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Efficacy of Combined Oral-Intravesical Oxybutynin Hydrochloride Treatment for Patients with Overactive Detrusors and Indwelling Urethral Catheters
The purpose of this article is to investigate the efficacy of intravesical oxybutynin hydrochloride (OH) to treat patients with overactive detrusors who are unresponsive to oral anticholinergic therapy alone. Twenty-five patients who were treated with oral OH for overactive detrusor (but who did not respond to treatment and were using indwelling urethral catheters) were given intravesical OH without changing oral treatment. Pre- and posttreatment bladder capacities were compared in urodynamic studies. The study showed that positive clinical results can be achieved with combined oral and intravesical OH treatments in patients with overactive detrusors who had indwelling urethral catheters because of severely reduced bladder capacity. However, a significant number of patients discontinued this treatment because of infection and difficulty in performing the procedure. Clinicians and rehabilitation nurses should provide education and support to eliminate these problems. In addition, the development of single-use standard sterile OH preparations for intravesical applications may increase the efficacy of the method.
It is important to begin bladder rehabilitation immediately after spinal cord injury (SCI). The goals of treating neurogenic dysfunction of the urinary system are to maintain storage and perform urination at low bladder pressures, ensure proper renal function, and achieve low-residue urine and continence (Frost, 2000). The primary risk factor for patients with SCI is increased detrusor pressure and renal damage (Jürgen, Hans, Uwe, & Theodor, 2000; Kaplinsky, Greenfield, Wan, & Fera, 1996; Pannek, Diederichs, & Bötel, 1997). Clean intermittent catheterization, oral anticholinergic treatment, and sterile intermittent catheterizations (i.e., performed using sterile gloves, cover, and catheters) are effectively used to treat patients with neurogenic bladder who have overactive detrusors (Jürgen et al.; O’Flynn & Thomas, 1993; Prasad & Vaidyanathan, 1993).
Oxybutynin hydrochloride (OH) is a tertiary amine with postganglionic effect that inhibits the binding of acetylcholine to the cholinergic receptors (Ferrara, D’Aleo, Tarquini, Saluatore, & Salvaggio, 2001; Prasad & Vaidyanathan, 1993). OH is widely used orally in adult and pediatric patients with overactive detrusors (Greenfield & Fera, 1991; Kaplinsky et al., 1996; Pannek et al., 1997). Although OH is used at maximum dose to treat overactive detrusors, sufficient clinical response may not exist or side effects (e.g., dryness of mouth or eyes, constipation, blurry vision, decline in sweating, drowsiness) may occur that inhibit the medication process (Jürgen et al., 2000; Kaplinsky et al.; Lehtoranta, Tainio, Lukkari-Lax, Hakonen, & Tammela, 2002). To increase the treatment’s efficiency and decrease side effects, OH is typically administered intravesically (Fowler, 2000; Lehtoranta et al.; Saito, Tabuchi, Otsubo, & Miyagawa, 2000). In clinical studies, the side effects that may appear during oral OH treatment have not been present with intravesical instillations (Brendler, Radebaugh, & Mohler, 1989; Madersbacher & Jilg, 1991; Massad, Kogan, & Trigo-Rocha, 1992; Saito et al.).
In previous studies, intravesical OH application was administered during clean intermittent catheterization (Buyse, Verpoorten, Vereecken, & Casaer, 1998; Ferrara et al., 2001; Kaplinsky et al., 1996; Madersbacher & Jilg, 1991; Prasad & Vaidyanathan, 1993; Weese, Roskamp, Leach, & Zimmern, 1993). However, in this study, all of the patients used indwelling urethral catheters for bladder emptying and did not have enough bladder capacity for a clean intermittent catheterization program.
The purpose of this research was to study the efficacy of using intravesical OH in combination with oral OH in patients with overactive detrusors who were unresponsive to oral anticholinergic therapy alone and who had indwelling urethral catheters because of severely reduced bladder capacity. The goal was to achieve sufficient bladder capacity and shift patients to intermittent catheterization from indwelling urethral catheters, which are associated with a high rate of urinary tract infection.
OH is metabolized in the liver, and the metabolite N-desethyl oxybutynin is primarily responsible for the anticholinergic side effects that emerge after oral application (Lehtoranta et al., 2002). Oral anticholinergic treatment for overactive bladder may not always be successful and may cause adverse effects, leading patients to abandon the treatment process (Brendler et al., 1989; Buyse et al., 1998; Madersbacher & Jilg, 1991). In such patients, certain surgical interventions (e.g., sphincterotomy, enterocyctoplasty of the bladder, autoaugmentation or sacral root rizotomy) may be required (Leng, Blalock, Fredriksson, English, & McGuire, 1999). During the past 15 years, many studies have been conducted on the application of intravesical agents in cases of patients with neurogenic bladders with overactive detrusors. Moreover, in vitro tests and animal studies have shown that intravesical OH applications allow increased pharmacological effects and higher concentrations in bladder tissue when compared with oral treatment (Massad et al., 1992). When OH is applied in intravesical form, it metabolizes at a low level during a first pass through the liver; therefore, the production of N-desethyl oxybutynin metabolite, which is responsible for the systemic side effects, is decreased (Buyse et al.; Lehtoranta et al.). Massad and colleagues indicated that OH in intravesical form undergoes a more rapid absorption process compared to the oral form. In addition, intravesical OH treatment has local effects on the smooth muscle tissue caused by increased drug concentration (Buyse et al.). In previous studies, it has also been demonstrated that OH is absorbed easily through the bladder, its effect is more prolonged than oral OH, and the OH serum level peaks 1 hour after oral application (it takes 3 hours to reach the same level with intravesical treatment; Lehtoranta et al.; Madersbacher & Jilg). It has been reported that intravesical OH applications decrease bladder pressure while increasing bladder capacity and continence rate (Buyse et al.; Ferrara et al., 2001; Greenfield & Fera, 1991; Kaplinsky et al., 1996; Madersbacher & Jilg; Prasad & Vaidyanathan, 1993; Weese et al., 1993).
According to Landau and colleagues’ (1994) study, pressure-specific bladder volume provides a better measure of bladder storage function than total bladder capacity because it relates volume to intravesical pressure, does not rely on a subjective end point to bladder filling, and is objective and reproducible. Previous studies reported that resting intravesical pressure is 12–32 cmH2O (mean = 22) in normal subjects (James, Niblett, MacNaughton, & Shaldon, 1987), and 98.1% of total bladder capacity can be stored at a detrusor pressure of less than 20 cmH2O in more than 95% of children, independently of age or body surface area (Houle, Gilmour, Churchill, Graumond, & Bissonnette, 1993). Another study reported that the average storage pressure of chronic SCI patients with upper-tract deterioration is 58 cmH2O compared to 24 cmH2O for patients with preserved upper tracts (Gerridzen, Thijssen, & Dehoux, 1992).
In previous studies, the solutions for intravesical applications were prepared by mixing 5 mg OH in 10–30 ml of physiological serum, sterile water, or tap water, which were boiled and cooled and injected into the bladder of the patient two to three times a day (Kaplinsky et al., 1996; Palmer, Zebold, Firlit, & Kaplan, 1997; Prasad & Vaidyanathan, 1993; Weese et al., 1993). During the second step of treating lower urinary tract dysfunction, patients were given 5 mg of OH intravesically twice a day in combination with the unchanged oral therapy (Ferrara et al., 2001; Kaplinsky et al.; Madersbacher & Jilg, 1991; Prasad & Vaidyanathan; Weese et al.), though application techniques varied. Although Brendler and colleagues (1989) suggested that the ideal temperature for intravesical application of the solution should be 37 °C to decrease bladder contraction, Prasad and Vaidyanathan, as well as Kaplinsky and colleagues, preferred applying the oxybutynin solution at room temperature (≥10 °C, ≤35 °C).
Intravesical treatment combined with oral treatment decreases anticholinergic side effects such as dryness of mouth or eyes, constipation, blurry vision, decline in sweating, and feeling sleepy. Jürgen and colleagues (2000) found that in 11 of 25 patients with adult SCI, the oral oxybutynin dose could be decreased through intravesical instillation combined with oral OH. To avoid serious anticholinergic side effects, a combined treatment is preferred (rather than administering only a high dose of oral OH), and the oral dose can be decreased incrementally if the combined treatment is successful. In another study using oral OH to treat overactive detrusors, Weese and colleagues (1993) reported side effects in 31 of 41 patients and unsatisfactory results in 11 patients. The results led them to conclude intravesical treatment is preferable to oral treatment.
In recent years, efforts have been made to improve the efficiency of intravesical treatments. Saito and colleagues (2000) administered a modified oxybutynin solution combined with hydroxy-propyle-cellulose (which is a mucosal-adhesion molecule) intravesically and established that the concentration of serum OH was lower and its duration of efficiency was longer than when intravesical OH was used alone.
Materials and Methods
Twenty-five patients with spinal cord lesions and severe lower urinary tract dysfunction who were hospitalized between October 2002–June 2004 for rehabilitation at the Ankara Physical Medicine and Rehabilitation Training and Research Hospital in Ankara, Turkey, were evaluated retrospectively using records from the urodynamics laboratory. All of these patients had detrusor overactivity determined through urodynamic examinations and were using indwelling urethral catheters because of severely reduced bladder capacity. None of these patients had responded to oral OH treatment after receiving at least 3 weeks of effective doses (15- or 20-mg daily doses were given according to body weight for adult patients and 10 mg was given to pediatric patients). Measuring pressure-specific bladder volume to determine lower urinary tract dysfunction has been reported previously (Landau et al., 1994). The threshold of 25 cm H2O was selected by taking into account previous studies (Gerridzen et al., 1992; Houle et al., 1993; James et al., 1987). SCI patients with 25 cm H2O pressure-specific bladder capacities exceeding 200 ml were excluded from the study. The study group consisted of 2 patients with traumatic tetraplegia, 15 patients with traumatic paraplegia, 6 patients with nontraumatic paraplegia, and 2 patients with myelomeningocele (Table 1).
Approval for the study was obtained from the ethics committee of the hospital. All patients were informed about the intravesical OH treatment and agreed to the procedure. In this study, the solution used to treat patients was a preparation of 5 mg OH mixed in 20 ml of physiological serum at room temperature; intravesical applications were administered by injecting the solution into the bladder through the indwelling urethral catheter two times a day at 12-hour intervals with a single-use 20-ml syringe. After the intravesical application, patients were advised to clamp their catheters for no longer than 1 hour in a manner consistent with their bladder capacity so the agent could be linked to the receptors in the bladder. Nurses and physicians explained and demonstrated the procedure to all patients and their caregivers. With the exception of the two patients with myelomeningocele, all of the study’s participants had the physical ability to perform the instillation procedure. The intravesical applications were performed by patients or their caregivers; nurses oversaw the intervention.
Two urodynamic examinations of the study’s participants were performed using the Libra+ (MMS, Enschede, The Netherlands) urodynamic measurement system and double lumen 8 F sterile urethral catheters. After draining urine from the bladder using the urodynamic catheter, room-temperature sterile physiological serum was filled through the urodynamic catheter at at rate of 50 ml/minute. All patients were out of spinal shock and had indwelling urethral catheters. In the preurodynamic evaluation, urinalysis and urine culture were performed. In patients with urinary tract infection, urodynamic examination was postponed until the infection had been treated. The following criteria were used to determine total bladder volume: sensation of bladder filling (i.e., strong desire to void), intravesical pressure >40 cm H2O, symptoms of an episode of autonomic dysreflexia, changes in blood pressure that may reflect a silent autonomic dysreflexia episode, significant leakages, infused volumes of more than 500 ml, and patient discomfort. Twenty-five cm H2O intravesical pressure-specific bladder volumes and total bladder volumes were determined and compared for each patient during the urodynamic examinations performed before and after intravesical OH treatment in combination with the unchanged oral therapy. The mean increase in 25 cm H2O intravesical pressure-specific bladder volume and total bladder volume after the treatment and increased percentages were calculated. The probable side effects were also examined.
To produce descriptive statistics, data analysis was performed using SPSS software Version 9.0 (Chicago, USA). To evaluate the treatment’s efficacy, a t-test for paired samples was conducted; the results were considered statistically significant (p < .05).
Demographic and clinical data of the study population are presented in Table 1. Sixteen of 25 patients (64%) with persistent overactive detrusor who had been given intravesical OH treatment did not attend the control urodynamic examination. The remaining 9 patients (36%)—7 of whom were male and 2 of whom were female—participated in the second round of urodynamic examinations (Figure 1). Two of these patients had traumatic tetraplegia, 4 had traumatic paraplegia, and 3 had nontraumatic paraplegia. Demographic and clinical data of these patients are presented in Table 2.
During the urodynamic examinations, mean pre- and posttreatment 25 cm H2O intravesical pressure-specific bladder volumes were 122.1 ± 31.9 ml (minimum: 64, maximum: 163) and 207.8 ± 92.8 ml (minimum: 119, maximum: 416), respectively (Table 3). There was a statistically significant difference between pre- and posttreatment volumes (p = .024). After the intravesical treatment, the mean increase in 25 cm H2O intravesical pressure-specific bladder volume was 85.7 ± 92.7 ml (minimum: -1, maximum: 311)—a 79.3% increase in volume. Mean pre- and posttreatment total bladder volumes were 164.6 ± 47.5 ml (minimum: 105, maximum: 230) and 288.6 ± 128.8 ml (minimum: 151, maximum: 500), respectively (p = .011). The mean increase in total bladder volume was 124.1 ± 113.4 ml (minimum: -8, maximum: 311)—an 82.8% increase in volume (Table 3). Six of the nine patients (66.7%) were shifted to an intermittent catheterization program from indwelling catheters after the intravesical OH treatment (Figure 1).
Although not documented uniformly, a majority of patients reported dry mouth and a significant number reported constipation during oral treatment. Despite these complaints, none of the patients asked to discontinue the oral treatment. No additional major side effects were reported when the intravesical treatment was combined with oral treatment.
Although 16 of the 25 patients who started intravesical treatment did not participate in the control visit during which urodynamic measurements were performed, 10 were contacted by phone. Five patients discontinued intravesical treatment because of urinary tract infection, 3 because the procedure was difficult, 1 because of economic difficulty obtaining medical material, and 1 because of transportation problems; none of these patients attributed discontinuation to side effects (Figure 1).
According to several studies (Gerridzen et al., 1992; Houle et al., 1993; James et al., 1987), correctly determining (and replicating) total bladder volume is difficult to do for patients with SCI because they have bladder-filling sensation deficits (Ersoz & Akyuz, 2004) and various factors (e.g., bladder-filling sensation, intravesical pressure, autonomic dysreflexia episode, significant leakage, infused volume, and patient discomfort) may change from study to study.
After the intravesical instillation process, the 9 participants who attended the second urodynamic examination had increased their 25 cm H2O intravesical pressure-specific cystometric bladder volume by 79% and total bladder volume by 82.8%. Statistically significant differences were observed between pre- and posttreatment 25 cm H2O intravesical pressure-specific bladder volumes and total bladder volumes. According to these results, combining intravesical OH with oral OH can be an effective treatment for patients who have detrusor overactivity and use indwelling urethral catheters. Kaplinsky and colleagues (1996) reported that the positive effect of the treatment also continued in patients who had initially responded positively to intravesical OH treatment. In this study, bladder capacity increased dramatically after intravesical OH treatment.
The combination therapy of oral and intravesical OH was used to increase the effectiveness and decrease the side effects and dose of oral OH treatment reported in previous studies (Lehtoranta et al., 2002; Madersbacher & Jilg, 1991; Jürgen et al., 2000). In this study, the primary reason for adding intravesical oxybutynin applications to oral treatments was to improve the results of the oral treatment.
Intravesical OH treatment had been previously reported to be an effective and safe treatment choice in patients with detrusor overactivity (Buyse et al., 1998; Ferrara et al., 2001; Kaplinsky et al., 1996; Madersbacher & Jilg, 1991; Prasad & Vaidyanathan, 1993; Weese et al., 1993). The investigators in this study chose to use an oxybutynin solution at room temperature (Kaplinsky et al.; Prasad and Vaidyanathan) because it could be easily prepared. In 6 of the 9 patients (66.7%) who could be evaluated after intravesical treatment, acceptable bladder capacities were reached and these patients could be shifted from using an indwelling catheter to intermittent catheterization programs.
According to a study by Kaplinsky and colleagues (1996), anticholinergic side effects had been detected in 26% of patients during intravesical oxybutynin treatment. In another study of 101 pediatric patients with spina bifida, Ferrara and colleagues (2001) reported anticholinergic side effects that caused 16% of the group taking oral oxybutynin to abandon the treatment process. In addition, certain cognitive side effects (such as lack of concentration and difficulty with mathematics) were detected in the intravesical treatment group.
As many as 65% of patients with overactive detrusors discontinue intravesical treatment because the procedure is difficult (Kasabian et al., 1994; Lehtoranta et al., 2002). Nineteen of 25 patients who were included in our study provided information about treatment; 9 participants attended the second urodynamic examination (whose data were used to measure the efficacy of intravesical treatment), and the remaining 10 patients could not attend the second urodynamic evaluation for several reasons but were contacted by phone. The abandonment rate in this study was 52.6%, which was consistent with results found in the literature (Jürgen et al., 2000; Kasabian et al.). According to our study results, the leading reason patients stopped intravesical treatment was urinary tract infection. The high frequency of urinary tract infection observed in our study may be a result of using indwelling urethral catheters to empty the bladder. In previous studies, intravesical OH had been applied during clean intermittent catheterization (Buyse et al., 1998; Jürgen et al.; Kasabian et al.; Prasad & Vaidyanathan, 1993; Weese et al., 1993). In addition, undesired environmental and hygenic conditions may have affected the frequency of infection. Three patients (15.8%) abandoned the treatment because they found the procedure too difficult; the remaining 2 patients discontinued the treatment because of social reasons (rather than medical).
It is important for future studies to examine why the abandonment rate for this treatment is so high. Our study demonstrated the primary problems patients experienced (e.g., urinary tract infections, difficulty performing the procedure and obtaining medical material) that caused them to discontinue the intravesical treatment. These results may help other researchers develop strategies for increasing the treatment’s efficacy. Possible strategies for facilitating treatment may include improving patient education provided by clinicians and rehabilitation nurses and developing single-use standard sterile OH preparations for intravesical applications. Rehabilitation nurses play a crucial role in informing patients and caregivers about intravesical application; training them to perform the procedure and informing them about how to prevent, identify, and manage infection. Periodic evaluations of patients undergoing the procedure and outpatient support provided by phone may also increase efficacy of the treatment.
Our study had several limitations. The small sample size and specific patient group limit the generalizability of our findings to other populations. In addition, the study was retrospective and did not have a long duration for follow up. Our conclusions need to be confirmed by new prospective studies with larger sample sizes.
About the Authors
Murat Ersoz, MD, is an associate professor of physical medicine and rehabilitation and vice clinical chief at Ankara Physical Medicine and Rehabilitation Training and Research Hospital of Ministry of Health in Ankara, Turkey.
Necmettin Yildiz, MD, is an assistant professor of physical medicine and rehabilitation at Pamukkale University Medical School in Denizli, Turkey. Address correspondence to him at firstname.lastname@example.org.
Mufit Akyuz, MD, is an associate professor of physical medicine and rehabilitation and clinical chief at Ankara Physical Medicine and Rehabilitation Training and Research Hospital of Ministry of Health in Ankara, Turkey.
Fusun Koseoglu, MD, is an associate professor of physical medicine and rehabilitation and clinical chief at Ankara Physical Medicine and Rehabilitation Training and Research Hospital of Ministry of Health in Ankara, Turkey.
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