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Effect of Failed Initial Closure on Bladder Growth in Children With Bladder Exstrophy
Effect of Failed Initial Closure on Bladder Growth in Children With Bladder Exstrophy Nima Baradaran, Raimondo M. Cervellione, Ryan Orosco, Bruce J. Trock, Ranjiv I. Mathews and John P. Gearhart* From the Division of Pediatric Urology, Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland
Abbreviations and Acronyms BC ⫽ bladder capacity BNR ⫽ bladder neck reconstruction EM ⫽ electron microscopy Submitted for publication February 9, 2011. Study received institutional review board approval. * Correspondence: The Johns Hopkins Hospital, Marburg 146, 600 N. Wolfe St., Baltimore, Maryland 21287 (telephone: 410-955-5358; FAX: 410-955-0833; e-mail: [email protected]).
Purpose: Failed initial bladder exstrophy closure may hinder the natural course of bladder growth compared to successful primary reconstruction. By measuring successive bladder capacities within the first 5 years of life, we compared the rate of bladder growth in children with failed vs successful initial closure. Materials and Methods: We used an approved bladder exstrophy database to identify and review retrospectively patients with classic bladder exstrophy who underwent repeat cystograms between ages 1 and 6 years. Two groups of patients were identified—those with successful neonatal closure (group 1) and those with successful reclosure after an initial failed procedure (group 2). A generalized linear mixed model was fit to evaluate the impact of treatment group and age on bladder growth. Results: We identified 48 patients in group 1 (75% male) and 62 in group 2 (71% male). Initial pelvic osteotomy was done in 60% of group 1 and 34% of group 2. Patients in group 1 had significantly larger cystographic capacity at 2, 4, 5 and 6 years after successful bladder closure compared to those in group 2 (p ⬍0.05). The bladder tended to grow at a significantly slower rate in group 2 (9.38 cc yearly) compared to group 1 (14.76 cc yearly, p ⫽ 0.005). Conclusions: Patients with initial failed bladder exstrophy closure showed significantly smaller cystographic capacities and slower bladder growth compared to those who underwent successful neonatal bladder closure. These data clearly underscore the importance of a secure, successful primary closure. Key Words: bladder exstrophy, postoperative complications, treatment failure, urologic surgical procedures
1450
www.jurology.com
PRIMARY bladder closure accompanied by posterior urethral, pelvic bone and abdominal wall repairs is the first step in the modern staged repair of bladder exstrophy. Should this repair fail, additional surgeries may be required, which can severely jeopardize bladder growth and ultimate clinical outcome. It has been demonstrated that children undergoing bladder reclosure after failed initial repair are less likely to achieve urinary continence compared to those with a suc-
cessful primary closure after bladder neck reconstruction.1 Oesterling and Jeffs observed that initial closure failure significantly compromises the ability of the bladder to grow.2 Regardless of the type of repair (complete primary repair, Kelly, modern staged repair), the importance of successful early bladder closure to achieve adequate bladder capacity and subsequent continence is indisputable. However, objective comparison of bladder capacity in children with failed initial
0022-5347/11/1864-1450/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 1450-1454, October 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.05.067
AND
RESEARCH, INC.
BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
closure and those with a successful primary closure is lacking in the literature. We longitudinally investigated bladder volumes in patients with failed initial closure and compared those results to patients with successful primary closure during the first 6 years of life before a continence procedure.
MATERIALS AND METHODS With institutional review board approval we retrospectively reviewed medical records of patients with classic bladder exstrophy born between 1980 and 2004 who underwent either primary closure during the neonatal period (group 1) or reclosure due to failed initial closure (group 2). Failed closure was defined as dehiscence, bladder prolapse or severe stricture requiring reclosure. An institutionally approved exstrophy database was used to identify patients who underwent cystographic BC measurements during the first 6 years of life. The retrieved information was gender, age at initial closure, location of initial closure, use of osteotomy, cystographic BC with corresponding age at measurement during the first 6 years of life and continence procedures performed during that period. Bladder measurements performed before successful closure (only group 2) and after continence procedures (bulking agents, augmentation or BNR) were excluded. Gravity cystogram was performed with the patient under anesthesia by instillation of normal saline into the bladder using a catheter at 30 cm above the symphysis while the bladder outlet was occluded by an overinflated catheter balloon to prevent leakage. Expected BC was calculated using Koff’s formula (age ⫹2) ⫻ 30.3 Descriptive statistics were compared between the 2 groups using the Mann-Whitney and chi-square tests for continuous and categorical measurements, respectively. A generalized linear mixed model was used to evaluate and compare the impact of treatment group and age on BC.4 This procedure allows the model to be estimated even if BC measurements at different ages do not have a multivariate normal distribution. The Bayesian information criterion was used to compare models that assumed fixed vs random effects. The latter assumes that the initial post-closure BC and growth rate are not fixed, but can vary randomly from person to person.
Table 1. Demographic and clinical characteristics of patients with successful and failed primary closure Group 1 No. male (%) Mean days age at initial closure (range) Mean days age at successful closure (range) Mean yrs age at epispadias repair in males (range) No. osteotomy at initial closure (%) No. BNR (%) No. augmentation (%)
Group 2
p Value
36 3
(75) (0–12)
44 5
(71) (0–23)
3
(0–12)
408
(5–2,380)
1.65 (0.6–4)
2.41
0.64 0.45 ⬍0.0001
(0.5–6)
0.01
29
(60)
21
(34)
0.01
18 7
(39) (15)
18 17
(29) (27)
0.34 0.12
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Table 2. Bladder capacity by age in first 6 years of life Group 1 Median cc BC by age (range): 1 2 3 4 5 6 Median age at BC measurement (range): 1 2 3 4 5 6 Median No. BC measurements (range)
51 82 82 90 100 127
(17–125) (30–240) (10–200) (31–250) (37–297) (67–288)
1.07 (0.41–1.53) 2.03 (1.63–2.86) 3.07 (2.20–3.57) 4.05 (3.51–4.78) 5.08 (4.58–5.88) 6.10 (5.52–6.51) 4 (1–8)
Group 2
30 47.5 67 70 75 85.5
p Value
(10–85) (10–100) (20–180) (17–145) (18–185) (28–170)
0.11 0.003 0.18 0.007 0.007 0.005
1.43 (0.63–1.48) 2.17 (1.56–2.59) 3.03 (2.64–3.49) 4.12 (3.40–4.97) 5.12 (4.19–5.82) 5.83 (5.48–6.87) 3 (1–7)
0.15 0.39 0.46 0.54 0.91 0.43 0.002
All analyses were performed in SAS®, version 9.2, and regression plots were graphed using Prism®, version 5. A p value of 0.05 was considered statistically significant.
RESULTS Patient characteristics are depicted in table 1. A total of 110 patients were identified, of whom 48 (36 males, 12 females) underwent successful closure neonatally (group 1) and 62 (44 males, 18 females) underwent reoperation due to failed initial closure (group 2). Median ages for successful closure were 3 and 13 months for groups 1 and 2, respectively. During initial closure pelvic osteotomy was performed in 29 children (60%) in group 1 and 21 (34%) in group 2 (p ⫽ 0.01). Children in group 1 underwent epispadias repair earlier (1.6 years) than those in group 2 (2.4 years, p ⫽ 0.01). In the reclosure group all but 1 patient underwent initial closure elsewhere in the United States or Canada before presenting to our institution. Annual cystographic BC and corresponding ages are presented in table 2. Children in group 2 underwent repeat closure at a later time, and, therefore, the number of bladder measurements at each age point are inherently different between the 2 groups. There were more data available in group 1 at earlier ages, and this trend reversed at age 6. The final model considers this difference. Patients with successful primary closure had a larger BC at all measurements, and the difference was statistically significant at years 2, 4, 5 and 6 following successful closure (table 2). Appropriate BC of approximately 100 cc for BNR was eventually reached by 39% of children in group 1 and 29% in group 2. Bladder augmentation was required to achieve continence in 15% of children in group 1 and
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BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
27% in group 2. Indication for bladder augmentation was small BC despite desire of patient to be dry. The remainder of the patients are awaiting a continence procedure. Epispadias repair in boys in group 2 was performed at a significantly older age (2.4 years) compared to boys in group 1 (1.6 years, p ⫽ 0.01). There were no significant differences in outcomes after patients were stratified by type of initial failure. A generalized linear mixed model was used to compare the rate of bladder growth between the 2 groups (see figure). Children in both groups had significant increases in BC during the study period. The annual rate of bladder growth was significantly higher in group 1 than in group 2 (14.76 vs 9.38 cc yearly, p ⫽ 0.005). When these rates were compared to expected bladder growth rate for age (30 cc yearly5), both revealed overall smaller bladders and a significant impairment in bladder growth. Other factors (gender, pelvic osteotomy) did not significantly influence bladder growth rate (data not shown).
DISCUSSION The results confirm that bladder growth is compromised in response to failed closure in children treated for bladder exstrophy during the first years of life. This age span has been demonstrated to be the most influential period regarding bladder growth in children.6 According to our data, children whose initial closure fails have smaller bladder capacities at every time point, their bladders grow at a slower pace and they are less likely to be eligible for BNR. The difference in BC between the 2 groups
Predicted bladder growth for successful neonatal closure vs reoperation after failed initial closure during first 6 years of life. Model includes interaction of age times closure group. All measurements are after successful closure.
does not seem to resolve in subsequent years, and these children are more likely to require bladder augmentation to achieve continence. Bladder growth failure significantly jeopardizes the functional urological outcome and long-term urinary continence prognosis of children. Surer et al found that patients who achieve sufficient BC after successful primary closure and epispadias repair are more likely to benefit from BNR, are less likely to require bladder augmentation, and ultimately have improved compliance and continence status.7 In a study of 131 patients with exstrophy undergoing successful initial closure Baird et al concluded that patients with a mean bladder capacity of 85 cc had better urological outcomes after BNR.8 Moreover, Novak et al observed that the BNR success rate in children with at least 1 failed closure attempt decreased by about 50% compared to children with successful initial closures,1 and our results support this claim. In addition, successful initial closure enables patients to continue on the reconstructive pathway earlier in life, which may lead to improved bladder growth and continence potential. We observed a significant association between pelvic osteotomy and initial closure success, which is in line with previous data from our institution.9 This finding emphasizes the role of osteotomy to achieve proper bladder closure when applicable. Number of failed closures has also been associated with suboptimal growth and undesirable outcome. Gearhart et al studied 23 patients with multiple previous failures (complete dehiscence or severe prolapse) and found that 60% of those with more than 2 previous failures did not achieve adequate capacity for BNR, and only 20% ultimately became dry.10 They concluded that after 2 closures the ability of the bladder to reach sufficient capacity to allow continence after BNR is markedly reduced, and after 3 closures most patients will require bladder neck closure, augmentation and/or continent diversion. Novak et al also reported continence outcomes in 122 patients with exstrophy with 1 or more failed primary closures.1 They found that continence was significantly compromised in these children and further declined with increasing number of failed closures. Our results provide further evidence of the importance of successful initial closure for subsequent bladder growth. Children with successful primary closure had significantly larger bladders during the first years of life, the bladders tended to grow at a greater rate and the children were more likely to undergo BNR instead of bladder augmentation to achieve continence. Each failed closure subjects the bladder and surrounding tissues to several environmental irritations. Tissue fibrosis and inflammatory response following each surgery could also be postulated in
BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
this regard. An intrinsic predisposition of the bladder to growth retardation in the exstrophy population has also been hypothesized by several investigators. Histological comparison between exstrophy and normal bladder structures shows that exstrophic bladders have lower myelinated nerve fibers and have worse extracellular matrix parameters, including increased collagen, decreased muscle-to-collagen ratio and lower expression of developmental genes.11,12 Mathews at al compared bladder ultrastructure and subsequent growth rate among 4 groups of patients with exstrophy at different levels of reconstruction.13 In the group with failed closure all bladder samples evaluated by EM demonstrated degenerating or poorly arranged smooth muscle, absence of intracellular organelles and caveolae, large amounts of collagen and poor nerve profiles. We previously reported decreased bladder growth rate in patients with failed vs successful closure (average 15 vs 24 cc yearly),9 which is in line with our current results and is further substantiated with a larger sample size. In the aforementioned study the observed decrease was well correlated with poor EM parameters in reclosure cases, while in children with successful primary closure and good bladder growth EM parameters closely approximated those of normal bladders. While the initial EM appearance of the bladder is not always indicative of bladder growth and development of continence, failure of the initial closure remains a strong factor in growth and ultrastructural outcome of bladder exstrophy reconstruction. After successful reclosure the bladder may indeed grow to a size suitable for BNR. However, ultrastructural damage to the bladder muscle and organelles in failed primary closure may preclude the bladder from coordinated filling and emptying after BNR, 2 factors thought to have a significant role in bladder growth. Repair of failed bladder closure is also reportedly more costly, requires more complex surgical procedures and is associated with longer hospital
1453
stay.14 Rare and resource intensive conditions such as bladder exstrophy are best managed at regionalized centers of excellence at lower cost and with better clinical outcomes.14,15 In a study of surgical outcome after failed exstrophy closure Meldrum et al observed that exstrophy reclosure success rates and long-term continence outcomes are significantly higher among subspecialty trained surgeons.16 Therefore, to minimize the potentially devastating consequences of closure failure, initial bladder closure should be performed by experienced surgeons using a multidisciplinary treatment approach. Lastly defining and promoting the factors that contribute to enhanced bladder growth are important goals in prospective exstrophy research. Bladder exstrophy is a rare condition, and most of the research involves retrospective analyses and inferences. This is a known limitation to the majority of research in this field. We were also limited by the difference in age at epispadias repair between the groups. Epispadias repair increases outlet resistance and can potentially induce bladder growth.17 We included epispadias repair age in the final model with no additional predictive benefit.
CONCLUSIONS If initial bladder exstrophy closure fails, bladder growth is considerably compromised, and even after successful reclosure the rate of bladder growth is less than in patients with successful initial closure. Children who undergo reclosure of bladder exstrophy are less likely to have a bladder large enough for BNR, and require bladder augmentation. Therefore, regardless of the method of reconstruction, every attempt should be made to achieve a successful primary closure to offer these children the best chance of future urinary continence.
ACKNOWLEDGMENTS Dr. John Costello contributed to data gathering.
REFERENCES 1. Novak TE, Costello JP, Orosco J et al: Failed exstrophy closure: management and outcome. J Pediatr Urol 2010; 6: 381.
4. Breslow NE and Clayton DG: Approximate inference in generalized linear mixed models. J Am Stat Assoc 1993; 88: 9.
raphy in children: relationship to toilet training and frequency of micturition. Radiology 1993; 187: 803.
2. Oesterling JE and Jeffs RD: The importance of a successful initial bladder closure in the surgical management of classical bladder exstrophy: analysis of 144 patients treated at The Johns Hopkins Hospital between 1975 and 1985. J Urol 1987; 137: 258.
5. Nevéus T, von Gontard A, Hoebeke P et al: The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children’s Continence Society. J Urol 2006; 176: 314.
7. Surer I, Baker LA, Jeffs RD et al: Modified YoungDees-Leadbetter bladder neck reconstruction in patients with successful primary bladder closure elsewhere: a single institution experience. J Urol 2001; 165: 2438.
3. Koff SA: Estimating bladder capacity in children. Urology 1983; 21: 248.
6. Zerin JM, Chen E, Ritchey ML et al: Bladder capacity as measured at voiding cystourethrog-
8. Baird AD, Nelson CP and Gearhart JP: Modern staged repair of bladder exstrophy: a contemporary series. J Pediatr Urol 2007; 3: 311.
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BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
9. Meldrum KK, Baird AD and Gearhart JP: Pelvic and extremity immobilization after bladder exstrophy closure: complications and impact on success. Urology 2003; 62: 1109. 10. Gearhart JP, Ben-Chaim J, Sciortino C et al: The multiple reoperative bladder exstrophy closure: what affects the potential of the bladder? Urology 1996; 47: 240. 11. Mathews R, Wills M, Perlman E et al: Neural innervation of the newborn exstrophic bladder: an immunohistochemical study. J Urol 1999; 162: 506.
12. Hipp J, Andersson KE, Kwon TG et al: Microarray analysis of exstrophic human bladder smooth muscle. BJU Int 2008; 101: 100. 13. Mathews R, Gosling JA and Gearhart JP: Ultrastructure of the bladder in classic exstrophy: correlation with development of continence. J Urol 2004; 172: 1446. 14. Nelson CP, Dunn RL, Wei JT et al: Surgical repair of bladder exstrophy in the modern era: contemporary practice patterns and the role of hospital case volume. J Urol 2005; 174: 1099.
15. Nelson CP, North AC, Ward MK et al: Economic impact of failed or delayed primary repair of bladder exstrophy: differences in cost of hospitalization. J Urol 2008; 179: 680. 16. Meldrum KK, Mathews RI, Nelson CP et al: Subspecialty training and surgical outcomes in children with failed bladder exstrophy closure. J Pediatr Urol 2005; 1: 95. 17. Kufner M, Gearhart JP and Mathews R: Impact of epispadias repair on bladder growth in boys with classic bladder exstrophy. J Pediatr Urol 2010; 6: 578.
Abbreviations and Acronyms BC ⫽ bladder capacity BNR ⫽ bladder neck reconstruction EM ⫽ electron microscopy Submitted for publication February 9, 2011. Study received institutional review board approval. * Correspondence: The Johns Hopkins Hospital, Marburg 146, 600 N. Wolfe St., Baltimore, Maryland 21287 (telephone: 410-955-5358; FAX: 410-955-0833; e-mail: [email protected]).
Purpose: Failed initial bladder exstrophy closure may hinder the natural course of bladder growth compared to successful primary reconstruction. By measuring successive bladder capacities within the first 5 years of life, we compared the rate of bladder growth in children with failed vs successful initial closure. Materials and Methods: We used an approved bladder exstrophy database to identify and review retrospectively patients with classic bladder exstrophy who underwent repeat cystograms between ages 1 and 6 years. Two groups of patients were identified—those with successful neonatal closure (group 1) and those with successful reclosure after an initial failed procedure (group 2). A generalized linear mixed model was fit to evaluate the impact of treatment group and age on bladder growth. Results: We identified 48 patients in group 1 (75% male) and 62 in group 2 (71% male). Initial pelvic osteotomy was done in 60% of group 1 and 34% of group 2. Patients in group 1 had significantly larger cystographic capacity at 2, 4, 5 and 6 years after successful bladder closure compared to those in group 2 (p ⬍0.05). The bladder tended to grow at a significantly slower rate in group 2 (9.38 cc yearly) compared to group 1 (14.76 cc yearly, p ⫽ 0.005). Conclusions: Patients with initial failed bladder exstrophy closure showed significantly smaller cystographic capacities and slower bladder growth compared to those who underwent successful neonatal bladder closure. These data clearly underscore the importance of a secure, successful primary closure. Key Words: bladder exstrophy, postoperative complications, treatment failure, urologic surgical procedures
1450
www.jurology.com
PRIMARY bladder closure accompanied by posterior urethral, pelvic bone and abdominal wall repairs is the first step in the modern staged repair of bladder exstrophy. Should this repair fail, additional surgeries may be required, which can severely jeopardize bladder growth and ultimate clinical outcome. It has been demonstrated that children undergoing bladder reclosure after failed initial repair are less likely to achieve urinary continence compared to those with a suc-
cessful primary closure after bladder neck reconstruction.1 Oesterling and Jeffs observed that initial closure failure significantly compromises the ability of the bladder to grow.2 Regardless of the type of repair (complete primary repair, Kelly, modern staged repair), the importance of successful early bladder closure to achieve adequate bladder capacity and subsequent continence is indisputable. However, objective comparison of bladder capacity in children with failed initial
0022-5347/11/1864-1450/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 1450-1454, October 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.05.067
AND
RESEARCH, INC.
BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
closure and those with a successful primary closure is lacking in the literature. We longitudinally investigated bladder volumes in patients with failed initial closure and compared those results to patients with successful primary closure during the first 6 years of life before a continence procedure.
MATERIALS AND METHODS With institutional review board approval we retrospectively reviewed medical records of patients with classic bladder exstrophy born between 1980 and 2004 who underwent either primary closure during the neonatal period (group 1) or reclosure due to failed initial closure (group 2). Failed closure was defined as dehiscence, bladder prolapse or severe stricture requiring reclosure. An institutionally approved exstrophy database was used to identify patients who underwent cystographic BC measurements during the first 6 years of life. The retrieved information was gender, age at initial closure, location of initial closure, use of osteotomy, cystographic BC with corresponding age at measurement during the first 6 years of life and continence procedures performed during that period. Bladder measurements performed before successful closure (only group 2) and after continence procedures (bulking agents, augmentation or BNR) were excluded. Gravity cystogram was performed with the patient under anesthesia by instillation of normal saline into the bladder using a catheter at 30 cm above the symphysis while the bladder outlet was occluded by an overinflated catheter balloon to prevent leakage. Expected BC was calculated using Koff’s formula (age ⫹2) ⫻ 30.3 Descriptive statistics were compared between the 2 groups using the Mann-Whitney and chi-square tests for continuous and categorical measurements, respectively. A generalized linear mixed model was used to evaluate and compare the impact of treatment group and age on BC.4 This procedure allows the model to be estimated even if BC measurements at different ages do not have a multivariate normal distribution. The Bayesian information criterion was used to compare models that assumed fixed vs random effects. The latter assumes that the initial post-closure BC and growth rate are not fixed, but can vary randomly from person to person.
Table 1. Demographic and clinical characteristics of patients with successful and failed primary closure Group 1 No. male (%) Mean days age at initial closure (range) Mean days age at successful closure (range) Mean yrs age at epispadias repair in males (range) No. osteotomy at initial closure (%) No. BNR (%) No. augmentation (%)
Group 2
p Value
36 3
(75) (0–12)
44 5
(71) (0–23)
3
(0–12)
408
(5–2,380)
1.65 (0.6–4)
2.41
0.64 0.45 ⬍0.0001
(0.5–6)
0.01
29
(60)
21
(34)
0.01
18 7
(39) (15)
18 17
(29) (27)
0.34 0.12
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Table 2. Bladder capacity by age in first 6 years of life Group 1 Median cc BC by age (range): 1 2 3 4 5 6 Median age at BC measurement (range): 1 2 3 4 5 6 Median No. BC measurements (range)
51 82 82 90 100 127
(17–125) (30–240) (10–200) (31–250) (37–297) (67–288)
1.07 (0.41–1.53) 2.03 (1.63–2.86) 3.07 (2.20–3.57) 4.05 (3.51–4.78) 5.08 (4.58–5.88) 6.10 (5.52–6.51) 4 (1–8)
Group 2
30 47.5 67 70 75 85.5
p Value
(10–85) (10–100) (20–180) (17–145) (18–185) (28–170)
0.11 0.003 0.18 0.007 0.007 0.005
1.43 (0.63–1.48) 2.17 (1.56–2.59) 3.03 (2.64–3.49) 4.12 (3.40–4.97) 5.12 (4.19–5.82) 5.83 (5.48–6.87) 3 (1–7)
0.15 0.39 0.46 0.54 0.91 0.43 0.002
All analyses were performed in SAS®, version 9.2, and regression plots were graphed using Prism®, version 5. A p value of 0.05 was considered statistically significant.
RESULTS Patient characteristics are depicted in table 1. A total of 110 patients were identified, of whom 48 (36 males, 12 females) underwent successful closure neonatally (group 1) and 62 (44 males, 18 females) underwent reoperation due to failed initial closure (group 2). Median ages for successful closure were 3 and 13 months for groups 1 and 2, respectively. During initial closure pelvic osteotomy was performed in 29 children (60%) in group 1 and 21 (34%) in group 2 (p ⫽ 0.01). Children in group 1 underwent epispadias repair earlier (1.6 years) than those in group 2 (2.4 years, p ⫽ 0.01). In the reclosure group all but 1 patient underwent initial closure elsewhere in the United States or Canada before presenting to our institution. Annual cystographic BC and corresponding ages are presented in table 2. Children in group 2 underwent repeat closure at a later time, and, therefore, the number of bladder measurements at each age point are inherently different between the 2 groups. There were more data available in group 1 at earlier ages, and this trend reversed at age 6. The final model considers this difference. Patients with successful primary closure had a larger BC at all measurements, and the difference was statistically significant at years 2, 4, 5 and 6 following successful closure (table 2). Appropriate BC of approximately 100 cc for BNR was eventually reached by 39% of children in group 1 and 29% in group 2. Bladder augmentation was required to achieve continence in 15% of children in group 1 and
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BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
27% in group 2. Indication for bladder augmentation was small BC despite desire of patient to be dry. The remainder of the patients are awaiting a continence procedure. Epispadias repair in boys in group 2 was performed at a significantly older age (2.4 years) compared to boys in group 1 (1.6 years, p ⫽ 0.01). There were no significant differences in outcomes after patients were stratified by type of initial failure. A generalized linear mixed model was used to compare the rate of bladder growth between the 2 groups (see figure). Children in both groups had significant increases in BC during the study period. The annual rate of bladder growth was significantly higher in group 1 than in group 2 (14.76 vs 9.38 cc yearly, p ⫽ 0.005). When these rates were compared to expected bladder growth rate for age (30 cc yearly5), both revealed overall smaller bladders and a significant impairment in bladder growth. Other factors (gender, pelvic osteotomy) did not significantly influence bladder growth rate (data not shown).
DISCUSSION The results confirm that bladder growth is compromised in response to failed closure in children treated for bladder exstrophy during the first years of life. This age span has been demonstrated to be the most influential period regarding bladder growth in children.6 According to our data, children whose initial closure fails have smaller bladder capacities at every time point, their bladders grow at a slower pace and they are less likely to be eligible for BNR. The difference in BC between the 2 groups
Predicted bladder growth for successful neonatal closure vs reoperation after failed initial closure during first 6 years of life. Model includes interaction of age times closure group. All measurements are after successful closure.
does not seem to resolve in subsequent years, and these children are more likely to require bladder augmentation to achieve continence. Bladder growth failure significantly jeopardizes the functional urological outcome and long-term urinary continence prognosis of children. Surer et al found that patients who achieve sufficient BC after successful primary closure and epispadias repair are more likely to benefit from BNR, are less likely to require bladder augmentation, and ultimately have improved compliance and continence status.7 In a study of 131 patients with exstrophy undergoing successful initial closure Baird et al concluded that patients with a mean bladder capacity of 85 cc had better urological outcomes after BNR.8 Moreover, Novak et al observed that the BNR success rate in children with at least 1 failed closure attempt decreased by about 50% compared to children with successful initial closures,1 and our results support this claim. In addition, successful initial closure enables patients to continue on the reconstructive pathway earlier in life, which may lead to improved bladder growth and continence potential. We observed a significant association between pelvic osteotomy and initial closure success, which is in line with previous data from our institution.9 This finding emphasizes the role of osteotomy to achieve proper bladder closure when applicable. Number of failed closures has also been associated with suboptimal growth and undesirable outcome. Gearhart et al studied 23 patients with multiple previous failures (complete dehiscence or severe prolapse) and found that 60% of those with more than 2 previous failures did not achieve adequate capacity for BNR, and only 20% ultimately became dry.10 They concluded that after 2 closures the ability of the bladder to reach sufficient capacity to allow continence after BNR is markedly reduced, and after 3 closures most patients will require bladder neck closure, augmentation and/or continent diversion. Novak et al also reported continence outcomes in 122 patients with exstrophy with 1 or more failed primary closures.1 They found that continence was significantly compromised in these children and further declined with increasing number of failed closures. Our results provide further evidence of the importance of successful initial closure for subsequent bladder growth. Children with successful primary closure had significantly larger bladders during the first years of life, the bladders tended to grow at a greater rate and the children were more likely to undergo BNR instead of bladder augmentation to achieve continence. Each failed closure subjects the bladder and surrounding tissues to several environmental irritations. Tissue fibrosis and inflammatory response following each surgery could also be postulated in
BLADDER GROWTH AFTER FAILED EXSTROPHY CLOSURE
this regard. An intrinsic predisposition of the bladder to growth retardation in the exstrophy population has also been hypothesized by several investigators. Histological comparison between exstrophy and normal bladder structures shows that exstrophic bladders have lower myelinated nerve fibers and have worse extracellular matrix parameters, including increased collagen, decreased muscle-to-collagen ratio and lower expression of developmental genes.11,12 Mathews at al compared bladder ultrastructure and subsequent growth rate among 4 groups of patients with exstrophy at different levels of reconstruction.13 In the group with failed closure all bladder samples evaluated by EM demonstrated degenerating or poorly arranged smooth muscle, absence of intracellular organelles and caveolae, large amounts of collagen and poor nerve profiles. We previously reported decreased bladder growth rate in patients with failed vs successful closure (average 15 vs 24 cc yearly),9 which is in line with our current results and is further substantiated with a larger sample size. In the aforementioned study the observed decrease was well correlated with poor EM parameters in reclosure cases, while in children with successful primary closure and good bladder growth EM parameters closely approximated those of normal bladders. While the initial EM appearance of the bladder is not always indicative of bladder growth and development of continence, failure of the initial closure remains a strong factor in growth and ultrastructural outcome of bladder exstrophy reconstruction. After successful reclosure the bladder may indeed grow to a size suitable for BNR. However, ultrastructural damage to the bladder muscle and organelles in failed primary closure may preclude the bladder from coordinated filling and emptying after BNR, 2 factors thought to have a significant role in bladder growth. Repair of failed bladder closure is also reportedly more costly, requires more complex surgical procedures and is associated with longer hospital
1453
stay.14 Rare and resource intensive conditions such as bladder exstrophy are best managed at regionalized centers of excellence at lower cost and with better clinical outcomes.14,15 In a study of surgical outcome after failed exstrophy closure Meldrum et al observed that exstrophy reclosure success rates and long-term continence outcomes are significantly higher among subspecialty trained surgeons.16 Therefore, to minimize the potentially devastating consequences of closure failure, initial bladder closure should be performed by experienced surgeons using a multidisciplinary treatment approach. Lastly defining and promoting the factors that contribute to enhanced bladder growth are important goals in prospective exstrophy research. Bladder exstrophy is a rare condition, and most of the research involves retrospective analyses and inferences. This is a known limitation to the majority of research in this field. We were also limited by the difference in age at epispadias repair between the groups. Epispadias repair increases outlet resistance and can potentially induce bladder growth.17 We included epispadias repair age in the final model with no additional predictive benefit.
CONCLUSIONS If initial bladder exstrophy closure fails, bladder growth is considerably compromised, and even after successful reclosure the rate of bladder growth is less than in patients with successful initial closure. Children who undergo reclosure of bladder exstrophy are less likely to have a bladder large enough for BNR, and require bladder augmentation. Therefore, regardless of the method of reconstruction, every attempt should be made to achieve a successful primary closure to offer these children the best chance of future urinary continence.
ACKNOWLEDGMENTS Dr. John Costello contributed to data gathering.
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