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Urodynamic Effects of Oral Oxybutynin Chloride in Children With Myelomeningocele and Detrusor Hyperreflexia
PEDIATRIC UROLOGY
URODYNAMIC EFFECTS OF ORAL OXYBUTYNIN CHLORIDE IN CHILDREN WITH MYELOMENINGOCELE AND DETRUSOR HYPERREFLEXIA C. GOESSL, H. H. KNISPEL, U. FIEDLER, B. HA¨RLE, K. STEFFEN-WILKE,
AND
K. MILLER
ABSTRACT Objectives. To investigate the effects of oral oxybutynin chloride (OC) on standard urodynamic measures in children with myelomeningocele (MMC) and detrusor hyperreflexia. Methods. Forty-one MMC children with detrusor hyperreflexia (19 boys and 22 girls, aged 2 months to 15 years; mean 4.9 years) were evaluated urodynamically before and within 3 months after initiation of oral OC therapy (0.2 to 0.3 mg/kg/day). Therapy with oral OC was always combined with clean intermittent catheterization (CIC). Results. Oral OC treatment caused an increase in bladder capacity from 141 6 96 to 197 6 99 mL (140%; P ,0.01), a decrease in detrusor pressure at maximal capacity from 45 6 32 to 28 6 23 cm H2O (238%; P ,0.01), and an increase in detrusor compliance from 6.5 6 5.6 to 16.8 6 13.7 mL/cm H2O (1158%; P ,0.01). Improvement in urodynamic measures and continence were correlated. After a follow-up of at least 2 years, effective protection of renal function was achieved in 38 of the 41 children (93%) with conservative therapy alone. Adverse effects resulted in discontinuation of oral OC treatment in only 2 cases. Conclusions. Treatment with oral OC and CIC is effective and safe in children with MMC and detrusor hyperreflexia and should be initiated early when indicated by urodynamic findings. UROLOGY 51: 94–98, 1998. © 1998, Elsevier Science Inc. All rights reserved.
A
bout 0.6 to 4 newborn children per 1000 suffer from spinal dysraphism; myelomeningocele (MMC) is the most common form of this disorder.1 Urodynamic evaluation of MMC children often reveals detrusor hyperreflexia and decreased bladder capacity.2,3 Protection of renal function2– 4 and—in older MMC children—improvement in continence are pivotal for the urologist. Clean intermittent catheterization (CIC) alone5,6 was the standard management of MMC children until introduction of concomitant anticholinergic therapy since about 1980.7,8 Because of its favorable clinical effects, oxybutynin chloride (OC), an antimuscarinic substance with additional direct spasmolytic action,9 –11 has become the most widely used drug for MMC children with detrusor hyperreflexia. Although changes in urodynamic measures in MMC From the Department of Urology, Benjamin Franklin Medical Center, Free University of Berlin, Berlin, Germany Reprint requests: C. Goessl, M.D., Urologische Klinik, Klinikum Benjamin Franklin der FU Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany Submitted: May 28, 1997, accepted (with revisions): July 22, 1997
94
© 1998, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
children as a result of intravesical OC instillation have been extensively investigated,12–15 surprisingly few data on the urodynamic effects of oral OC in these patients exist.8,16 We measured urodynamic characteristics to investigate the effectiveness of oral OC for the nonsurgical management of children with MMC and detrusor hyperreflexia. Our data might also facilitate comparisons of the effectiveness of OC with that of newer candidate substances17 for treatment of MMC children. MATERIAL AND METHODS From June 1993 to March 1995, urodynamic investigation identified previously untreated detrusor hyperreflexia in 41 consecutive MMC children (19 boys and 22 girls). Ages ranged from 2 months to 15 years, with a mean of 4.9 years (Fig. 1). Detrusor hyperreflexia was defined by maximal detrusor pressures exceeding 40 cm H2O.3 Oral OC therapy (Dridase, Pharmacia-Upjohn, Germany; 0.2 to 0.3 mg/kg/day according to urodynamic results) combined with CIC at least 4 times a day was initiated in all children with detrusor hyperreflexia regardless of continence and voiding behavior. Urodynamic evaluation was repeated within 3 months (except in 1 patient after 6 months) under continued oral OC medication. No additional medication 0090-4295/98/$19.00 PII S0090-4295(97)00489-5
RESULTS MAXIMAL BLADDER CAPACITY Maximal bladder capacity (Vmax) increased from 141 6 96 to 197 6 99 mL (140%; P ,0.01) during treatment with oral OC (Fig. 2A). DETRUSOR PRESSURE AT MAXIMAL BLADDER CAPACITY Detrusor pressure at maximal filling (Pdet at V max) decreased from 45 6 32 to 28 6 23 cm H2O (238%; P ,0.01) during treatment with oral OC (Fig. 2B). DETRUSOR COMPLIANCE Detrusor compliance increased from 6.5 6 5.6 to 16.8 6 13.7 mL/cm H2O (1158%; P ,0.01) under treatment with oral OC (Fig. 2C). FIGURE 1. Distribution of age among 41 children with myelomeningocele and detrusor hyperreflexia.
with known effects on detrusor contractility was administered. Voluntary micturition and complete continence were found in 6 children at initial examination. Two patients regularly underwent CIC before entering the study. In the other 33 children, micturition occurred involuntarily, and diapers were required. A 2-year clinical follow-up was available for all patients; besides urodynamic findings, preservation of upper urinary tract function was assessed by ultrasonography, microbiologic tests, determination of serum creatinine, and patients’ reports (worsening of continence status). If urodynamic and/or clinical measures worsened, more detailed and invasive studies (MAG-3 renal scintigraphy and voiding cystourethrography) were performed. During follow-up, the dosage of OC was adjusted according to urodynamic findings and adverse effects in some patients. All urodynamic tests were carried out after exclusion or antibiotic therapy of urinary infection. Initial renal ultrasonography identified dilation of the renal pelvis in 2 patients, which could be manifested as vesicoureteral reflux on voiding cystourethrography. Urodynamic evaluation was done with a UD-2000 device (Medical Measurement Systems, Minden, Germany). The bladder was filled with distilled water via a 6F bilumen urethral catheter at a rate of 15 to 30 mL/min. Filling rate was adjusted to patient age; it was the same at initial examination and for control urodynamics. For estimation of intra-abdominal pressure and determination of net detrusor activity, a rectal catheter was also inserted. A simultaneous pelvic floor electromyogram was recorded with adhesive electrodes attached to the perineal region. Routine voiding cystourethrography was used in all cases at initial investigation and repeated only if reflux was present or urodynamic measures worsened. Maximal bladder capacity, detrusor pressure at maximal capacity, and detrusor compliance were determined, as were the occurrence of uninhibited detrusor activity (detrusor contractions exceeding 15 cm H2O),18 detrusor-sphincter dyssynergia, and vesicoureteral reflux. For statistical analysis, the Wilcoxon pair-difference test (one sided) was used; a P value ,0.01 was regarded as statistically significant. UROLOGY 51 (1), 1998
OTHER URODYNAMIC MEASURES Uninhibited detrusor contractions exceeding 15 cm H2O were found in 27 of the 41 patients with a mean pressure of 59 6 34 cm H2O; during oral OC treatment, uninhibited contractions disappeared in 13 of the 27 patients (48%), decreased to 25 6 6 cm H2O in 11 of these 27 patients (41%), and slightly increased in 2 patients (7%). Detrusorsphincter dyssynergia with corresponding findings in pelvic-floor electromyograms and voiding cystourethrography was present in 13 of the 41 patients (32%) at initial investigation; under oral OC, detectable detrusor-sphincter dyssynergia persisted in only 2 patients (5%). Initial voiding cystourethrography in all 41 patients identified 17 ureters with vesicoureteral reflux. Under oral OC treatment, reflux disappeared completely in 10 of the 17 ureters (59%) and was markedly diminished in 5 of the 17 ureters (29%). CONTINENCE Of the 41 patients, 6 (all older than 5 years) were continent (4 almost, 2 completely) at initial urodynamic evaluation and all 6 were completely continent under oral OC. The other 35 patients were incontinent at initial urodynamic evaluation; 11 of the 35 (31%) gained complete continence under oral OC, and a further 20 (57%) exhibited a marked improvement in continence. Of the 41 patients, 14 were older than 6 years at initial urodynamic evaluation and 10 of the 14 were incontinent. Of the 10 incontinent patients older than 6 years, 7 (70%) became completely continent under oral OC therapy. ADVERSE EFFECTS Side effects of oral OC were observed in 13 of the 41 patients (32%); dry mouth, fatigue, and temporary facial flushing were predominant. In 11 of the 13 patients, treatment with oral OC could be main95
tained at reduced doses without deterioration of urodynamic measures. FOLLOW-UP In 37 of the 41 patients (90%), conservative treatment with oral OC and concomitant CIC was found to be effective and was maintained during follow-up for at least 2 years. In 1 patient, intravesical instillation of OC was initiated because of intolerable mouth dryness and fatigue under oral OC. Under intravesical OC, side-effects were minimal and urodynamic measures improved. Another patient suffering from side-effects of oral OC was given instillation therapy. However, his parents later refused instillation therapy and eventually low-dose oral OC (0.08 mg/kg daily) was resumed. Urodynamic measures and renal function (as determined by MAG-3 renal scintigraphy) worsened only slightly and the patient is monitored carefully. In 2 patients, urodynamic measures remained poor under OC (oral and intravesical) as well as under alternative anticholinergic medication; deterioration of renal function was confirmed by MAG-3 renal scintigraphy, and both children underwent successful bladder augmentation at ages 6 and 7 years, respectively. COMMENT
FIGURE 2. Changes of urodynamic measures under oral oxybutinin chloride. Data (mean 6 SD) of 41 children suffering from myelomeningocele and detrusor hyperreflexia: (A) changes in maximal bladder capacity (Vmax); (B) changes in detrusor pressure at maximal capacity (Pdet at Vmax); (C) changes in detrusor compliance (Cdet). 96
OC is the most widely used anticholinergic drug for MMC children with detrusor hyperreflexia,19 but new substances with possibly better efficacy or tolerability17 are arising on the therapeutic horizon. Especially in MMC children, administration of drugs should be oral, because (self-)instillation of anticholinergic drugs is not feasible for many MMC patients.20,21 Data on the urodynamic effects of oral OC in MMC children are interesting for two reasons: (1) to compare efficacy of oral OC with that of intravesical OC12–15 and (2) to compare efficacy of OC with that of newer substances.17 However, surprisingly few reports address this issue. Hehir and Fitzpatrick16 investigated effects of oral OC on maximal bladder capacity and detrusor pressure in older MMC children (mean age 14 years), and Kasabian et al.8 investigated effects of oral OC on the same measures in MMC infants (aged about 12 to 36 months). Our patients were not selected for age; with a mean age of 4.9 years, they might be representative of the MMC patient population referred to urologists for initial urodynamic evaluation.19 Our decision to treat MMC children with oral OC and CIC did not depend on patient age, but solely on urodynamic findings. This rationale is based on recent reports of the prognostic value of urodynamic testing in MMC patients.2,3 According to the reports and recommendations by other auUROLOGY 51 (1), 1998
thors,1,8,22 treatment aimed at lowering detrusor pressure should be initiated early and consequently in MMC children at risk. In 90% (37 of 41) of our patients, conservative treatment with oral OC and CIC effectively protected upper urinary tract function. Likewise, continence status did not influence our decision to start oral OC and CIC in MMC children with detrusor hyperreflexia. Six of our patients (all older than 5 years) voided spontaneously and were continent (4 almost, 2 completely) at initial investigation. All of them had detrusor pressures greater than 40 cm H2O and had significant residual urine. Attempts with low-dose oral OC to lower detrusor pressures while preserving spontaneous micturition were therefore deemed unnecessary. The 4 patients, who were almost continent initially, became completely continent under oral OC with concomitant CIC. Gain of complete continence was especially gratifying in these patients because all of them attended regular school. The overall continence rate achieved with our nonsurgical regimen was 31%, which matches findings of Purcell and Gregory23 (24% complete continence). However, other investigators reported continence rates of 17%16 and as much as 84%24 after treatment with oral anticholinergic medication and CIC. These differences may be explained by variations in dosage and different definitions of continence (incomplete, social,23 complete). Because complete continence is a therapeutic goal mainly in older children, we investigated continence rates in patients older than 6 years separately. In this older group, we found a satisfactory continence rate of 70% produced by oral OC treatment. In contrast with many recent investigations indicating a more favorable efficacy/tolerability profile with intravesical instillation of OC,12–15,20 we preferred oral administration of OC. OC can be instilled into the bladder during regular CIC, but crushing the tablets and preparing a clean suspension is not feasible for many MMC children or their parents. According to Connor et al., 20 difficulties with intravesical instillation resulted in a dropout rate of 50% in their patients. Similar observations were reported recently by others.21 Recording changes in urodynamic measures evoked by oral OC and comparing them with published data on urodynamic effects of intravesical OC in MMC children was a main goal of our study. Comparison of increases in maximal bladder capacity and compliance and decreases in detrusor pressure revealed no relevant difference between our data and data obtained with intravesical instillation of OC in MMC children.12–15 Likewise, the overall success rate with regard to protection of renal function (more UROLOGY 51 (1), 1998
than 90%) was comparable with published data on intravesical OC.14 Although other investigators reported a better efficacy of intravesical OC in individual patients,12–15,25 our data indicate comparable effects of the two administration routes in the majority of MMC patients. The rate and extent of side-effects of oral OC were tolerable. An increased rate of side-effects in younger MMC children compared to older ones, which may be concluded from the results of Jonville et al.,26 was not found. Whereas in most cases dose reduction without worsening of urodynamic measures was sufficient, only two of our patients discontinued oral OC therapy because of side-effects. In 1 of these 2 patients, nonsurgical treatment could be continued by successful switching to intravesical instillation of OC. Again, by comparing our data to literature, a general advantage of intravesical OC versus oral OC with regard to sideeffects is not clearly discernible. Greenfield and Fera27 in 1991 reported side-effects of intravesical OC in MMC children to be 0%; 5 years later in a larger patient series, the same group noticed not only side-effects, but also reported dropout rates of 25% due to side-effects of intravesical OC.13 Comparison of the efficacy/tolerability profile of both routes of administration should be addressed by prospective, randomized studies. CONCLUSIONS Oral OC with concomitant CIC represents an effective and safe nonsurgical treatment regimen for upper urinary tract protection in the majority of MMC children with detrusor hyperreflexia. Therapy based on urodynamic findings should be initiated early. Selected patients with an unfavorable efficacy/tolerability profile may benefit from a switch to intravesical instillation of OC. REFERENCES 1. Bauer SB, Hallett M, Khoshbin S, Lebowitz RL, Winston KR, Gibson S, Colodny AH, and Retik AB: Predictive value of urodynamic evaluation in newborns with myelodysplasia. JAMA 252: 650 – 652, 1994. 2. Galloway NTM, Mekras JA, Helms M, and Webster GD: An objective score to predict upper tract deterioration in myelodysplasia. J Urol 145: 535–537, 1991. 3. McGuire EJ, Woodside JR, Borden TA, and Weiss RM: Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 126: 205–209, 1981. 4. Steinhardt GF, Goodgold HM, and Samuels LD: The effect of intravesical pressure on glomerular filtration rate in patients with myelomeningocele. J Urol 140(5 Pt 2): 1293– 1295, 1988. 5. Diokno AC, Kass E, and Lapides J: New approach to myelodysplasia. J Urol 116: 771–772, 1976. 6. Geraniotis E, Koff SA, and Enrile B: The prophylactic use of clean intermittent catheterization in the treatment of infants and young children with myelomeningocele and neurogenic bladder dysfunction. J Urol 139: 85– 86, 1988. 97
7. Hilwa N, and Perlmutter AD: The role of adjunctive drug therapy for intermittent catheterization and self-catheterization in children with vesical dysfunction. J Urol 119: 551–554, 1978. 8. Kasabian NG, Bauer SB, Dyro FM, Colodny AC, Mandell J, and Retik AB: The prophylactic value of clean intermittent catheterization and anticholinergic medication in newborns and infants with myelodysplasia at risk of developing urinary tract deterioration. Am J Dis Child 146: 840 – 843, 1992. 9. Lish PM, Labudde JA, Peters EL, and Robbins SI: Oxybutynin—a musculotropic antispasmodic drug with moderate anticholinergic action. Arch Int Pharmacodyn 156: 467– 488, 1965. 10. Diokno AC, and Lapides J: Oxybutynin: a new drug with analgesic and anticholinergic properties. J Urol 108: 307–309, 1972. 11. Thu¨roff JW, Bunke B, Ebner A, Faber P, de Geeter P, Hannappel J, Heidler H, Madersbacher H, Melchior H, Scha¨fer W, et al: Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol 145: 813– 817, 1991. 12. Buyse G, Verpoorten C, Vereecken R, and Casaer P: Treatment of neurogenic bladder dysfunction in infants and children with neurospinal dysraphism with clean intermittent (self)catheterization and optimized intravesical oxybutynin hydrochloride therapy. Eur J Pediatr Surg 5(suppl): 31–34, 1995. 13. Kaplinski R, Greenfield S, Wan J, and Fera M: Expanded followup of intravesical oxybutynin chloride use in children with neurogenic bladder. J Urol 156: 753–756, 1996. 14. Painter KA, Vates TS, Bukowski TP, Fleming P, Freedman AL, Smith CA, Gonzalez R, and Perlmutter AD: Longterm intravesical oxybutynin chloride therapy in children with myelodysplasia. J Urol 156: 1459 –1462, 1996. 15. Kasabian NG, Vlachiotis JD, Lais A, Klumpp B, Kelly MD, Siroky MB, and Bauer SB: The use of intravesical oxybutynin chloride in patients with detrusor hypertonicity and detrusor hyperreflexia. J Urol 151: 944 –945, 1994. 16. Hehir M, and Fitzpatrick JM: Oxybutinin and the pre-
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vention of urinary incontinence in spina bifida. Eur Urol 11: 254 –256, 1985. 17. Abrams P, Freeman RN, Anderstro¨m C, and Mattiasson A: Efficacy and tolerability of tolterodine vs. oxybutynin and placebo in patients with detrusor instability (abstract). J Urol 157 (suppl): 103, 1997. 18. The International Continence Society, February, 1975: First report on the standardisation of terminology of lower urinary tract function. Br J Urol 48: 39 – 42, 1976. 19. Hernandez RD, Hurwitz RS, Foote JE, Zimmern PE, and Leach GE: Nonsurgical management of threatened upper urinary tracts and incontinence in children with myelomeningocele. J Urol 152(5 Pt 2): 1582–1585, 1994. 20. Connor JP, Betrus G, Fleming P, Perlmutter AD, and Reitelmann C: Early cystometrograms can predict the response to intravesical instillation of oxybutynin chloride in myelomeningocele patients. J Urol 151: 1045–1047, 1994. 21. Palmer LS, Zebold K, Firlit CF, and Kaplan WE: Complications of intravesical oxybutynin chloride therapy in the pediatric myelomeningocele population. J Urol 157: 638 – 640, 1997. 22. Perez LM, Khoury J, and Webster GD: The value of urodynamic studies in infants less than 1 year old with congenital spinal dysraphism. J Urol 148(2 Pt 2): 584 –587, 1992. 23. Purcell MH, and Gregory JG: Intermittent catheterization: evaluation of complete dryness and independence in children with myelomeningocele. J Urol 132: 518 –520, 1984. 24. Mulcahy JJ, James HE, and McRoberts W: Oxybutynin chloride combined with intermittent clean catheterization in the treatment of myelomeningocele patients. J Urol 118: 95– 96, 1977. 25. Massad CA, Kogan BA, and Trigo-Rocha FE: The pharmacokinetics of intravesical and oral oxybutynin chloride. J Urol 148(2 Pt 2): 595–597, 1992. 26. Jonville AP, Dutertre JP, Barbellion M, and Autret E: Effets inde´sirables du chlorure d‘oxybutynine (Ditropant) en pe´diatrie. Arch Fr Pediatr 50: 27–29, 1993. 27. Greenfield SP, and Fera M: The use of intravesical oxybutynin chloride in children with neurogenic bladder. J Urol 146(2 Pt 2): 532–534, 1991.
UROLOGY 51 (1), 1998
URODYNAMIC EFFECTS OF ORAL OXYBUTYNIN CHLORIDE IN CHILDREN WITH MYELOMENINGOCELE AND DETRUSOR HYPERREFLEXIA C. GOESSL, H. H. KNISPEL, U. FIEDLER, B. HA¨RLE, K. STEFFEN-WILKE,
AND
K. MILLER
ABSTRACT Objectives. To investigate the effects of oral oxybutynin chloride (OC) on standard urodynamic measures in children with myelomeningocele (MMC) and detrusor hyperreflexia. Methods. Forty-one MMC children with detrusor hyperreflexia (19 boys and 22 girls, aged 2 months to 15 years; mean 4.9 years) were evaluated urodynamically before and within 3 months after initiation of oral OC therapy (0.2 to 0.3 mg/kg/day). Therapy with oral OC was always combined with clean intermittent catheterization (CIC). Results. Oral OC treatment caused an increase in bladder capacity from 141 6 96 to 197 6 99 mL (140%; P ,0.01), a decrease in detrusor pressure at maximal capacity from 45 6 32 to 28 6 23 cm H2O (238%; P ,0.01), and an increase in detrusor compliance from 6.5 6 5.6 to 16.8 6 13.7 mL/cm H2O (1158%; P ,0.01). Improvement in urodynamic measures and continence were correlated. After a follow-up of at least 2 years, effective protection of renal function was achieved in 38 of the 41 children (93%) with conservative therapy alone. Adverse effects resulted in discontinuation of oral OC treatment in only 2 cases. Conclusions. Treatment with oral OC and CIC is effective and safe in children with MMC and detrusor hyperreflexia and should be initiated early when indicated by urodynamic findings. UROLOGY 51: 94–98, 1998. © 1998, Elsevier Science Inc. All rights reserved.
A
bout 0.6 to 4 newborn children per 1000 suffer from spinal dysraphism; myelomeningocele (MMC) is the most common form of this disorder.1 Urodynamic evaluation of MMC children often reveals detrusor hyperreflexia and decreased bladder capacity.2,3 Protection of renal function2– 4 and—in older MMC children—improvement in continence are pivotal for the urologist. Clean intermittent catheterization (CIC) alone5,6 was the standard management of MMC children until introduction of concomitant anticholinergic therapy since about 1980.7,8 Because of its favorable clinical effects, oxybutynin chloride (OC), an antimuscarinic substance with additional direct spasmolytic action,9 –11 has become the most widely used drug for MMC children with detrusor hyperreflexia. Although changes in urodynamic measures in MMC From the Department of Urology, Benjamin Franklin Medical Center, Free University of Berlin, Berlin, Germany Reprint requests: C. Goessl, M.D., Urologische Klinik, Klinikum Benjamin Franklin der FU Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany Submitted: May 28, 1997, accepted (with revisions): July 22, 1997
94
© 1998, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
children as a result of intravesical OC instillation have been extensively investigated,12–15 surprisingly few data on the urodynamic effects of oral OC in these patients exist.8,16 We measured urodynamic characteristics to investigate the effectiveness of oral OC for the nonsurgical management of children with MMC and detrusor hyperreflexia. Our data might also facilitate comparisons of the effectiveness of OC with that of newer candidate substances17 for treatment of MMC children. MATERIAL AND METHODS From June 1993 to March 1995, urodynamic investigation identified previously untreated detrusor hyperreflexia in 41 consecutive MMC children (19 boys and 22 girls). Ages ranged from 2 months to 15 years, with a mean of 4.9 years (Fig. 1). Detrusor hyperreflexia was defined by maximal detrusor pressures exceeding 40 cm H2O.3 Oral OC therapy (Dridase, Pharmacia-Upjohn, Germany; 0.2 to 0.3 mg/kg/day according to urodynamic results) combined with CIC at least 4 times a day was initiated in all children with detrusor hyperreflexia regardless of continence and voiding behavior. Urodynamic evaluation was repeated within 3 months (except in 1 patient after 6 months) under continued oral OC medication. No additional medication 0090-4295/98/$19.00 PII S0090-4295(97)00489-5
RESULTS MAXIMAL BLADDER CAPACITY Maximal bladder capacity (Vmax) increased from 141 6 96 to 197 6 99 mL (140%; P ,0.01) during treatment with oral OC (Fig. 2A). DETRUSOR PRESSURE AT MAXIMAL BLADDER CAPACITY Detrusor pressure at maximal filling (Pdet at V max) decreased from 45 6 32 to 28 6 23 cm H2O (238%; P ,0.01) during treatment with oral OC (Fig. 2B). DETRUSOR COMPLIANCE Detrusor compliance increased from 6.5 6 5.6 to 16.8 6 13.7 mL/cm H2O (1158%; P ,0.01) under treatment with oral OC (Fig. 2C). FIGURE 1. Distribution of age among 41 children with myelomeningocele and detrusor hyperreflexia.
with known effects on detrusor contractility was administered. Voluntary micturition and complete continence were found in 6 children at initial examination. Two patients regularly underwent CIC before entering the study. In the other 33 children, micturition occurred involuntarily, and diapers were required. A 2-year clinical follow-up was available for all patients; besides urodynamic findings, preservation of upper urinary tract function was assessed by ultrasonography, microbiologic tests, determination of serum creatinine, and patients’ reports (worsening of continence status). If urodynamic and/or clinical measures worsened, more detailed and invasive studies (MAG-3 renal scintigraphy and voiding cystourethrography) were performed. During follow-up, the dosage of OC was adjusted according to urodynamic findings and adverse effects in some patients. All urodynamic tests were carried out after exclusion or antibiotic therapy of urinary infection. Initial renal ultrasonography identified dilation of the renal pelvis in 2 patients, which could be manifested as vesicoureteral reflux on voiding cystourethrography. Urodynamic evaluation was done with a UD-2000 device (Medical Measurement Systems, Minden, Germany). The bladder was filled with distilled water via a 6F bilumen urethral catheter at a rate of 15 to 30 mL/min. Filling rate was adjusted to patient age; it was the same at initial examination and for control urodynamics. For estimation of intra-abdominal pressure and determination of net detrusor activity, a rectal catheter was also inserted. A simultaneous pelvic floor electromyogram was recorded with adhesive electrodes attached to the perineal region. Routine voiding cystourethrography was used in all cases at initial investigation and repeated only if reflux was present or urodynamic measures worsened. Maximal bladder capacity, detrusor pressure at maximal capacity, and detrusor compliance were determined, as were the occurrence of uninhibited detrusor activity (detrusor contractions exceeding 15 cm H2O),18 detrusor-sphincter dyssynergia, and vesicoureteral reflux. For statistical analysis, the Wilcoxon pair-difference test (one sided) was used; a P value ,0.01 was regarded as statistically significant. UROLOGY 51 (1), 1998
OTHER URODYNAMIC MEASURES Uninhibited detrusor contractions exceeding 15 cm H2O were found in 27 of the 41 patients with a mean pressure of 59 6 34 cm H2O; during oral OC treatment, uninhibited contractions disappeared in 13 of the 27 patients (48%), decreased to 25 6 6 cm H2O in 11 of these 27 patients (41%), and slightly increased in 2 patients (7%). Detrusorsphincter dyssynergia with corresponding findings in pelvic-floor electromyograms and voiding cystourethrography was present in 13 of the 41 patients (32%) at initial investigation; under oral OC, detectable detrusor-sphincter dyssynergia persisted in only 2 patients (5%). Initial voiding cystourethrography in all 41 patients identified 17 ureters with vesicoureteral reflux. Under oral OC treatment, reflux disappeared completely in 10 of the 17 ureters (59%) and was markedly diminished in 5 of the 17 ureters (29%). CONTINENCE Of the 41 patients, 6 (all older than 5 years) were continent (4 almost, 2 completely) at initial urodynamic evaluation and all 6 were completely continent under oral OC. The other 35 patients were incontinent at initial urodynamic evaluation; 11 of the 35 (31%) gained complete continence under oral OC, and a further 20 (57%) exhibited a marked improvement in continence. Of the 41 patients, 14 were older than 6 years at initial urodynamic evaluation and 10 of the 14 were incontinent. Of the 10 incontinent patients older than 6 years, 7 (70%) became completely continent under oral OC therapy. ADVERSE EFFECTS Side effects of oral OC were observed in 13 of the 41 patients (32%); dry mouth, fatigue, and temporary facial flushing were predominant. In 11 of the 13 patients, treatment with oral OC could be main95
tained at reduced doses without deterioration of urodynamic measures. FOLLOW-UP In 37 of the 41 patients (90%), conservative treatment with oral OC and concomitant CIC was found to be effective and was maintained during follow-up for at least 2 years. In 1 patient, intravesical instillation of OC was initiated because of intolerable mouth dryness and fatigue under oral OC. Under intravesical OC, side-effects were minimal and urodynamic measures improved. Another patient suffering from side-effects of oral OC was given instillation therapy. However, his parents later refused instillation therapy and eventually low-dose oral OC (0.08 mg/kg daily) was resumed. Urodynamic measures and renal function (as determined by MAG-3 renal scintigraphy) worsened only slightly and the patient is monitored carefully. In 2 patients, urodynamic measures remained poor under OC (oral and intravesical) as well as under alternative anticholinergic medication; deterioration of renal function was confirmed by MAG-3 renal scintigraphy, and both children underwent successful bladder augmentation at ages 6 and 7 years, respectively. COMMENT
FIGURE 2. Changes of urodynamic measures under oral oxybutinin chloride. Data (mean 6 SD) of 41 children suffering from myelomeningocele and detrusor hyperreflexia: (A) changes in maximal bladder capacity (Vmax); (B) changes in detrusor pressure at maximal capacity (Pdet at Vmax); (C) changes in detrusor compliance (Cdet). 96
OC is the most widely used anticholinergic drug for MMC children with detrusor hyperreflexia,19 but new substances with possibly better efficacy or tolerability17 are arising on the therapeutic horizon. Especially in MMC children, administration of drugs should be oral, because (self-)instillation of anticholinergic drugs is not feasible for many MMC patients.20,21 Data on the urodynamic effects of oral OC in MMC children are interesting for two reasons: (1) to compare efficacy of oral OC with that of intravesical OC12–15 and (2) to compare efficacy of OC with that of newer substances.17 However, surprisingly few reports address this issue. Hehir and Fitzpatrick16 investigated effects of oral OC on maximal bladder capacity and detrusor pressure in older MMC children (mean age 14 years), and Kasabian et al.8 investigated effects of oral OC on the same measures in MMC infants (aged about 12 to 36 months). Our patients were not selected for age; with a mean age of 4.9 years, they might be representative of the MMC patient population referred to urologists for initial urodynamic evaluation.19 Our decision to treat MMC children with oral OC and CIC did not depend on patient age, but solely on urodynamic findings. This rationale is based on recent reports of the prognostic value of urodynamic testing in MMC patients.2,3 According to the reports and recommendations by other auUROLOGY 51 (1), 1998
thors,1,8,22 treatment aimed at lowering detrusor pressure should be initiated early and consequently in MMC children at risk. In 90% (37 of 41) of our patients, conservative treatment with oral OC and CIC effectively protected upper urinary tract function. Likewise, continence status did not influence our decision to start oral OC and CIC in MMC children with detrusor hyperreflexia. Six of our patients (all older than 5 years) voided spontaneously and were continent (4 almost, 2 completely) at initial investigation. All of them had detrusor pressures greater than 40 cm H2O and had significant residual urine. Attempts with low-dose oral OC to lower detrusor pressures while preserving spontaneous micturition were therefore deemed unnecessary. The 4 patients, who were almost continent initially, became completely continent under oral OC with concomitant CIC. Gain of complete continence was especially gratifying in these patients because all of them attended regular school. The overall continence rate achieved with our nonsurgical regimen was 31%, which matches findings of Purcell and Gregory23 (24% complete continence). However, other investigators reported continence rates of 17%16 and as much as 84%24 after treatment with oral anticholinergic medication and CIC. These differences may be explained by variations in dosage and different definitions of continence (incomplete, social,23 complete). Because complete continence is a therapeutic goal mainly in older children, we investigated continence rates in patients older than 6 years separately. In this older group, we found a satisfactory continence rate of 70% produced by oral OC treatment. In contrast with many recent investigations indicating a more favorable efficacy/tolerability profile with intravesical instillation of OC,12–15,20 we preferred oral administration of OC. OC can be instilled into the bladder during regular CIC, but crushing the tablets and preparing a clean suspension is not feasible for many MMC children or their parents. According to Connor et al., 20 difficulties with intravesical instillation resulted in a dropout rate of 50% in their patients. Similar observations were reported recently by others.21 Recording changes in urodynamic measures evoked by oral OC and comparing them with published data on urodynamic effects of intravesical OC in MMC children was a main goal of our study. Comparison of increases in maximal bladder capacity and compliance and decreases in detrusor pressure revealed no relevant difference between our data and data obtained with intravesical instillation of OC in MMC children.12–15 Likewise, the overall success rate with regard to protection of renal function (more UROLOGY 51 (1), 1998
than 90%) was comparable with published data on intravesical OC.14 Although other investigators reported a better efficacy of intravesical OC in individual patients,12–15,25 our data indicate comparable effects of the two administration routes in the majority of MMC patients. The rate and extent of side-effects of oral OC were tolerable. An increased rate of side-effects in younger MMC children compared to older ones, which may be concluded from the results of Jonville et al.,26 was not found. Whereas in most cases dose reduction without worsening of urodynamic measures was sufficient, only two of our patients discontinued oral OC therapy because of side-effects. In 1 of these 2 patients, nonsurgical treatment could be continued by successful switching to intravesical instillation of OC. Again, by comparing our data to literature, a general advantage of intravesical OC versus oral OC with regard to sideeffects is not clearly discernible. Greenfield and Fera27 in 1991 reported side-effects of intravesical OC in MMC children to be 0%; 5 years later in a larger patient series, the same group noticed not only side-effects, but also reported dropout rates of 25% due to side-effects of intravesical OC.13 Comparison of the efficacy/tolerability profile of both routes of administration should be addressed by prospective, randomized studies. CONCLUSIONS Oral OC with concomitant CIC represents an effective and safe nonsurgical treatment regimen for upper urinary tract protection in the majority of MMC children with detrusor hyperreflexia. Therapy based on urodynamic findings should be initiated early. Selected patients with an unfavorable efficacy/tolerability profile may benefit from a switch to intravesical instillation of OC. REFERENCES 1. Bauer SB, Hallett M, Khoshbin S, Lebowitz RL, Winston KR, Gibson S, Colodny AH, and Retik AB: Predictive value of urodynamic evaluation in newborns with myelodysplasia. JAMA 252: 650 – 652, 1994. 2. Galloway NTM, Mekras JA, Helms M, and Webster GD: An objective score to predict upper tract deterioration in myelodysplasia. J Urol 145: 535–537, 1991. 3. McGuire EJ, Woodside JR, Borden TA, and Weiss RM: Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 126: 205–209, 1981. 4. Steinhardt GF, Goodgold HM, and Samuels LD: The effect of intravesical pressure on glomerular filtration rate in patients with myelomeningocele. J Urol 140(5 Pt 2): 1293– 1295, 1988. 5. Diokno AC, Kass E, and Lapides J: New approach to myelodysplasia. J Urol 116: 771–772, 1976. 6. Geraniotis E, Koff SA, and Enrile B: The prophylactic use of clean intermittent catheterization in the treatment of infants and young children with myelomeningocele and neurogenic bladder dysfunction. J Urol 139: 85– 86, 1988. 97
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