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Complete primary repair of bladder exstrophy: A systematic review
Journal Pre-proof Complete primary repair of bladder exstrophy: A systematic review Joshua D. Ring, MD, Piyush Pathak, MD MPH, Kristin R. Delfino, PhD, Danuda I. Dynda, MD MBA, Ranjiv I. Mathews, MD PII:
S1477-5131(20)30005-X
DOI:
https://doi.org/10.1016/j.jpurol.2020.01.004
Reference:
JPUROL 3359
To appear in:
Journal of Pediatric Urology
Received Date: 8 February 2019 Accepted Date: 7 January 2020
Please cite this article as: Ring JD, Pathak P, Delfino KR, Dynda DI, Mathews RI, Complete primary repair of bladder exstrophy: A systematic review, Journal of Pediatric Urology, https://doi.org/10.1016/ j.jpurol.2020.01.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Title: COMPLETE PRIMARY REPAIR OF BLADDER EXSTROPHY: A SYSTEMATIC REVIEW Authors: Joshua D. Ring MD1, Piyush Pathak MD MPH1, Kristin R. Delfino PhD1, Danuda I. Dynda MD MBA,1 and Ranjiv I. Mathews MD1
Corresponding Author Information: Piyush Pathak, MD, MPH1 Southern Illinois University School of Medicine1 301 N 8th Street, Suite 4B P.O. Box 19665 Springfield, Illinois 62794-9665 Phone: 217-545-3262 Fax: 217-545-7305
Summary word count: 252 Manuscript word count: 2109
Summary Objectives: Complete Primary Repair of Exstrophy (CPRE) was established as a method to reduce numbers of procedures for the reconstruction of Bladder Exstrophy (BE). Performed since 1989, some suggest it as a replacement for the Staged Reconstructive Procedure (SRP), the gold standard. Does CPRE reduce the numbers of procedures for reconstruction of BE? Methods: Literature was reviewed from 1989 – 2016, and articles evaluating outcomes of patients undergoing CPRE extracted. Effort was made to obtain final data from each reporting institution/group. Eleven articles meeting criteria were evaluated for qualitative systematic review. Age at initial closure, complications, additional procedures, and outcomes were evaluated to provide an overview of CPRE. Results: Ten groups reported BE management using the CPRE technique. 236 patients (153 boys; 72 girls; 11 unknown sex) had primary closure ranging from birth to 5.6 years. Osteotomy was favored by most in infants closed beyond the first 72 hours of life along with spica cast immobilization. Three groups recommended concomitant augmentation for infants with small bladder capacities. Ureteral reimplantation was required in 58 patients with recurrent urinary tract infections resistant to prophylaxis. Hypospadias repair was required for the majority of boys having complete penile disassembly, and the majority of children eventually required bladder neck reconstruction (BNR) for continence. Overall, voiding
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without BNR was noted in 16 – 37% of children in the reported series. Conclusions: CPRE has been suggested as a single procedure for the management of BE. Literature review suggests most patients require multiple procedures to complete reconstruction and attain continence.
Keywords: urinary bladder, urinary incontinence, congenital abnormalities, reconstructive surgical procedures, complete primary repair, bladder exstrophy
Abbreviations and Acronyms: BE, bladder exstrophy; BNR, bladder neck reconstruction; BUR, bilateral ureteral reimplantation; CIC, clean intermittent catheterization; CPRE, complete primary repair of bladder exstrophy; MSRE, Modern Staged Repair of Bladder Exstrophy; SRP, Staged Reconstructive Procedure; VUR, vesicoureteral reflux
2
INTRODUCTION: Bladder exstrophy is a rare congenital malformation of the lower genitourinary tract within a spectrum of defects knowns as the exstrophy-epispadias complex. The overall incidence is estimated to be between 1 in 10,000 and 1 in 50,000 live births [1] with a male-to-female ratio of 2.3:1[2]. Failure of the development of the cloacal membrane disrupts mesenchymal migration medially and results in abnormal lower abdominal wall development [3]. The spectrum can range from the most severe as in cloacal exstrophy to the least severe with distal epispadias. Associated musculoskeletal, genitourinary, and gastrointestinal anomalies are commonly noted. Surgical reconstruction of bladder exstrophy aims to achieve voided continence while preserving renal and sexual function, and remains a challenge for pediatric surgeons and urologists. Multiple approaches for the surgical management of bladder exstrophy have been described in the literature. The traditional approach involves multiple operations with a staged paradigm [4] of two to three procedures that has been termed the Modern Staged Repair of Bladder Exstrophy (MSRE) or Staged Reconstructive Procedure (SRP) [5,6]. The stepwise reconstruction involves primary bladder closure, which is most commonly performed when the child is a newborn, and may or may not include pelvic osteotomies to facilitate pelvic ring and secure abdominal wall closure. The next stage focuses on epispadias repair and urethral reconstruction later in infancy. The final stage is directed at achieving voided continence through bladder neck reconstruction with bilateral ureteral reimplantation if an adequate bladder capacity has been achieved. Multiple variations to this staged approach have been suggested. Various other staged approaches have been utilized for the management of
3
exstrophy. The Kelly technique begins with primary bladder closure, a second stage consisting of radical dissection of the proximal sphincteric tissue and penile lengthening, followed by a final stage of urethral reconstruction [7]. The Warsaw approach similarly begins with initial bladder closure followed by staging epispadias repair with bladder neck reconstruction at a second stage [8]. A “total” reconstruction, combining all stages of reconstruction into a single procedure was performed by the Erlangen group [9]. This represents probably the most aggressive surgical management strategy for reconstruction as an initial procedure. In 1989, Mitchell developed the Complete Primary Repair of Bladder exstrophy (CPRE) as an alternative management strategy for the reconstruction of bladder exstrophy [10]. Combining bladder closure with epispadias repair using a disassembly of the penis, was determined to permit “appropriate” cycling of the bladder, which would lead to bladder growth and provide for some outlet resistance. These modifications were designed to reduce the need for later bladder neck reconstruction to achieve continence. Since that initial report, multiple centers have reported modifications to improve on the outcomes of the procedure. As more institutions gain experience with this procedure long-term data is becoming available as to the necessity for additional procedures that are needed to achieve the functional and cosmetic outcomes of exstrophy reconstruction [11–14]. In this systematic review, we aim to amalgamate the most updated results and surgical outcomes after CPRE from each performing institution with regards to voided continence rates, correction of penile epispadias, and total number of procedures performed to complete reconstruction.
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METHODS: The PubMed® database was queried with restrictions for original articles in English without year limits. Keyword queries were arranged in multiple combinations to improve search results, with additional references identified from the reference lists of the aforementioned articles. Search terms included “Complete Primary Repair of Bladder Exstrophy” and “the Mitchell technique”. Twelve academic institutions were identified that have reported long-term data related to the management of exstrophy using this surgical strategy (CPRE). As many institutions report on their patient cohorts repeatedly during follow-up, only the most recent published data from each institution was considered, so as to avoid redundancy in patient numbers Study selection was performed independently by 2 authors and consensus achieved on the included/excluded studies in the review. The initial search yielded a total of 78 articles. With title and abstract screening, 57 articles were found to have published data related to CPRE. After performing a full text review, fifty-one studies remained, of which 27 were related to long-term outcome data. Eligible studies included primary outcome data on patients with BE treated with CPRE, in which all study designs except case reports were included in the analysis. Eligibility criteria for study inclusion considered number of patients, reported outcomes, complications, and length of follow-up. Only those studies that reported outcome data on the use of CPRE for primary bladder closure were included, thus revision CPRE procedures were excluded in order to eliminate variability and confounding factors. To produce a final cohort of an allencompassing CPRE population, we only focused on the most recent published data from each of the major academic institutions with long-term data for outcomes in order to eliminate redundancies in reported outcomes for the same patient population from each
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group, which produced 11 total publications [11, 12, 14–22]. Ten groups or institutions in 11 articles included in this review produced a total of 236 patients with bladder exstrophy treated with the CPRE approach. We hope to elucidate the full picture of the globally published long-term outcome data for patients treated for BE with CPRE in relation to success of primary closure, epispadias repair, achievement of continence, additional procedure rate, and overall complications. Figure 1 is a flowchart that illustrates this search process and literature selection.
Pubmed® initial search: 78 articles
51 articles related to CPRE
27 articles with long-term data
11 articles meeting eligibility criteria Figure 1: Literature search process RESULTS: Ten groups in 11 articles reported BE management using the CPRE technique between 1989 and 2018 with a total of 236 patients (153 boys; 72 girls; 11 sex unreported). Timing of the primary closure ranged from birth to 5.6 years within this cohort. Infants reported having closure beyond the first 72 hours of life (34/236 patients) were most
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commonly managed with osteotomy and spica cast immobilization. Eight patients had concomitant augmentation at the time of initial bladder closure, for a small capacity bladder. Complications of primary closure were reported in 63 children. Most were considered minor, including superficial infections, however 8 patients had failure of the closure, 2 had complete dehiscence, 20 fistulas (18 required fistula closure) and 2 deaths were reported. Further reported surgical interventions included ureteral reimplantation (58 patients) or injection of dextranomer/hyaluronidase (3 patients) for recurrent urinary tract infections, resistance to antibiotic prophylaxis, or concerns for upper tract deterioration; hypospadias repair (11 patients) in boys that had initial penile disassembly; bladder neck reconstruction (33 patients), bladder neck bulking procedures (7 patients) for management of incontinence and revision of epispadias (10 patients). Continence status was not universally reported by all centers. Volitional voiding was reported in 34 patients. This was achieved following bladder neck reconstruction (14 patients), bladder neck injection (4 patients) or combined bladder neck reconstruction and injection (5 patients). Eleven patients were reported to be dry with only primary bladder closure. Dry interval was not defined in any of the reports. Seven patients had bladder neck closure and 6 children were using intermittent catheterization for bladder emptying. Some younger children were reported to have a dry interval when last evaluated. DISCUSSION: The goals for the reconstruction of exstrophy of the bladder include preservation of renal function, closure of the bladder and abdominal wall, creation of a functional,
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cosmetically appealing penis in the male, or patent, functional vagina in the female, and construction of a bladder and urethra that permits voided continence. The ideal management strategy to achieve these goals remains elusive. The most frequently utilized methods to achieve these goals are the SRP and CPRE. While the SRP has been developed with the intentional utilization of 2 – 3 procedures in a series of stages to accomplish complete reconstruction, the CPRE was developed as a single “complete” reconstructive procedure to achieve all of the goals of reconstruction in a single operation. Most importantly, it was felt that closure of the bladder in conjunction with epispadias reconstruction, led to more normal cycling of the bladder permitting bladder growth and increasing potential for voided continence without the necessity for formal bladder neck reconstruction. As significant experience has been gained with the use of CPRE, a systematic review was conducted to determine how well the procedure was able to achieve the stated goals for successful reconstruction. Reports from high volume centers, using CPRE as the primary treatment modality were evaluated. We excluded reports of patients that focused on patients undergoing reoperative procedures for failure following prior reconstruction and also did not include any reports based on reoperative cases performed at a secondary institution. The final cohort of 236 children with BE treated with CPRE between 1989 and 2016 were based on the reports of patient data from 10 major centers. As shown in the results, the majority of patients being treated using the CPRE, required multiple procedures to achieve the stated goals for successful reconstruction. This reflects the experience in patients undergoing a staged reconstruction. Boys having CPRE that included complete
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penile disassembly were usually left with a secondary hypospadias - 22.7-68% [10, 11, 23, and 24] - that required surgical reconstruction in another procedure. Ureteral reimplantation to reduce recurrent urinary tract infections, or for preservation of the upper tracts, was performed as a separate procedure in 48-66% [11, 25–27] of the patients. The majority of patients that had CPRE, also needed BNR to achieve continence. This also reflects the outcomes previously reported - 63-86% [11, 12, and 28] in children undergoing reconstruction using a staged approach. In a 2005 literature review [29], 15-90% of patients required BNR to gain urinary continence, with 5-10% requiring both a bladder augmentation and BNR [17, 23, 25, 30, 31]. Shoukry et al. had to perform bladder augmentation in all of the children that underwent CPRE to achieve continence [21]. Borer et al performed a review of 47 patients who underwent CPRE after assessment with ultrasound, voiding cystourethrogram, and urodynamics, finding that bladder neck reconstruction was needed in 9 of 22 males (41%) and 3 of 11 females (27%). The authors concluded that further bladder neck procedures were frequently required [32], with 65-70% of children undergoing CPRE ultimately requiring a bladder neck outlet procedure [28]. This experience with CPRE is similar to staged reconstructive procedures, where 14% of children [33], usually girls, are continent without the need for a formal continence procedure. Many centers have reported making modifications to the CPRE procedure as initially described by Grade and Mitchell [25]. Most centers have stopped complete disassembly of the penis, due to concerns for corporal and glans ischemia and loss. Additionally, some centers have reported using a bladder neck tightening procedure to enhance voided continence, without formal BNR. The long term outcomes of these changes
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remain to be determined. Our systematic review of the literature to date, indicates that CPRE does not decrease the numbers of procedures needed to complete reconstruction in exstrophy. This literature review substantiates previous observations that the CPRE and SRP use different techniques with nearly the same number of procedures. Ebert et al. reported that the mean number of procedures for patients after SRP was 2.95 (range 1-8) with only 13.6% requiring more than 4 procedures; these data were self-reported however, and did not differentiate between major and minor cases [34]. Stjernqvist and Kockum reported a median of 12 procedures after SRP [35]. In comparison, Gargollo et al. described a total of 193 procedures in 32 patients that underwent CPRE (mean 4+/-5.8, range 1-31) with the majority of the surgeries being minor and endoscopic[36]. There are significant limitations to any systematic review of published data; ours is no exception. All of the studies that were utilized to compile the review were retrospective in nature. Not all institutions reported outcomes in all of their patients. Some patients have had CPRE, but continue to remain incontinent and are awaiting further procedures (BNR, augmentation, BNI, etc.). Outcome reports and the definition of success or failure had to be gleaned from the data presented. The definition of voided continence was also not uniform among authors. Despite these limitations, it remains clear that the management of bladder exstrophy remains a significant surgical challenge, typically requiring multiple procedures to achieve successful reconstruction. CONCLUSION: Historically, BE has been managed with the SRP and expectation that such a large undertaking will take multiple procedures to complete reconstruction and achieve
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continence in this difficult and complex patient population. CPRE was introduced in 1989 and has been suggested as a single procedure for the management of BE. However, literature review suggests the majority of patients require multiple procedures to complete reconstruction and attain continence. Parents and patients should be made aware of the variability of the exstrophy epispadias complex and the possible multiple procedures that are going to be required for completion of reconstruction.
Acknowledgments: None.
Ethical Approval: No animals were used in this study.
Funding Source: None.
Conflict of Interest Statement: None.
References:
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Braga LHP, Lorenzo AJ, Jrearz R, Bagli DJ, Salle JLP. Bilateral Ureteral Reimplantation at Primary Bladder Exstrophy Closure. J Urol 2010. doi:10.1016/j.juro.2010.02.032.
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Author responses
Thank you for the thoughtful review of our article, submitted for possible inclusion in the Journal of Pediatric Urology. The article has been revised extensively to reflect some of the concerns raised by the reviewers. Attached are our responses to the concerns that were raised. Reviewer 1 1. All of the studies that were included were retrospective in nature and were taken from the literature. Since most cohorts of patients with exstrophy at individual institutions remains small, there really is very little potential for a truly randomized or prospective study to be performed. 2. Only patients with bladder exstrophy were included in this review. 3. Recent reports from the MIBEC (Multi-institutional Consortium for Exstrophy) have suggested that changes are being made to the procedure over time. Since the purpose of this review was not to determine how the procedure is being modified, but rather to highlight the fact that the complexity of Bladder exstrophy typically requires multiple procedures for reconstruction, we have only peripherally mentioned these changes (Para 2, pg 10) 4. Since this was a review of the experience of the 10 largest reported series, the age ranges were varied. Also there has been an evolution for the timing of reconstruction. In the past, exstrophy reconstruction was done semi-emergently, within a 72 hour window, to reduce the need for osteotomy. More recently, the trend has been to do surgical repair beyond the 72 hour time line, at the surgeon’s
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discretion. Trying to determine a mean and median for this data set would skew to those sites that had a larger cohort and did not seem appropriate for a systematic review. 5. Since this is a review of published work from multiple institutions, no specific definition of continence could be identified. While most pediatric urologists consider a 3 hour dry interval during the day and nighttime dryness as continence, this was not explicitly stated in any of the reports and therefore was not included in this study. 6. Although some studies did separate their cohorts, male and female continence rates were not separated, and only overall continence was reported. In patients undergoing MSRE, patients that were dry following only initial closure, were typically female. 7. Since the data for continence was not consistently reported, and some centers performed augmentation on children at the time of initial closure and other combining bladder neck procedures with augment, it is hard to put this into a coherent single table. 8. The results section has been completely reworded to address the concerns raised. Since not all patients had completed reconstruction, and also not all patients had complete data reported. 9. We have added a paragraph to describe the limitations of the study. The authors would welcome a critical comment, so that we can continue the conversation in how to achieve the best surgical outcomes for our patients. Reviewer 2:
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We have further modified the Discussion, try to focus on the reason for the systematic review. This was not done to promote one method of reconstruction over another, but to rather try to determine some of the misconceptions associated with terms that are used to define our surgical approaches. Our goal is to bring into focus the fact that many parents, when confronted with a major birth defect, may be lulled into believing that a single stage reconstruction implies only need for a single operation.
18
S1477-5131(20)30005-X
DOI:
https://doi.org/10.1016/j.jpurol.2020.01.004
Reference:
JPUROL 3359
To appear in:
Journal of Pediatric Urology
Received Date: 8 February 2019 Accepted Date: 7 January 2020
Please cite this article as: Ring JD, Pathak P, Delfino KR, Dynda DI, Mathews RI, Complete primary repair of bladder exstrophy: A systematic review, Journal of Pediatric Urology, https://doi.org/10.1016/ j.jpurol.2020.01.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Title: COMPLETE PRIMARY REPAIR OF BLADDER EXSTROPHY: A SYSTEMATIC REVIEW Authors: Joshua D. Ring MD1, Piyush Pathak MD MPH1, Kristin R. Delfino PhD1, Danuda I. Dynda MD MBA,1 and Ranjiv I. Mathews MD1
Corresponding Author Information: Piyush Pathak, MD, MPH1 Southern Illinois University School of Medicine1 301 N 8th Street, Suite 4B P.O. Box 19665 Springfield, Illinois 62794-9665 Phone: 217-545-3262 Fax: 217-545-7305
Summary word count: 252 Manuscript word count: 2109
Summary Objectives: Complete Primary Repair of Exstrophy (CPRE) was established as a method to reduce numbers of procedures for the reconstruction of Bladder Exstrophy (BE). Performed since 1989, some suggest it as a replacement for the Staged Reconstructive Procedure (SRP), the gold standard. Does CPRE reduce the numbers of procedures for reconstruction of BE? Methods: Literature was reviewed from 1989 – 2016, and articles evaluating outcomes of patients undergoing CPRE extracted. Effort was made to obtain final data from each reporting institution/group. Eleven articles meeting criteria were evaluated for qualitative systematic review. Age at initial closure, complications, additional procedures, and outcomes were evaluated to provide an overview of CPRE. Results: Ten groups reported BE management using the CPRE technique. 236 patients (153 boys; 72 girls; 11 unknown sex) had primary closure ranging from birth to 5.6 years. Osteotomy was favored by most in infants closed beyond the first 72 hours of life along with spica cast immobilization. Three groups recommended concomitant augmentation for infants with small bladder capacities. Ureteral reimplantation was required in 58 patients with recurrent urinary tract infections resistant to prophylaxis. Hypospadias repair was required for the majority of boys having complete penile disassembly, and the majority of children eventually required bladder neck reconstruction (BNR) for continence. Overall, voiding
1
without BNR was noted in 16 – 37% of children in the reported series. Conclusions: CPRE has been suggested as a single procedure for the management of BE. Literature review suggests most patients require multiple procedures to complete reconstruction and attain continence.
Keywords: urinary bladder, urinary incontinence, congenital abnormalities, reconstructive surgical procedures, complete primary repair, bladder exstrophy
Abbreviations and Acronyms: BE, bladder exstrophy; BNR, bladder neck reconstruction; BUR, bilateral ureteral reimplantation; CIC, clean intermittent catheterization; CPRE, complete primary repair of bladder exstrophy; MSRE, Modern Staged Repair of Bladder Exstrophy; SRP, Staged Reconstructive Procedure; VUR, vesicoureteral reflux
2
INTRODUCTION: Bladder exstrophy is a rare congenital malformation of the lower genitourinary tract within a spectrum of defects knowns as the exstrophy-epispadias complex. The overall incidence is estimated to be between 1 in 10,000 and 1 in 50,000 live births [1] with a male-to-female ratio of 2.3:1[2]. Failure of the development of the cloacal membrane disrupts mesenchymal migration medially and results in abnormal lower abdominal wall development [3]. The spectrum can range from the most severe as in cloacal exstrophy to the least severe with distal epispadias. Associated musculoskeletal, genitourinary, and gastrointestinal anomalies are commonly noted. Surgical reconstruction of bladder exstrophy aims to achieve voided continence while preserving renal and sexual function, and remains a challenge for pediatric surgeons and urologists. Multiple approaches for the surgical management of bladder exstrophy have been described in the literature. The traditional approach involves multiple operations with a staged paradigm [4] of two to three procedures that has been termed the Modern Staged Repair of Bladder Exstrophy (MSRE) or Staged Reconstructive Procedure (SRP) [5,6]. The stepwise reconstruction involves primary bladder closure, which is most commonly performed when the child is a newborn, and may or may not include pelvic osteotomies to facilitate pelvic ring and secure abdominal wall closure. The next stage focuses on epispadias repair and urethral reconstruction later in infancy. The final stage is directed at achieving voided continence through bladder neck reconstruction with bilateral ureteral reimplantation if an adequate bladder capacity has been achieved. Multiple variations to this staged approach have been suggested. Various other staged approaches have been utilized for the management of
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exstrophy. The Kelly technique begins with primary bladder closure, a second stage consisting of radical dissection of the proximal sphincteric tissue and penile lengthening, followed by a final stage of urethral reconstruction [7]. The Warsaw approach similarly begins with initial bladder closure followed by staging epispadias repair with bladder neck reconstruction at a second stage [8]. A “total” reconstruction, combining all stages of reconstruction into a single procedure was performed by the Erlangen group [9]. This represents probably the most aggressive surgical management strategy for reconstruction as an initial procedure. In 1989, Mitchell developed the Complete Primary Repair of Bladder exstrophy (CPRE) as an alternative management strategy for the reconstruction of bladder exstrophy [10]. Combining bladder closure with epispadias repair using a disassembly of the penis, was determined to permit “appropriate” cycling of the bladder, which would lead to bladder growth and provide for some outlet resistance. These modifications were designed to reduce the need for later bladder neck reconstruction to achieve continence. Since that initial report, multiple centers have reported modifications to improve on the outcomes of the procedure. As more institutions gain experience with this procedure long-term data is becoming available as to the necessity for additional procedures that are needed to achieve the functional and cosmetic outcomes of exstrophy reconstruction [11–14]. In this systematic review, we aim to amalgamate the most updated results and surgical outcomes after CPRE from each performing institution with regards to voided continence rates, correction of penile epispadias, and total number of procedures performed to complete reconstruction.
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METHODS: The PubMed® database was queried with restrictions for original articles in English without year limits. Keyword queries were arranged in multiple combinations to improve search results, with additional references identified from the reference lists of the aforementioned articles. Search terms included “Complete Primary Repair of Bladder Exstrophy” and “the Mitchell technique”. Twelve academic institutions were identified that have reported long-term data related to the management of exstrophy using this surgical strategy (CPRE). As many institutions report on their patient cohorts repeatedly during follow-up, only the most recent published data from each institution was considered, so as to avoid redundancy in patient numbers Study selection was performed independently by 2 authors and consensus achieved on the included/excluded studies in the review. The initial search yielded a total of 78 articles. With title and abstract screening, 57 articles were found to have published data related to CPRE. After performing a full text review, fifty-one studies remained, of which 27 were related to long-term outcome data. Eligible studies included primary outcome data on patients with BE treated with CPRE, in which all study designs except case reports were included in the analysis. Eligibility criteria for study inclusion considered number of patients, reported outcomes, complications, and length of follow-up. Only those studies that reported outcome data on the use of CPRE for primary bladder closure were included, thus revision CPRE procedures were excluded in order to eliminate variability and confounding factors. To produce a final cohort of an allencompassing CPRE population, we only focused on the most recent published data from each of the major academic institutions with long-term data for outcomes in order to eliminate redundancies in reported outcomes for the same patient population from each
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group, which produced 11 total publications [11, 12, 14–22]. Ten groups or institutions in 11 articles included in this review produced a total of 236 patients with bladder exstrophy treated with the CPRE approach. We hope to elucidate the full picture of the globally published long-term outcome data for patients treated for BE with CPRE in relation to success of primary closure, epispadias repair, achievement of continence, additional procedure rate, and overall complications. Figure 1 is a flowchart that illustrates this search process and literature selection.
Pubmed® initial search: 78 articles
51 articles related to CPRE
27 articles with long-term data
11 articles meeting eligibility criteria Figure 1: Literature search process RESULTS: Ten groups in 11 articles reported BE management using the CPRE technique between 1989 and 2018 with a total of 236 patients (153 boys; 72 girls; 11 sex unreported). Timing of the primary closure ranged from birth to 5.6 years within this cohort. Infants reported having closure beyond the first 72 hours of life (34/236 patients) were most
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commonly managed with osteotomy and spica cast immobilization. Eight patients had concomitant augmentation at the time of initial bladder closure, for a small capacity bladder. Complications of primary closure were reported in 63 children. Most were considered minor, including superficial infections, however 8 patients had failure of the closure, 2 had complete dehiscence, 20 fistulas (18 required fistula closure) and 2 deaths were reported. Further reported surgical interventions included ureteral reimplantation (58 patients) or injection of dextranomer/hyaluronidase (3 patients) for recurrent urinary tract infections, resistance to antibiotic prophylaxis, or concerns for upper tract deterioration; hypospadias repair (11 patients) in boys that had initial penile disassembly; bladder neck reconstruction (33 patients), bladder neck bulking procedures (7 patients) for management of incontinence and revision of epispadias (10 patients). Continence status was not universally reported by all centers. Volitional voiding was reported in 34 patients. This was achieved following bladder neck reconstruction (14 patients), bladder neck injection (4 patients) or combined bladder neck reconstruction and injection (5 patients). Eleven patients were reported to be dry with only primary bladder closure. Dry interval was not defined in any of the reports. Seven patients had bladder neck closure and 6 children were using intermittent catheterization for bladder emptying. Some younger children were reported to have a dry interval when last evaluated. DISCUSSION: The goals for the reconstruction of exstrophy of the bladder include preservation of renal function, closure of the bladder and abdominal wall, creation of a functional,
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cosmetically appealing penis in the male, or patent, functional vagina in the female, and construction of a bladder and urethra that permits voided continence. The ideal management strategy to achieve these goals remains elusive. The most frequently utilized methods to achieve these goals are the SRP and CPRE. While the SRP has been developed with the intentional utilization of 2 – 3 procedures in a series of stages to accomplish complete reconstruction, the CPRE was developed as a single “complete” reconstructive procedure to achieve all of the goals of reconstruction in a single operation. Most importantly, it was felt that closure of the bladder in conjunction with epispadias reconstruction, led to more normal cycling of the bladder permitting bladder growth and increasing potential for voided continence without the necessity for formal bladder neck reconstruction. As significant experience has been gained with the use of CPRE, a systematic review was conducted to determine how well the procedure was able to achieve the stated goals for successful reconstruction. Reports from high volume centers, using CPRE as the primary treatment modality were evaluated. We excluded reports of patients that focused on patients undergoing reoperative procedures for failure following prior reconstruction and also did not include any reports based on reoperative cases performed at a secondary institution. The final cohort of 236 children with BE treated with CPRE between 1989 and 2016 were based on the reports of patient data from 10 major centers. As shown in the results, the majority of patients being treated using the CPRE, required multiple procedures to achieve the stated goals for successful reconstruction. This reflects the experience in patients undergoing a staged reconstruction. Boys having CPRE that included complete
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penile disassembly were usually left with a secondary hypospadias - 22.7-68% [10, 11, 23, and 24] - that required surgical reconstruction in another procedure. Ureteral reimplantation to reduce recurrent urinary tract infections, or for preservation of the upper tracts, was performed as a separate procedure in 48-66% [11, 25–27] of the patients. The majority of patients that had CPRE, also needed BNR to achieve continence. This also reflects the outcomes previously reported - 63-86% [11, 12, and 28] in children undergoing reconstruction using a staged approach. In a 2005 literature review [29], 15-90% of patients required BNR to gain urinary continence, with 5-10% requiring both a bladder augmentation and BNR [17, 23, 25, 30, 31]. Shoukry et al. had to perform bladder augmentation in all of the children that underwent CPRE to achieve continence [21]. Borer et al performed a review of 47 patients who underwent CPRE after assessment with ultrasound, voiding cystourethrogram, and urodynamics, finding that bladder neck reconstruction was needed in 9 of 22 males (41%) and 3 of 11 females (27%). The authors concluded that further bladder neck procedures were frequently required [32], with 65-70% of children undergoing CPRE ultimately requiring a bladder neck outlet procedure [28]. This experience with CPRE is similar to staged reconstructive procedures, where 14% of children [33], usually girls, are continent without the need for a formal continence procedure. Many centers have reported making modifications to the CPRE procedure as initially described by Grade and Mitchell [25]. Most centers have stopped complete disassembly of the penis, due to concerns for corporal and glans ischemia and loss. Additionally, some centers have reported using a bladder neck tightening procedure to enhance voided continence, without formal BNR. The long term outcomes of these changes
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remain to be determined. Our systematic review of the literature to date, indicates that CPRE does not decrease the numbers of procedures needed to complete reconstruction in exstrophy. This literature review substantiates previous observations that the CPRE and SRP use different techniques with nearly the same number of procedures. Ebert et al. reported that the mean number of procedures for patients after SRP was 2.95 (range 1-8) with only 13.6% requiring more than 4 procedures; these data were self-reported however, and did not differentiate between major and minor cases [34]. Stjernqvist and Kockum reported a median of 12 procedures after SRP [35]. In comparison, Gargollo et al. described a total of 193 procedures in 32 patients that underwent CPRE (mean 4+/-5.8, range 1-31) with the majority of the surgeries being minor and endoscopic[36]. There are significant limitations to any systematic review of published data; ours is no exception. All of the studies that were utilized to compile the review were retrospective in nature. Not all institutions reported outcomes in all of their patients. Some patients have had CPRE, but continue to remain incontinent and are awaiting further procedures (BNR, augmentation, BNI, etc.). Outcome reports and the definition of success or failure had to be gleaned from the data presented. The definition of voided continence was also not uniform among authors. Despite these limitations, it remains clear that the management of bladder exstrophy remains a significant surgical challenge, typically requiring multiple procedures to achieve successful reconstruction. CONCLUSION: Historically, BE has been managed with the SRP and expectation that such a large undertaking will take multiple procedures to complete reconstruction and achieve
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continence in this difficult and complex patient population. CPRE was introduced in 1989 and has been suggested as a single procedure for the management of BE. However, literature review suggests the majority of patients require multiple procedures to complete reconstruction and attain continence. Parents and patients should be made aware of the variability of the exstrophy epispadias complex and the possible multiple procedures that are going to be required for completion of reconstruction.
Acknowledgments: None.
Ethical Approval: No animals were used in this study.
Funding Source: None.
Conflict of Interest Statement: None.
References:
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Author responses
Thank you for the thoughtful review of our article, submitted for possible inclusion in the Journal of Pediatric Urology. The article has been revised extensively to reflect some of the concerns raised by the reviewers. Attached are our responses to the concerns that were raised. Reviewer 1 1. All of the studies that were included were retrospective in nature and were taken from the literature. Since most cohorts of patients with exstrophy at individual institutions remains small, there really is very little potential for a truly randomized or prospective study to be performed. 2. Only patients with bladder exstrophy were included in this review. 3. Recent reports from the MIBEC (Multi-institutional Consortium for Exstrophy) have suggested that changes are being made to the procedure over time. Since the purpose of this review was not to determine how the procedure is being modified, but rather to highlight the fact that the complexity of Bladder exstrophy typically requires multiple procedures for reconstruction, we have only peripherally mentioned these changes (Para 2, pg 10) 4. Since this was a review of the experience of the 10 largest reported series, the age ranges were varied. Also there has been an evolution for the timing of reconstruction. In the past, exstrophy reconstruction was done semi-emergently, within a 72 hour window, to reduce the need for osteotomy. More recently, the trend has been to do surgical repair beyond the 72 hour time line, at the surgeon’s
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discretion. Trying to determine a mean and median for this data set would skew to those sites that had a larger cohort and did not seem appropriate for a systematic review. 5. Since this is a review of published work from multiple institutions, no specific definition of continence could be identified. While most pediatric urologists consider a 3 hour dry interval during the day and nighttime dryness as continence, this was not explicitly stated in any of the reports and therefore was not included in this study. 6. Although some studies did separate their cohorts, male and female continence rates were not separated, and only overall continence was reported. In patients undergoing MSRE, patients that were dry following only initial closure, were typically female. 7. Since the data for continence was not consistently reported, and some centers performed augmentation on children at the time of initial closure and other combining bladder neck procedures with augment, it is hard to put this into a coherent single table. 8. The results section has been completely reworded to address the concerns raised. Since not all patients had completed reconstruction, and also not all patients had complete data reported. 9. We have added a paragraph to describe the limitations of the study. The authors would welcome a critical comment, so that we can continue the conversation in how to achieve the best surgical outcomes for our patients. Reviewer 2:
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We have further modified the Discussion, try to focus on the reason for the systematic review. This was not done to promote one method of reconstruction over another, but to rather try to determine some of the misconceptions associated with terms that are used to define our surgical approaches. Our goal is to bring into focus the fact that many parents, when confronted with a major birth defect, may be lulled into believing that a single stage reconstruction implies only need for a single operation.
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