Accepted Manuscript Initial urological evaluation and management of children with neurogenic bladder due to myelomeningocele C. Sager, C. Burek, J.P. Corbetta, S. Weller, J. Ruiz, R. Perea, E. Lago, Y. Gomez, D. Victor, J.C. Lopez PII:
S1477-5131(17)30044-X
DOI:
10.1016/j.jpurol.2016.12.024
Reference:
JPUROL 2433
To appear in:
Journal of Pediatric Urology
Received Date: 23 July 2016 Accepted Date: 29 December 2016
Please cite this article as: Sager C, Burek C, Corbetta JP, Weller S, Ruiz J, Perea R, Lago E, Gomez Y, Victor D, Lopez JC, Initial urological evaluation and management of children with neurogenic bladder due to myelomeningocele, Journal of Pediatric Urology (2017), doi: 10.1016/j.jpurol.2016.12.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
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Initial urological evaluation and management of children with neurogenic bladder due to myelomeningocele
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C. Sager*, C. Burek, J. P. Corbetta, S. Weller, J. Ruiz, R. Perea, E. Lago, Y. Gomez, D.
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Victor, J. C. Lopez
Urology Department, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires,
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Argentina
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*Corresponding author: Combate de los Pozos 1881 (CP 1245), C.A.B.A. República Argentina. Tel/Fax: (+54-11) 4122-6000.
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E-mail address:
[email protected] (C. Sager)
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60 8 32 21 22 12 18
53,3 35 36,6 20 30
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%
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Patients Mean age (month) Males Symptomatic urinary tract infections Dilatation urinary Vesicoureteral reflux Abnormal scintigraphy-DMSA
n
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Summary Introduction: The proactive management of children with myelomeningocele (MMC) has
urological evaluation and timing implementation of treatments.
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contributed to decreasing their progression to end-stage renal disease, thanks to early
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Objective: To demonstrate that early urological evaluation of the urinary tract in MMC shows functional alterations in most cases, and that it requires medical intervention, even
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when in some cases the complementary imaging studies do not show any abnormalities.
Material and Methods: A retrospective study including 60 patients aged 20 cmH2O, 43.3%; inefficient bladder voiding, 98.3%; indirect dyssynergic patterns, 28.8%. The high-risk videourodynamic findings were observed in 28 cases (46.6%). DMSA was abnormal in 30%. Renal impairment was detected in 6.6% of cases. A total of 66% of cases received oxybutynin.
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Discussion: Almost all the children in this sample population showed urinary dysfunction, and approximately half of them had high-risk videourodynamic findings. Although many
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cases showed reflex urinary contractions, almost the entire sample had inefficient bladder voiding. An important limitation of this work was the lack of simultaneity in obtaining each
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of the requested studies.
Conclusions: In the initial urological evaluation of patients with myelomeningocele,
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almost all the urodynamic studies showed abnormalities and one-third showed abnormal DMSA, which led to therapeutic actions being initiated, although imaging studies were normal in a great number of patients. CIC alone, starting immediately after birth, is not sufficient. To eliminate or decrease upper tract damage, oxybutynin should be started in
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addition.
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Keywords: Myelomeningocele; Videourodynamics; Neurogenic bladder; Children
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Introduction Since the development of proactive management for children with spina bifida [1], the
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progression of kidney failure towards end-stage renal disease has been substantially reduced [2]. When a neonate is diagnosed with myelomeningocele (MMC), it is essential to stabilize the patient and resolve the defect with surgery. Afterwards, assessment of the
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urinary tract is crucial.
Before the urodynamic studies are performed, CIC is initiated in order to measure
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intravesical pressure (generally during the first 2 or 3 months of life) [1,2,3]. High bladder filling pressure and/or overactivity require the use of anticholinergic drugs [1,2,4,5]. If renal/bladder ultrasound reveals ureterohydronephrosis or the urodynamic records show poor compliance, VCUG is required to confirm VUR [6].
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The aim of the present study was to demonstrate that the initial urological evaluation in MMC shows bladder and renal functional alterations in most cases, and requires early medical intervention, even when other complementary imaging studies may
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not show abnormalities in many of the cases.
Material and Methods This was a retrospective study with an algorithm approved by the Myelomeningocele team at the present center. It consisted of the following methods: renal/bladder ultrasound, videourodynamic studies, renal scintigraphy with DMSA and laboratory tests to assess kidney function.
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Among the 175 cases with MMC, the population sample was selected. It consisted of 60 patients aged 40 cmH2O at expected bladder capacity or DLPP >40
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cmH2O; 2) high pressure values in neurogenic detrusor overactivity >65 cmH2O for girls and >80 cmH2O for boys (indirect sign of dyssynergia); and 3) presence of VUR. Non-
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ionic iodinated contrast at 28 °C and drip at a speed 10% and/or hypocapturing area scarring or irregular distribution. During their first days of life, all the patients in the present study received CIC, performed by a specialized and trained nurse, and an overnight indwelling catheter.
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Oral oxybutynin therapy at a dose of 0.25 mg/kg/day was started in patients who showed bladder overactivity and high-pressure bladder. Antibiotic prophylaxis with
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cephalexin at 25 mg/kg/day was indicated until 30 days after CIC training. Signed informed consent was obtained from the legal parents or guardians of the
children for each diagnostic study performed. For the statistical analysis, descriptive statistics in percent were used. The
association between potential predictors and response variable (renal scintigraphy/DMSA and febrile UTI was performed with Logistic Regression Analysis in SAS 9.2 (univariate analysis). The results were reported in odds ratio (OR) and 95% confidence intervals (CI).
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Results The mean age of patients at the time the videourodynamic studies were performed was 8.2
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months (range 2–12). The evaluation was performed at 6 months after birth in 13 cases; at 4 months in nine cases, and at 2 months in four cases. The other patients were evaluated beyond 6 months of age. In the present study, 32 patients (53.3%) were male. All cases had
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an open myelomeningocele defect that was closed within: the first 24 hours of life in 70% of cases; 24–48 hours of life in 15% of cases; 48–72 hours in 6%; 72–96 hours in 5%; and
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4–7 days in 4%. Even though the children in the present study presented with Chiari malformation, 12% of them required Chiari surgery and 73% needed drainage in the form of a ventriculo-peritoneal shunt due to hydrocephalus.
A total of 35% of children (10 male and 11 female) presented febrile UTI within the
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first year of life.
Dilation of the upper urinary tract was detected in 22 patients (36.6%); ectasia in 18 cases (30%), five of which were bilateral. The other four cases (4.4%) presented
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hydronephrosis. Ureteral dilation was observed in five (out of 60) children, four of which were associated with ectasia and hydronephrosis. Bladder wall thickening was observed in
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two patients.
The urodynamic findings are described in Table 1: 55% presented overactivity and
the detrusor contractions (DO) reached pressure values of an average 46 cmH2O (range 19–111). Urine leaks occurred in six (18%) of them. In nine patients, detrusor overactivity was observed as terminal overactivity: the only ineffective reflex contraction at reduced cystometric capacity. Inefficient bladder emptying was present in 59 cases (98.3%). One patient presented effective detrusor contraction with adequate voiding pressure.
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As evidenced in the urodynamic records, most patients had a compromised voiding phase and they shared one or more pathological urodynamic variables. The high-risk videourodynamic findings were observed in 28 cases (46.6%). Videourodynamic studies
III, four cases were Grade IV, and one case was Grade V.
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showed 12 cases (20%) with VUR and three of them were bilateral; seven cases with Grade
The renal scintigraphy/DMSA scans were performed at an average age of 9 months
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(range 6–12). Renal scintigraphy/DMSA was abnormal in 18 cases (30%). Of them, 14 presented high-risk videourodynamic results (77.7%). Even though there was a tendency
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for higher percentages of urodynamic alterations, VUR and UTI in patients with abnormal DMSA, only the variable Pdet >20 cmH2O at expected cystometric capacity was statistically significant in the univariate analysis (Pr > Chi-squared: 0.0436) (Table 2). In the case of nine patients with abnormal renal scintigraphy/DMSA, there was no urinary
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infection.
This study compared the subgroup of children with urinary infection with the subgroup without urinary infection in relation to variables such as: abnormal urodynamic
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parameters, presence and grades of VUR and hydronephrosis, and abnormal scintigraphy. Although higher percentages existed of abnormalities in all the variables in the subgroup
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with urinary infections, none of them showed statistical significance (Table 3). Abnormal global renal function or renal disease was detected in four cases (6.6%).
Of them, two patients presented high reflex contraction pressures and one case had Grade V VUR. In 66% of the cases, it was necessary to start oral oxybutynin therapy. Adherence to therapy was adequate in all patients and parents. There was no record of unwanted or side effects.
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Discussion Renal/bladder ultrasound is generally performed as soon as possible after closure of the
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spinal cord defect [9]. Around 15% of newborns present with abnormal urinary images when they are evaluated for the first time [10]. In the present study, pyelocaliceal dilation was observed in almost 36% of patients.
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During the first months of life, urodynamic records show that 63% of infants present with reflex bladder contractions, and approximately 50% show detrusor
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overactivity [11]. Overactivity due to disturbance of the nervous system is called neuropathic or neurogenic detrusor overactivity [7].
In order to predict the potential urodynamic risk, the most representative variable is the relationship between pressures >20 cmH2O at age-related capacity [12]; however, some
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authors have established the cut-off point at 30 cmH2O [13]. In the present study, 13% of participants showed pressures >20 cmH2O at expected or age-related capacity. However, >40% of infants showed >20 cmH2O at the end of the filling phase. Almost 30% had high
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pressure levels on reflex contraction, which indirectly suggested possible detrusor-sphincter dyssynergia, which is one of the findings of urinary tract deterioration [10,14,15]. If this
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defect is untreated, when children are around 3 years of age, deterioration of the urinary tract increases up to 70% [11]. In the present study, approximately 50% of the videourodynamic findings were
defined as high risk, and of these, around a third showed pelvic ectasia. These findings urge physicians to initiate proactive actions in order to protect the urinary system. In several studies in the literature, it has been shown that the patients who have been adequately
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managed since the neonatal stage may reach adolescence with a normal upper urinary tract [16,17,18,19]. It has been demonstrated that CIC and anticholinergic agents can reduce the urinary
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deterioration to 8–10% [20]. This has been translated into a reduction in renal damage, compared with the results of other groups who have adopted expectant management. The deterioration of the bladder and kidney functions has been evidenced, especially in the
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presence of VUR and late indication for intermittent catheterization [16]. In the present study, all the patients entered the CIC program and had overnight indwelling
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catheterization. The benefits of this approach have already been confirmed, especially in the case of children with poor bladder compliance [21,22,23]. There is level-1 evidence to assert that the use of oxybutynin diminishes overactivity and storage bladder pressure when there is low bladder wall compliance [24]. Taking into account the findings of the
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urodynamic studies in the present study, oral oxybutynin was prescribed to 66% of patients. Renal scarring was detected in 15–31% of cases, although some studies in the literature have reported 2.1% scarring in the kidneys of patients with spina bifida [17,25]. Many
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publications have reported kidney damage in different age groups, mainly in children aged >1 year. The main risk factors for deterioration of the renal function are VUR, febrile UTI
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and time.
Some authors, such as DeLair et al. [16], have found VUR and female gender as
independent risk factors for renal scarring. The differences in the results between the present study and the one by DeLair et al. may be due to the different characteristics of the sample populations that were analyzed and the complementary imaging studies performed. In the study by DeLair et al., the age of patients and follow-up time were more heterogeneous: 4.1 years (range 0.2–15.5). There was also a different age at when CIC
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started. The present study only analyzed children aged ≤1 year. All the patients received CIC in the first days of life. Another important difference was the use of different methods to measure renal
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cortical loss and/or presence of renal scarring. DeLair et al. used renal ultrasound and DMSA scan. They reported 10% of renal cortical loss in 220 cases; however, the real percentage of renal damage may be underestimated with the use of renal ultrasound.
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In the present study, approximately 30% of patients had abnormal DMSA, and within this subgroup, almost 78% showed high-risk videourodynamic results and a
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tendency to greater percentages of urodynamic alterations and presence of VUR. A significant relationship was found between Pdet >20 cmH2O at expected cystometric capacity and alterations in renal scintigraphy/DMSA, but half of this population (nine cases) with abnormal DMSA did not have a history of UTI (although six cases in this
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subgroup presented with VUR), which led speculation that there was prenatal renal dysplasia. In the present study, the relationship between urinary infections and urodynamic variables, presence of VUR and abnormal scintigraphy was not statistically significant.
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However, hydronephrosis showed a trend regarding febrile UTI. Thus, a dilemma arises: what is the cause of renal damage in some patients with
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MMC? Is it possible that some of them were born with pre-existing renal damage? It is true for a subgroup, especially those with VUR, in which if VUR is unresolved that there would be a greater risk of developing symptomatic urinary infection and greater damage of the renal parenchyma? To what extent can physician intervention modify or diminish renal damage? It is well known that time is an important factor when it comes to starting treatment in children with neurogenic bladder. In addition, it is known that even when the appropriate treatment is initiated in a timely and adequate way, renal deterioration will
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appear in time in a subgroup of patients. These are questions that might be answered in further studies. An important limitation of the present study was the lack of simultaneity in
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obtaining each of the requested studies, although all participants completed all the tests before they turned 1 year of age. In the case of some families who lived far away or had different socio-economic constraints that made them unable to come to consultation earlier,
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the time to conduct urodynamics and administer anticholinergic drugs that were needed was delayed for some months. Another weakness was the relatively small sample population
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size in relation to the number of variables analyzed and correlated. Lastly, the present study was not subject to multivariate analysis, since there were no dominant variables with statistical significance. In order to confirm detrusor-sphincter dyssynergia it would have been very useful to perform perineal electromyography, but it was difficult to use surface
Conclusion
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age.
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electrodes, due to the reduced perineal/perianal surface that children have at such a young
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In the initial evaluation of patients with MMC, almost all the performed urodynamic studies showed abnormal results: mainly detrusor overactivity and emptying alterations, which prompted initiation of therapy. Almost one third of the population showed renal parenchyma damage. Nevertheless, the other complementary imaging methods did not always show alterations, especially renal/bladder ultrasound. Therefore, it is considered essential to perform urodynamic studies in the early evaluation of the urinary tract.
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Performing just CIC, starting immediately after birth, seems to be insufficient in preserving the upper tracts. Oxybutynin therapy should be started as well, to eliminate or decrease
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upper tract damage.
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Conflict of interest: None.
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Funding: None.
Acknowledgments: We thank nurses Carmen Machado, Florencia Gómez and Lysa
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Altamirano for their contribution in the Multidisciplinary team.
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scarring and vesicoureteral reflux in children with myelodysplasia. J Urol
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Summary table.
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Table 1. Urodynamic findings of patients with maximal cystometric capacity.
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DLPP, detrusor leak point pressure; MCC, maximal cystometric capacity; ECC, expected cystometric capacity
Table 2. Distribution of variables and the state of scintygraphy DMSA.
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NS, not significant; ECC, expected cystometric capacity; MCC, maximal cystometric capacity; DLPP, detrusor leak point pressure
Table 3. Distribution of variables agree of the present or not UTI
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NS, not significant; ECC, expected cystometric capacity; MCC, maximal cystometric capacity; DLPP, detrusor leak point pressure
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Reduced cystometric capacity Increased cystometric capacity Age-related normal values of cystometric capacity Detrusor overactivity DLPP < 40 cmh2o DLPP > 40 cmh2o Filling pressure > 20 cmh2o MCC Filling pressure > 20 cmh2o ECC Inefficient bladder emptying Dyssynergia Acontractile bladder Underactive bladder
13 35 12 33 24 4 26 8 59 17 31 11
21,6 58,3 20 55 40 6,6 43,3 13,3 98,3 28,8 52,5 18,7
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%
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n: 60
Table 1: Urodynamic findings of patients with MMC
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Ref.: DLPP: detrusor leak point pressure; MCC: maximal cystometric capacity; ECC: expected cystometric capacity.
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*Odds Ratio (95% CI): 0.200 (0.042-0.955)
%
Pr>ChiSq
19 7 38 0 4,7 52,3 23,8 14,2 42,8 38 28,5
NS 0,0436* NS NS NS NS NS NS NS NS NS
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27,7 38,8 55,5 5,5 11 61 38,8 33,3 55,5 33,3 50
Normal DMSA 42 8 3 16 0 2 22 10 6 18 16 12
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%
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n: Reduced cystometric capacity Filling pressure > 20 cmh2o ECC Filling pressure > 20 cmh2o MCC Filling pressures > 40 cmh2o ECC DLPP > 40 cmh2o Detrusor overactivity Dyssynergia VUR (grade III-V) Females Dilatation urinary (grade 2-4) Symptomatic UTI
Abnormal DMSA 18 5 7 10 1 2 11 7 6 10 6 9
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Table 2: Distribution of variables and the state of scintygraphy DMSA
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Ref.: NS: Not significant; DMSA: dimercaptosuccinic acid; ECC:expected cystometric capacity, MCC: maximal cystometric capacity; DLPP:Detrusor leak point pressure;UTI: urinary tract infection VUR: vesicoureteral reflux
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28,5 42,8 19 42,8 19 38 28,5 66,6 42,8 52,3
No UTI 39 7 24 4 14 3 9 6 8 9 17
%
Pr > ChiSq
17,9 61,5 10,2 35,8 7,6 23 15,3 20,5 23 43,5
NS NS NS NS NS NS NS NS NS NS
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%
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n: Reduced cystometric capacity Detrusor overactivity Filling pressure > 20 cmh2o ECC Filling pressure > 20 cmh2o MCC DLPP > 40 cmh2o Dyssynergia VUR (grade III-V) Dilatation urinary (grade 2-4) Abnormal scintigraphy-DMSA Female
With UTI 21 6 9 4 9 4 8 6 14 9 11
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Table 3: Distribution of variables agree of the present or not UTI
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Ref.: NS: Not significant; DMSA: dimercaptosuccinic acid; ECC:expected cystometric capacity, MCC: maximal cystometric capacity; DLPP:Detrusor leak point pressure; VUR: vesicoureteral reflux, UTI: Urinary tract infection
