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Intravesical Instillations for SCI-Related Detrusor Overactivity

Intravesical instillations are intended as a means for increasing bladder capacity, lowering pressures, and decreasing incontinence, with the potential for decreased systemic side effects compared to oral medications. Capsaicin and resiniferotoxin have been discussed above in toxins. Other medications used as intravesical installations are anticholinergics such as oxybutynin and propantheline which are presented below. Most of these protocols consist of dissolving the medication in a liquid solution and instilling the medication after emptying the bladder by IC, then leaving it in place until the next scheduled intermittent catherization.

Table 5 Intravesical Instillations for SCI-Related Detrusor Overactivity

 

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
George et al. 2007

India

RCT

PEDro=3

N=18

 

Population: Age range 20-53 yr; Gender: males=17, females=1.

Intervention: Oxybutynin, propantheline, and capsaicin solution were instilled intravesically. Oxybutynin and propantheline were administered 3 times daily by a double-blind method with a 6 d washout period between each drug.  Urodynamic studies done at baseline and 3 hours after the instillation of the third dose. A capsaicin instillation was also adminstered and urodynamic studies were repeated 1 and 2 weeks after instillation of the drug.

Outcome Measures: Reflex volume, detrusor leak point pressure, cystometric capacity, and urine leak frequency.

1.     Pre and post responses between intravesical oxybutynin, propantheline, and capsaicin showed significant differences at 2 weeks with respect to leak volume (p=0.017) and leak frequency (p=0.003).

2.     However, individually, only propantheline had significant improvement in leak frequency (p=0.039), and neither had significant changes in the other parameters.

 

Ersoz et al.

2010

Turkey

Pre-Post

N=25

 

Population: Mean age: 30.2 yr; Gender: male=16, female=9; Mean time post-injury: 40.7 mo; Severity of injury: tetraplegia=2, paraplegia=21.

Intervention: intravesical oxybutynin hydrochloride treatment.

Outcome Measures: Urodynamic variables and adverse events.

1.     The bladder volumes improved significantly post-treatment (p=0.024). The increase in bladder volume was 82% (mean=124.1mL).

2.     10 individuals discontinued treatment due to UTI, procedure difficulty and economic difficulty.

3.     6 of 9 individuals shifted from indwelling catheters to intermittent catheterization after the treatment

Haferkamp et al. 2000

Germany

Pre-Post

N=32

Population: SCI (n=17), myelomeningocele (n=15); all individuals had neurogenic bladders with detrusor hyperflexia. Mean age: 12 yr (range 1-34 yr); Gender: male=18, female=14; Level of impairment: tetraplegic=10, paraplegic=22.

Intervention: A standard dose of intravesical oxybutynin (0.3 mg/kg daily) or increasing dose of 0.2mg/kg/d up to 0.9 mg/kg.

Outcome Measures: Continence, age-adjusted bladder capacity (ABC), compliance, maximal detrusor pressure (MDP).

1.     21 individuals became completely continent using just the standard dose of treatment.

2.     Of the 21 individuals there was a significant decrease in median MDP (p<0.01), a significant increase in both the median compliance and median ABC (p<0.01).

3.     In the remaining 11 individuals: 7 out of 11 individuals became continent with increased dosage (0.7 mg/kg was the median dose required). In these 7 individuals median MDP significantly decreased (p<0.05), and both median compliance and median ABC increased significantly (p<0.05).

Pannek et al. 2000

Germany

Pre-Post

N=25

Population: All individuals had SCI and had either a detrusor storage pressure greater than 40 cmH2O (n=20) or dysreflexia (n=5) despite oral oxybutynin treatment (5 mg four times daily); Mean age: 36.7 yr (range18-64 yr); Gender: males=19, females=6, Level of SCI: cervical (n=14), thoracic (n=11); Time from lesion to treatment: 5.2 yr (range 0.3-20.9 yr).

Intervention: Intravesical oxybutynin (15 mg) three times daily.

Outcome Measures: Bladder storage volume, maximum storage pressure, detrusor storage pressure.

1.     Intravesical treatment increased bladder storage volume (349ml- to 420 ml).

2.     Mean maximum storage pressure significantly reduced from 54 to 26.5 cmH2O (p<0.00001).

3.     In the individuals with elevated detrusor storage pressures, 18 out of 21 had detrusor pressures return to less than 40 cmH2O (mean pressure 18 cmH2O).

4.     19 individuals were incontinent pre-treatment, 15 (79%) achieved continence post-treatment.

5.     9 out of the 25 individuals had chronic urinary tract infections pre-treatment; urinary tract infections were resolved in all 9 individuals post-treatment.

Vaidyananthan et al.

1998

England

Pre-Post

N=7

 

 

 

Population: SCI; Age range 22-69 yr; Level=C6-T12; Time post-injury=6-38 yr.

Intervention: Intermittent catheterization (IC) 5-6/d alone first then with intra-vesical instillation of oxybutynin (5mg in 30mL) 1-3 times/d for 14 to 30 mo in individuals originally managed by condom catheterization.

Outcome Measures: Customized scales of urinary continence, sexuality, quality of life (QoL) and monitoring of side effects.

1.   All subjects showed increased continence with IC and much moreso with oxybutynin added.

2.   6 subjects reported increased sexuality with IC and all subjects had higher ratings with oxybutynin added.

3.   Mixed results with QoL with IC but consistently increased QoL when added oxybutynin.

4.   Decreased UTIs with IC and oxybutynin.

Szollar & Lee 1996

USA

Pre-Post

N=13

Population: SCI individuals with neurogenic bladder dysfunction; Mean age: 41 yr (range 20-68 yr); Level of injury: C5-L1; Time post-injury: 8.7 yr (range 1-26 yr).

Intervention: Intravesical oxybutynin; videourodynamic study.

Outcome Measures: Bladder capacity, leak point pressure, volume at first urge to void.

1.     Mean bladder capacity and volume at first contraction both increased (bladder: 344-400 cc; volume: 167-184 cc) at the 3 mo follow-up, but this improvement was not significant.

2.     Leak point pressure significantly decreased (65-47 cmH2O).

Singh & Thomas 1995

UK

Pre-Post

N=6

Population: Mean age: 36 yr; Gender: males=6, females=0.

Intervention: Oxybutynin hydrochloride (10mg) was instilled through the urethral catheter and left in the bladder for 60 minutes.

Outcome Measures: Maximum Detrussor Pressure (DPmax), peak flow rate. Video urodynamic assessment was conducted before and after oxybutynin instillation.

1.     No significant difference was seen before and after oxybutynin instillation in:

·       DPmax (p=0.2).

·       Peak flow rate (p=0.54).

2.     Urinary residual did not increase after oxybutynin instillation.

Prasad & Vaidyanathan 1993

India
Pre-Post

N=14

Population: Injury etiology: SCI (n=8), myelomeningocele (n=2), transverse myelitits (n=1), post-rabies vaccine polyradiculopathy (n=1), prolapsed interverterbral disc (n=1), retroperitoneal neuroblastoma (n=1); all individuals practiced clean intermittent catheterization and their maximum cystometric capacity was below 250 ml or vesical compliance was less than 5.

Intervention: Intravesical oxybutynin chloride (5 mg tablet)

Outcome Measures: Bladder capacity, and vesical compliance.

1.     No local or systemic side effects were observed during follow-up (6-12 mo) in the majority of individuals; one individual however could not retain the drug intravesically and was excluded, while one was lost to follow-up.

2.     The remaining 12 individuals demonstrated increases in maximum cystometric capacity and vesical compliance.

Discussion

George et al. (2007) described results of a double-blind crossover (6 day washout) trial comparing propantheline (15mg) and oxybutynin (5mg) solutions (10ml) for thrice daily intravesical instillation in 18 individuals with SCI that managed their neurogenic bladder dysfunction with clean IC. Capsaicin was also included as a comparator but because instillation required local anesthesia to prevent hyperreflexia, CAP treatment could not be blinded. Although the study suggests that all of the intravesical agents exhibited effective attributes as adjuvant treatments, more subjects demonstrated improvement with propantheline (vs. oxybutynin) for residual volume, detrusor leak point pressure and clean IC volume. However, there was a significant worsening of leak frequency (p=0.039) for propantheline versus oxybutynin. Conversely, the pre-post CAP results revealed significant improvement for leak volume and leak frequency and significant worsening for residual volume and cystometric capacity. Two of the individuals with the oxybutynin instillations developed systemic side effects (e.g., dry mouth) typical of those on oral oxybutynin. Two individuals experienced autonomic dysreflexia following CAP instillation.

Vaidyananthan et al. (1998) reported a pre-post trial (n=7) for which individuals originally managed by condom catheterization were switched to IC. Oral oxybutynin was provided to five study participants to overcome mild to moderate urine leakage between intermittent catheterizations. As a result of unacceptable side effects, oral oxybutynin was replaced with intravesical instillation to overcome the unaceptable side effects of the oral formulation. However, despite daytime continence, reduced UTI frequency and cessation of dry mouth, three of the five study participants reported continued nocturnal leaking 1-2 times per week when IC was accompanied by intravesical instillation. In all seven individuals, QoL scores were mixed with IC alone but showed a definite improvement when oxybutynin was added.

Ersoz et al. (2010) studied individuals who used indwelling catheters and were treated simultaneously with oral and intravesical oxybutynin. With this combination treatment, significantly improved bladder volumes were reported, however, 52.6% of individuals were lost to attrition and reports of difficulty with intravesical instillation of oxybutynin were common.

Haferkamp et al. (2000) studied the addition of intravesical oxybutynin instillation in indviduals who performed IC five times daily and who were not adequately treated with oral anticholinergic medication (n=15) and/or experienced intolerable side effects from the oral medication (n=13). Four additional pediatric participants were included who had difficulty swallowing oxybutynin tablets. Of the 32 participants with SCI and neurogenic bladder function, twenty-one became continent with a standard dosage (0.3-0.7mg/kg/day) and eleven required a higher dosage (0.9mg/kg/day). Two participants treated with the higher dose complained of constipation and dryness of the mouth; none of the participants withdrew from treatment.

Intravesical oxybutynin (15mg TID) treatment was combined with oral treatment (5 mg four times daily) in a group of 25 individuals with SCI that had detrusor storage pressures greater than 40cm H2O (n=21) or persistent autonomic dysregulation (n=5) for at least 3 months (Pannek et al. 2000). All participants performed clean IC and 8 of 25 participants also received desipramine treatment. Although detrusor storage pressure responded well and no participants discontinued treatment as a result of side effects, autonomic dysregulation was not resolved with the combination treatment. This study reported that surgical intervention for detrusor hyperreflexia was avoided in 80% of individuals as a result of combination treatment with intravesical and oral oxybutynin. When combined therapy proved successful, a structured reduction of oral oxybutynin was undertaken in 11 of 25 participants and this likely contributed to the lack of side effects reported in this study.

Intravesical instillation of oxybutynin (5 mg suspended in 10 ml water) combined with clean IC was reported to increase bladder capacity in a group of 12 individuals (SCI n=8) with neurogenic bladder dysfunction (Prasad & Vaidyanathan 1993). Six to 12 months of follow-up revealed significantly improved maximum cystometric capacity and vesical compliance (both p<0.001) and decreased clean IC frequency (p<0.05). Notably, no local or systemic side effects were reported.

Szollar & Lee (1996) also reported significantly decreased leak point pressure and improved mean bladder capacity and mean volume at first contraction, for 10 of 13 individuals (including an initial non-responder) with SCI treated with intravesical oxybutynin (5 mg diluted in 30 ml saline, tid for 3 months). Participants were selected if they practiced clean IC but were intolerant to 5 mg TID oral oxybutynin. After 3 months of treatment, no local or systemic side effects were reported. An initial non-responder continued to experience incontinence after augmentation cystoplasty but did eventually respond positively to oxybutynin instillation post-operatively.

In contrast, Singh and Thomas (1995) presented a pre-post study with oxybutynin instillations (10 mg) in 6 male participants with SCI who had Brindley anterior root stimulators implanted and who failed to demonstrate significant improvements in peak detrusor pressure during voiding and peak flow rate. During implantation of the Brindley anterior root stimulator, sacral dorsal rhizotomies are performed. Considering oxybutynin’s effectiveness in individuals who manage their neurogenic bladder dysfunction with catheterization; the lack of efficacy in the above study could be attributable to the absence of an intact sacral arc and therefore may provide additional insight into the mechanism of action for oxybutynin.

Conclusions

There is level 2 evidence (from one RCT; George et al. 2007) advocating for propantheline and oxybutynin intravesical instillation as adjuvant therapy for neuropathic bladder dysfunction managed with clean intermittent catheterization; with propantheline being superior in more cystometric parameters,.

There is level 4 evidence (from a pre-post study; George et al. 2007) supporting the use of capsaicin intravesical instillation in reducing leak volume and frequency. However, this study also revealed that capsaicin intravesical instillation increased residual volume and decreased cystometric capacity, and can induce hyperreflexia in individuals with SCI and neurogenic bladder dysfunction.

There is level 4 evidence (from three pre-post studies; Vaidyanathan et al. 1998; Szollar & Lee 1996; Parsad & Vaidyannathan 1993) that intermittent catheterization combined with intravesical oxybutynin instillation is effective for the treatment of neuropathic bladder dysfunction following SCI.

There is level 4 evidence (from three pre-post studies; Haferkamp et al. 2000; Pannek et al. 2000; Ersoz et al. 2010) that the intravesical instillation of oxybutynin is an effective adjuvant therapy for individuals with SCI who manage their neurogenic bladder dysfunction with intermittent catheterization and oral oxybutynin.

There is level 4 evidence (from one pre-post study; Singh & Thomas 1995) that intravesical oxybutynin instillation is not effective in males with SCI following the surgical implantation of a Brindley anterior root stimulator.

Both propantheline and oxybutynin intravesical instillations improve cystometric parameters in individuals with SCI and neuropathic bladder, but propantheline provides superior improvement in more parameters.

Catheterization combined with intravesical instillation of oxybutynin alone or in addition to oral oxybutynin is effective in improving the symptoms of neuropathic bladder in individuals with SCI.

For individuals with SCI and neuropathic bladder, capsaicin can improve leak volume and frequency but can also worsen residual volume and cystometric capacity as well as induce hyperreflexia.

Intravesical instillation of oxybutynin is ineffective for male individuals with SCI who have an implanted Brindley anterior root stimulator.