IRB 13-106.
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